Diana Girnita MD PhD

Rheumatology Fellow

1898 ndashMiculicz-Radecki J(Polish

surgeon) -First lacrimal and salivary glands enlargement

1925 ndashGougerot H (French dermatologist) -Few cases of atrophy of the salivary glands with dryness of eyes mouth and vagina

1933- Sjo gren H (Swedish ophthalmologist) ndash Doctoral thesis described keratoconjunctivitis sicca and his description became a basis for pSSpicture

History

May be primary or secondary to connective tissue

disease (mainly SLE Rheumatoid Arthritis Scleroderma)

Primary SS (pSS) occurs from 01 to 30 in general population

Femalemale ratio 91

Ages of 40ndash60

Sjoumlgren Syndrome (SS)

Keratoconjuctivitis sicca

Pathology mononuclear infiltration and destruction of salivary and lacrymal glands leading to xerostomia and xerophthalmia

Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can give extraglandular manifestations

Definition of Sjoumlgren

Antibody Prevalence Association

RoSSALaSSb

60-80 With severe glandular manifestations longer duration of the disease presence of splenomegaly lymphadenopathy vasculitis and high infiltration of salivary glands

ANA 80 predictor of internal organ involvement and the development of lymphoproliferative disorders

RFAnti -CCP

74rare

early stage of disease and onset of the disease at a younger age extraglandular symptoms (arthritis)

ACA (anticentromere)

17 Specific for limited systemic sclerosis overlap sdr

M3 muscarinic rec Ab

high specificity 95 but relatively low sensitivity 43 (Deng C et al 2015)

Other Ab rare AMA (anti -mitocondrial)CAII(anti -carbonic anhidrase) + RTAAnti cytoskeletal proteins-α and β fodrinAnti protein 1 (SP-1) carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) Anti-TPO anti- TG -thyroid disease in pSS patients in up to 30 compared with 4 of the control group (diseases may coexist)

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

1898 ndashMiculicz-Radecki J(Polish

surgeon) -First lacrimal and salivary glands enlargement

1925 ndashGougerot H (French dermatologist) -Few cases of atrophy of the salivary glands with dryness of eyes mouth and vagina

1933- Sjo gren H (Swedish ophthalmologist) ndash Doctoral thesis described keratoconjunctivitis sicca and his description became a basis for pSSpicture

History

May be primary or secondary to connective tissue

disease (mainly SLE Rheumatoid Arthritis Scleroderma)

Primary SS (pSS) occurs from 01 to 30 in general population

Femalemale ratio 91

Ages of 40ndash60

Sjoumlgren Syndrome (SS)

Keratoconjuctivitis sicca

Pathology mononuclear infiltration and destruction of salivary and lacrymal glands leading to xerostomia and xerophthalmia

Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can give extraglandular manifestations

Definition of Sjoumlgren

Antibody Prevalence Association

RoSSALaSSb

60-80 With severe glandular manifestations longer duration of the disease presence of splenomegaly lymphadenopathy vasculitis and high infiltration of salivary glands

ANA 80 predictor of internal organ involvement and the development of lymphoproliferative disorders

RFAnti -CCP

74rare

early stage of disease and onset of the disease at a younger age extraglandular symptoms (arthritis)

ACA (anticentromere)

17 Specific for limited systemic sclerosis overlap sdr

M3 muscarinic rec Ab

high specificity 95 but relatively low sensitivity 43 (Deng C et al 2015)

Other Ab rare AMA (anti -mitocondrial)CAII(anti -carbonic anhidrase) + RTAAnti cytoskeletal proteins-α and β fodrinAnti protein 1 (SP-1) carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) Anti-TPO anti- TG -thyroid disease in pSS patients in up to 30 compared with 4 of the control group (diseases may coexist)

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

May be primary or secondary to connective tissue

disease (mainly SLE Rheumatoid Arthritis Scleroderma)

Primary SS (pSS) occurs from 01 to 30 in general population

Femalemale ratio 91

Ages of 40ndash60

Sjoumlgren Syndrome (SS)

Keratoconjuctivitis sicca

Pathology mononuclear infiltration and destruction of salivary and lacrymal glands leading to xerostomia and xerophthalmia

Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can give extraglandular manifestations

Definition of Sjoumlgren

Antibody Prevalence Association

RoSSALaSSb

60-80 With severe glandular manifestations longer duration of the disease presence of splenomegaly lymphadenopathy vasculitis and high infiltration of salivary glands

ANA 80 predictor of internal organ involvement and the development of lymphoproliferative disorders

RFAnti -CCP

74rare

early stage of disease and onset of the disease at a younger age extraglandular symptoms (arthritis)

ACA (anticentromere)

17 Specific for limited systemic sclerosis overlap sdr

M3 muscarinic rec Ab

high specificity 95 but relatively low sensitivity 43 (Deng C et al 2015)

Other Ab rare AMA (anti -mitocondrial)CAII(anti -carbonic anhidrase) + RTAAnti cytoskeletal proteins-α and β fodrinAnti protein 1 (SP-1) carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) Anti-TPO anti- TG -thyroid disease in pSS patients in up to 30 compared with 4 of the control group (diseases may coexist)

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Keratoconjuctivitis sicca

Pathology mononuclear infiltration and destruction of salivary and lacrymal glands leading to xerostomia and xerophthalmia

Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can give extraglandular manifestations

Definition of Sjoumlgren

Antibody Prevalence Association

RoSSALaSSb

60-80 With severe glandular manifestations longer duration of the disease presence of splenomegaly lymphadenopathy vasculitis and high infiltration of salivary glands

ANA 80 predictor of internal organ involvement and the development of lymphoproliferative disorders

RFAnti -CCP

74rare

early stage of disease and onset of the disease at a younger age extraglandular symptoms (arthritis)

ACA (anticentromere)

17 Specific for limited systemic sclerosis overlap sdr

M3 muscarinic rec Ab

high specificity 95 but relatively low sensitivity 43 (Deng C et al 2015)

Other Ab rare AMA (anti -mitocondrial)CAII(anti -carbonic anhidrase) + RTAAnti cytoskeletal proteins-α and β fodrinAnti protein 1 (SP-1) carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) Anti-TPO anti- TG -thyroid disease in pSS patients in up to 30 compared with 4 of the control group (diseases may coexist)

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Antibody Prevalence Association

RoSSALaSSb

60-80 With severe glandular manifestations longer duration of the disease presence of splenomegaly lymphadenopathy vasculitis and high infiltration of salivary glands

ANA 80 predictor of internal organ involvement and the development of lymphoproliferative disorders

RFAnti -CCP

74rare

early stage of disease and onset of the disease at a younger age extraglandular symptoms (arthritis)

ACA (anticentromere)

17 Specific for limited systemic sclerosis overlap sdr

M3 muscarinic rec Ab

high specificity 95 but relatively low sensitivity 43 (Deng C et al 2015)

Other Ab rare AMA (anti -mitocondrial)CAII(anti -carbonic anhidrase) + RTAAnti cytoskeletal proteins-α and β fodrinAnti protein 1 (SP-1) carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) Anti-TPO anti- TG -thyroid disease in pSS patients in up to 30 compared with 4 of the control group (diseases may coexist)

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Diagnostic criteria

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Exclusion criteria

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Neurologic involvement has been reported in pSS since its

initial clinical description 1935

Varies between 10-60 in primary SS (pSS)

PNS involvement is relatively well documented

CNS manifestations are still a matter of discussion

Prevalence

Alexander EL Provost TT Stevens MB Alexander GE Neurologic complications of primary Sjogrenrsquos syndrome Medicine (Baltimore) 198261247ndash257Alexander EL Central nervous system (CNS) manifestations of primary Sjogrenrsquos syndrome an overview Scand J RheumatolSuppl 198661 161ndash165 Delande S et al Neurologic manifestations in primary Sjogren syndrome a study of 82 patients Medicine (Baltimore) 200483280ndash291 Lafitte C et al Neurological complications of primary Sjogrenrsquos syndrome J Neurol 2001248577ndash584

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

CNS manifestations

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Mostly females

Age 40-50 yo

Duration of disease aprox 10-11 years

Prevalence 32 to 79

CNS involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Authors Pts CNS Type of CNS manifestation

Teixeira et al 2015 93 15 HeadachesSpinal cord involvementSeizuresNMOMovement disorders

Morreale et al 2014 120 79 HeadachesCognitive deficitsMood disorders

Delalande et al 2004 83 68 Spinal cord involvementMotor neuron diseaseFocalmultifocal brain involvementOptic neuritis

Lafitte et al 2001 25 17 Spinal cord dysfunctionTransverse myelitisSeizures tetrapiramydal sdr cerebellar sdr

Anaya et al 2000 95 32 MS like sdr Optic neuritisEpilepsy

Escudero et al 1995 48 23 Focal neurological deficits

Moll et al 1993 48 9 Transverse myelitisStrokeBell palsyPyramidal signs

Binder et al 1988 50 6 EpilepsyVertigoRecurrent TIAs

Alexander et al 1986 20 MS-like sdr

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Focal vs

The main CNS manifestation

Motorsensory loss with hemiparesis

Aphasia

Dysatria

Seizures

Movement disorders

Cerebellar syndrome

Subacute transverse myelitis

Spinal cord disorders (progressive myelopathies neurogenic bladder)

Optic neuritis

Large tumefactive brain lesion

Diffuse

Encephalopathy

Cognitive dysfunction(frontal executive dysfunction impairment in attention control intellectual decline and deterioration of instrumental abilities)

Dementia

Psychiatric abnormalities

Aseptic meningoencephalitis

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

CNS

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

1493 patients(15)

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

81120 (67) CNS + PNS

involvement

64 pts with CNS (79) vs17 PNS disease (p 0001)

64 pts

Headache (469)

Cognitive (444) dysfunction

Mood disorders (383)

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS ONE

9(1) e84605

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

82 patients

25 (30) both CNS + PNS involvement

31 (38) had isolated CNS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Extraglandularmanifestations

Accompanying CNS

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Common extraglandularmanifestations in association with CNS manifestations

Sicca symptoms

Raynauds

MSK manifestations

Autoimmune Thyroiditis

Lung involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Morreale M et al (2014) Neurological Involvement in Primary Sjogren Syndrome A Focus on Central Nervous System PLoS

ONE 9(1) e84605

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

All pts Pts wout CNS Pts wCNS p value

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

More frequent extraglandularmanifestations in PNS-Sjogren

NeuroSS with PNS involvement is more frequently associated with -dermatologic -Raynauds-pulmonary -hematologic manifestations

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Sicca vsNeurologic manifestations

-who is first

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Neurologic involvement frequently preceded the diagnosis of pSS in 12 (46) patients (was the first symptom of the disease)

Neurologic symptoms before sicca

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Neurologic symptoms occurring at onset of SS involved the CNS more frequently than the PNS (p = 0005)

CNS manifestations preceded sicca symptoms more frequently than did PNS manifestations (p = 002)

Neurologic symptoms before sicca

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

47

15

38

before

same time

after

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

CSF

Serology (antibodies)

BrainSpinal MRI

SPECTPET

Cerebral Angiography

Meet SjoumlgrenCriteria

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Lymphocytosis

usually -50cellsmm3 with higher counts ( up to 30) in aseptic lymphoid meningitis

IgG index raised (33 -ALL with CNS involvement)

Oligoclonal bands lt2

These bands have been reported in about 20 to 25 of pSScompared to more than 90 in MS patients

Only 17 (14) with isolated PNS involvement had CSF abnormalities (increased cell count)

CSF in active CNS disease

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Alexander L et al ldquoPrimary Sjo grenrsquos syndrome with central nervous system disease mimicking multiple sclerosisrdquo Annals of Internal Medicine vol 104 no 3 pp 323ndash330 1986 M Vrethem et al ldquoImmunoglobulins within the central nervous system in primary Sjo grenrsquos syndromerdquo Journal of the Neurological Sciences vol 100 no 1-2 pp 186ndash192 1990

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Serology

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Labs

Lymphopenia hypergammaglobulinemia ANA cryoglobulins complement were more frequent in cases with pSS and PNS than in those with CNS involvement

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Role of Antibodies

Antibody Prevalence Authors

RoSSALaSSB

40-506 (CNS) vs 19 (PNS)

Delalande et al 2004

Anti-alpha-fodrin (IgA and

IgG)

64 (of 31 pts) no difference between pts with or without neurologic sx

De Seze J et al 2004

Anti-GM1 (IgMand IgG)

12 pts ( 6 with 6 without neuropathy)No difference

Giordano N et al 2003

Antineuronal AbAntiganglion

neuron Ab

882 pts with neurological disorders ndashdetected also in patients with pSS

Murata et al 2005Vianello M et al 2004

Anti-GW182 Patients with mixed motor andor sensory neuropathy without pSS andneurological pSS (18200 patients -9)

Eystathioy T et al 2003

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Anti-Ro + associated with the severity of CNS

disease as well as with findings on cerebral angiography suggestive of small vessel angiitis

Therefore in a patient with known SS who presents with CNS manifestations testing for anti-Ro antibodies is of prognostic rather than diagnosticvalue

Anti-Ro have prognostic values

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908 Alexander EL et al Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjo grenrsquos syndrome (CNS-SS) clinical neuroimaging and angiographic correlates Neurology 199444899ndash908

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Abnormal in 61 of the patients tested

Confirmed optic neuritis in patients with a history of visual loss (13)

Can define additional patients with subclinical optic neuritis (12)

Visual evoked potential

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Limited value

Abnormal in frac12 patient with pSS+severe progressive CNS disease

Pts with Focal deficits - focal slow wave activity decreased

amplitude or spikes

Epilepsy - seizure discharges

Encephalopathy or dementia -diffuse slow wave activity

Useful in detecting sublinical abnormalities that precede the development of clinical pSS- CNS

EEG

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

MRI are more sensitive than CT scans to detect

anatomical abnormalities in pSS-CNS

Multiple areas of increased signal intensity (T2 weighted images) predominantly in subcortical and periventricular white matter

Lesions were found more frequently in patients with CNS (80) vs patients without CNS involvement (25 p = 0008)

These findings have been observed in both patients with and those without CNS impairment

MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)Pierot L Sauve C Leger JM et al Asymptomatic cerebral involvement in Sjo grenrsquos syndrome MRI findings of 15 cases Neuroradiology 1993 35 378ndash380 Morgen K McFarland HF Pillemer SR Central nervous system disease in primary Sjo grenrsquos syn- drome the role of magnetic resonance imaging Semin Arthritis Rheum 2004 34623ndash630

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Brain MRI

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

MRI brain -FLAIR showing white matter lesions and severe atrophy suggestive of but not specific to multiple sclerosis in a patient with relapsing-remitting symptoms

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Cerebral Venous Thrombosis

Mercurio A et al ndashcerebral venous thrombosis revealing pSS-report f 2 cases case reports in medicine 2013

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

A and B Axial FLAIR (A) and postgadolinium T1-weighted (B) images show a ring-enhancing

frontoparietal tumefactive lesion with edema and mass effect

J Sanahuja et al AJNR Am J Neuroradiol 2008291878-

1879

copy2008 by American Society of Neuroradiology

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

lsquoMRI detects focal CNS but not always diffuse CNS diseasersquorsquo

19 patients with SS +neuropsychological abnormalities mostly frontal lobe syndrome and memory problems ndashNone had abnormal brain MRI (Berlin et al 1999)

Alexander et al -58 patients with psychiatric or cognitive dysfunction had abnormalities on brain MRI

Belin C et al Central nervous system involvement in Sjogrenrsquos syndrome evidence from neuropsychological testing and HMPAO- SPECT Ann Med Interne (Paris) 1999150598ndash604

Alexander EL et al MRI of cerebral lesions in patients with the Sjogren syndrome Ann Intern Med 1988108815ndash23

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Spinal MRI

Spinal cord involvement showed T2-weighted hyperintensities

Involvement Cervical in 82

Dorsal in 47

Lumbar in 12

65 with a single lesion

40 with centromedullar lesions

35 with extended lesions (cases of acute myelopathy)

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Spinal MRI

Spinal cord MRI ( T2-weighted) showing an extended hypersignal in the cord in a

patient with acute myelopathy

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Extensive transverse myelitis

Longitudinal extensive transverse myelitismdashits not all neuromyelitis optica Corinna Trebst et alNature Reviews Neurology 7 688-698 (December 2011)

a | Initial MRI scan showing hyperintense spinal cord enlargement from C2 to T22 b | MRI scan taken 3 days after the initial examination the hyperintensities are almost unchanged Follow-up scans taken at c | 2 weeks and d | 15 years after the initial examination show progressive spinal cord atrophy

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Dg optic neuritis were +

anti- Aquaporin4 (AQ4) antibodies

Spinal cord MRI extensive centromedularlesion from C2 to C5C7

Brain MRIs were normal

Neuromyelitisoptica (NMO)

Teixeira F et al ACTA REUMATOL PORT 20133829-36Moreira I Teixeira F et al Frequent involvement of CNS in primary SS -Rheumatol Int (2015) 35289ndash294

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Neuromyelitis optica (NMO)

Bhattacharyya S Helfgott SSemin Neurol201434425ndash436

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Voxel-based morphometry (VBM) is a method

commonly used for quantitative and objective evaluation of differences in regional cerebral volume between groups

53 patients vs controls (18 systemic sclerosis 35 healthy) and evaluated for differences in brain volume

MRI and Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

3853 patients with pSS had White

matter hyperintensities (WMHIs) vs 618 with scleroderma 1735 of healthy controls

The numbers of WMHIs ge 2 mm were higher in patients with pSSthan in controls (ge 2 mm p = 0004)

Voxel-Based Morphometry

Good CD et al A voxel-based morphometric study of ageing in 465 normal adult human brains Neuroimage 2001 1421ndash36

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

pSS had decreased gray matter volume in the cortex deep gray matter and cerebellum Associated loss of white matter volume was ob-served in areas corresponding to gray matter atrophy and in the corpus callosum (p lt 005)

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Patients with pSS have WMHIs and gray and white matter atrophy probably related to cerebral vasculitis

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Brain hypoperfusion has been associated with brain

atrophy

SPECT and PET studies have shown reduced cerebralblood flow and decreased glucose metabolism inpatients with pSS

SPECTPET

Kao CH Ho YJ Lan JL ChangLai SP Chieng PU Regional cerebral blood flow and glucose metabolism in Sjogrenrsquos syndrome J NuclMed 1998 391354ndash1356 Huang WS Chiu PY Kao A Tsai CH Lee CC Detecting abnormal regional cerebral blood flow in patients with primary Sjogrenrsquossyndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain a preliminary report Rheumatol Int 2003 23174ndash177

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

10 F(lt55 years old) with pSS defined using EA criteria +anti-SSA andor anti-SSB no history of neurological involvement were prospectively investigatedvs 10 healthy controls

within 1 month brain MRI neuropsychological testing including overallevaluation and focal cognitive function assessment and (99m)Tc-ECD brainSPECT

(99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (1010) than controls (210 plt005)

Cognitive dysfunctions (executive and visuospatial disorders) were also significantly more common in patients with pSS (810) than controls (010 plt001)

MRI abnormalities in patients and controls did not differ significantly

CONCLUSIONS Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS

Neuropsychological testing and(99m)Tc-ECD brain SPECT

Le Guern V Belin C et al Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primarySjogren syndrome a case-control Study Ann Rheum Dis 2010 Jan69(1)132-7

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

(99m)Tc-ECD brain SPECT

Chang CP et al Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjogrenrsquossyndrome and normal findings on brain magnetic resonance imaging Ann Rheum Dis 200261774ndash778

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Exclude other causes of CNS disease (arteriovenousmalformations congenital aneurysms and othervascular abnormalities and cerebrovascular disease)

Up to 45 of highly selected pSS with active CNSdisease have angiographic findings suggestive ofsmall vessel vasculitis (stenosis dilatation orocclusion of small cerebral blood vessels)

Cerebral angiography

Alexander EL Neurologic disease in Sjogrenrsquos syndrome mononuclear inflammatory vasculopathy affecting centralperipheral nervous system and muscle A clinical review and update of immunopathogenesis Rheum Dis Clin North Am 199319869ndash908

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Differential Diagnosis

Multiple sclerosis

SLE

Vasculitis

Sarcoidosis

Behccediletrsquos disease

Infectious ndashLyme syphilis PMLE

HTLV-1 infection herpes zoster

Genetic (lysosomaldisorders

adrenoleucodystrophy mitochondrial

disorders)

Metabolic (vitamin B12 deficiency)

CNS lymphoma

Spinal (degenerative and vascular

malformations)

Dementia

AML sclerosis

Parkinsonrsquos disease

Dorsal root ganglionitis

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Multiple Sclerosis

(MS)

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Hard to differentiate even for experienced clinicians

CNS ndashSS seems to mimic ldquorelapsing- remitting MS ldquo or in patients with chronic myelopathies seems to mimic ldquoprimary progressiverdquo MS

Features found in common

both tend to involve the spinal cord brain and the optic tract

CNS-SS mimics MS

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

CNS-SS vs MS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291)

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

The pattern ldquoprimary-progressiverdquo more frequent in pSS(gradual period of deterioration reflecting progressive myelitis)

pSS when peripheral or cranial nerve involvement occurs the

diagnosis of MS is less likely

may have less brain disease on MRI (pSS rarely touch the basal ganglia or the cerebral cortex)

may have lesser amounts of protein in CSF (less ldquooligoclonalrdquo bands lt2 in MS gt 3)

ANA SSASSB RF more frequent in SS vs MS

SICCA simptoms

Red Flags against MS

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

SLE vs CNS-SS

Onset abrupt

Autoimmune featuresmdashrash serositis polyarthritis or nephritis

Younger patients

MRI grey matter disease

Antibody profile anti-Sm and anti-dsDNA

+APL ab

Insidious subtle waning and waxing in SS

Sicca symptoms

Older patients

MRI white matter disease

Autoantibody profile anti- Ro -La

+APL Ab

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Nocturne G amp Mariette X (2013) Advances in understanding the pathogenesis of primary Sjoumlgrenrsquos syndrome Nat Rev Rheumatol doi101038nrrheum2013110

bull Innate immunityactivatepDC high levels of INF stimulates BAFF (B cell activating factor)autoantibodies and promotes the survival and maturation of B cells polyclonal activation

bull Epithelium is infiltrated mainly by CD 4+ lim- phocytesT subtype and immune response is balanced toward Th1 response and also Th17mdashwith interleukin 17(IL-17) as a main cytokine

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Hypothesis CNS-SS

CNS-SS

CNS lymphocytic infiltration

Small vessel

vasculitisAntibodies ndashAntiRo anti-M3

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

1 CSF analysis of patients with active CNS disease reveals evidence of lymphocytosis elevated IgG index and oligoclonal bands (Alexander et al 1986)

1 Lymphocytic CNS infiltration

Gono T Kawaguchi Y Katsumata Y et al Clinical manifestations of neurological involvement in primary Sjo grenrsquos syndromeClin Rheumatol 2011 30485ndash490 Chai J Logigian E Neurological manifestations of primary Sjogrenrsquos syndrome Current Opinion in Neurology 2010 23509ndash511

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

2 Vascular injury may be related to the presence of

antineuronal and anti-Ro antibodies or due to ischemia secondary to diffuse small vessel vasculitis (angiographic studies -Alexander et al 1994) 1 SPECT ndash reveal hypoperfusion (parietal and temporal lobes)

(Kao et al 1998 Chang et al 2002)

2 Significant correlation between cortical hypoperfusion and cognitive dysfunction (Le et al 2010)

3 Necrotizing vasculitis has been associated with spinal cord complication (sensory ataxia and transverse myelitis (Mori et al 2001)

4 MRI findings in CNS-SS with diffuse small foci of hyperintensity suggestive of small vessel disease (Segal et al 2008)

2 Small vessel vasculitis

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

3 May bind to the brain cells and mediate (at least

partially) small vessel changes

1 anti-RoSS-A Ab shown to correlate with CNS disease severity and abnormal neuroimaging (small-vessel angiitis) (Alexander et al 1994)

2 anti-RoSS-A overexpressed in the brain microvascular compartment (Shusta et al 2003)

3 CNS SS patients with anti-RoSS-A antibodies in the CSF pathogenic role (Megevand et al 2007)

3 Antibodies roles

Minesh Kapadia Boris Sakic Autoimmune and inflammatory mechanisms of CNS damage Progress in Neurobiology 95 (2011) 301ndash333 Shusta EV et al The Ro52SS-A autoantigen has elevated expression at the brain microvasculature Neuroreport 2003 Oct 614(14)1861-5Megevand P et al Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogrens syndrome with central nervous system involvement Eur Neurol 200757(3)

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Autoantibodies that recognize M3 muscarinic

acetylcholine receptors (mAChRIgG) cause dysfunction of of exocrine glands (Dawson et

al 2006) interact with cerebral mAChRs expressed on the

surface of cells in the frontal cortex (Reina et al 2004)

M3 mAChR activationpromoting NO and prostaglandin biosynthesis (Orman et al 2007)

M3-mAchR antibodies

Reina S et al Human mAChR antibodies from Sjoumlgren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level Clin Immunol 2004 Nov113(2)193-202Orman B et al Anti-brain cholinergic auto antibodies from primary Sjoumlgren syndrome sera modify simultaneously cerebral nitric oxide and prostaglandin biosynthesisInt Immunopharmacol 2007 Dec 57(12)1535-43 Epub 2007 Aug 16

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

No consensus

Corticosteroids -usually first initiated in high dose

45 pts with durable neurologic amelioration or stabilization

Ineffective mostly in patients with spinal cord involvement

Treatment CNS-SS

Delalande S et al Neurologic Manifestations in Primary Sjogren Syndrome A Study of 82 Patients Medicine 200483280ndash291) Teixeira F et al ACTA REUMATOL PORT 20133829-36 Moreira I Teixeira F et al Frequent involvement of CNS in primarySS -Rheumatol Int (2015) 35289ndash294

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Immunosuppressive therapy

Cyclophosphamide- monthly (700 mgm2 IV for 6 or 12 months )

It resulted in a partial recovery or stabilization treated patients with spinal cord involvement

Treatment CNS-SS

Williams C et al Treatment of myelopathy in Sjogren syndrome with a combination of prednisone and cyclophosphamide Arch Neurol 200158815ndash819

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Plasmapheresis efficacy (+prednisone) reported in a

sporadic case of acute transverse myelopathy

In severe cases IVIG have been used successfully in a small sample of patients with ganglionopathy

Treatment CNS-SS

Konttinen YT et al Acute transverse myelopathy successfully treated with plasmapheresis and prednisonse in a patient with primary Sjogrenrsquos syndrome Arthritis Rheum 1987 30339 ndash344 Takahashi Y et alBenefit of IV immunoglobulin for a long-standing ataxic sensory neuronopathy with SS Neurology 200360503ndash505

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Neurologic involvement (CNS) is common in pSS

and often precede the diagnosis

The accurate prevalence of these manifestations is difficult to assess because the heterogeneity of the series

Could be disabling disease with severe consequences

Prospective controlled studies are needed with large numbers of patients to assess treatment

Conclusion

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

J Clin Rheumatol 2012 Dec18(8)389-92 doi 101097RHU0b013e318277369e Neurosjoumlgren early therapy is associated with successful outcomes Santosa A1 Lim AY Vasoo S Lau TC Teng GG Author information

Abstract BACKGROUND Primary Sjoumlgren syndrome (PSS) is a systemic autoimmune condition with an estimated prevalence of 06 The frequency of neurologic manifestations in PSS varies widely from 0 to 60 METHODS We report the characteristics of PSS patients with neurologic involvement seen at a single tertiary hospital in Singapore Eight consecutive women (median age 51 years [range 38-67 years]) with neurologic

manifestations of PSS seen between March 2009 to June 2011 were followed up for a mean duration of 19 months from the onset of neurologic manifestations RESULTS Six of 8 patients with neurosjoumlgren had their neurologic manifestation at time of PSS diagnosis The lag times of neurologic manifestations from PSS diagnosis for the remaining 2 patients were 9 and 30 years

respectively Sicca symptoms were not readily volunteered as a presenting complaint in the majority of patients All our patients received early aggressive therapy with pulse corticosteroids and intravenouslyadministered cyclophosphamide The mean duration from initial presentation to initiation of treatment was 11 days (1-26 days) All achieved good recovery regardless of the type or site of neurologic involvement initial erythrocyte sedimentation rate immunoglobulin and complement levels

CONCLUSIONS Neurologic disease when present is a strong contributor to disease activity and damage Confirmatory tests should be conducted early regardless of the presence of sicca symptoms Vigilance for the development

of new neurologic symptoms is imperative even in chronic apparently stable patients It is likely that early initiation of treatmentcontributed to good recovery in our patients

Lupus 200716(7)521-3 Successful treatment of refractory neuroSjogren with Rituximab Yamout B1 El-Hajj T Barada W Uthman I Author information

Abstract We report a 47-year-old female with Sjogrens syndrome (SS) and severe weakness in her lower extremities refractory to cyclophosphamide therapy who was treated with the monoclonal anti CD-20 antibody

rituximab at a weekly dose of 375 mgm2 for four consecutive weeks Patient responded within few days of the first dose and her motor power in the lower extremities started to improve gradually along with progressive resolution of the paresthesias and dysesthesias The improvement was sustained and progressive and eight months after the last dose she was able to walk for 60 meters without aid or rest Rituximabmay be considered as an effective and promising novel therapy in SS patients with neurological involvement

Fingolimod (INN trade name Gilenya Novartis) is an immunomodulating drug approved for treating multiple sclerosis It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by

approximately one-half over a two-year period[1] Fingolimod is a sphingosine-1-phosphate receptor modulator which sequesters lymphocytes in lymph nodes preventing them from contributing to an autoimmune reaction

Send to

See comment in PubMed Commons below Acta Neurol Scand 2015 Feb131(2)140-3 doi 101111ane12357 Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome Signoriello E1 Sagliocchi A Fratta M Lus G Author information

1Multiple Sclerosis Center II Division of Neurology Department of Clinical and Experimental Medicine Second University of Naples Naples Italy Abstract BACKGROUND Sjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20 of patients The neurological manifestations in

the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease and the treatments with immunosuppressive drugs have been undertaken CASE PRESENTATION We describe a case of 40-year-old woman with clinical and instrumental evidence of an MS characterized by numerous relapses and demyelinating lesions prevailing in the infratentorial and spinal cord

Immunological analysis showed biological data that were consistent with an SS The treatment with fingolimod showed not only an optimal response to the demyelinating events but also biological parameters CONCLUSION These data allow us to hypothesize possible combined efficacy of treatment with fingolimod in SS associated with definite MS copy 2014 John Wiley amp Sons AS Published by John Wiley amp Sons Ltd KEYWORDS Sjogren syndrome fingolimod multiple sclerosis

In two Phase III clinical trials fingolimod reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half compared both to placebo and to the active comparator interferon beta-1a[37]

A double-blind randomized control trial comparing fingolimod to placebo[38] found the drug reduced the annualized frequency of relapses to 018 relapses per year at 05 mgday or 016 relapses per year at 125 mgday compared to 040 relapses per year for those patients taking the placebo The probability of disease progression at 24 month followup was lower in the fingolimod groups compared to placebo (hazard ratio 070 at 05 mg and 068 at 125 mg) Fingolimod patients also had better results according to MRI imaging of new or enlarged lesions at 24 month followup Side effects leading to discontinuation of the study drug were more common in the higher dose group (142 of patients) than at the lower dose (75) or placebo (77) Serious adverse events in the fingolimod group included bradycardia relapse and basal-cell carcinoma Seven episodes of bradycardia occurred during the monitoring period after administration of the first dose and were asymptomatic in six of these cases There was a higher rate of lower respiratory tract infections (including bronchitis and pneumonia) in the fingolimod groups (96 at 05 mg 114 at 15 mg) than the placebo group (60) Other adverse events reported on the study drug included macular edema cancer and laboratory abnormalities[39]

Diana M Girnita MD PhD E-mail dianagirnitagmailcom Phone 513-917-0908

Fingomolid

1 No consensus on the definition of CNS involvement( some include psychiatric disease

headache or mood disturbances some not)2 The diagnostic criteria used for SS are not uniform ( Some include confirmatory

salivary gland biopsies whereas others have included patients with probable SS)3 Confounding factors that may increase the risk for cerebrovascular disease (DM HTN

HLD) or factors that may be associated with psychiatric disease such as thyroid disease ( high incidence of autoimmune endocrinopathies in patients with pSS)

4 Referral bias may occur in tertiary centres where complex cases with severe disease are referred (This may lead to overdiagnosis of CNS Underdiagnosis may be a result of symptoms being dismissed by the assessing physician Patients may also fail voluntarily to report symptoms neurological complications in elderly patients with SS may be attributed to their age)

5 The incidence of MS increases with latitude and therefore coexistence of SS with MS may explain the high incidence of MS-like disease reported in North America and Scandinavia compared with the low incidence in south European countries

6 To solve the controversy prospective controlled studies are needed with large numbers of patients because the prevalence of specific neurological syndromes in the general population is low

Why this variability in CNS disease prevalence in pSS

Extraglandularmanifestations

Extraglandularmanifestations