Teaching Course 8 Differential diagnoses and diagnostic dilemmas
Chairs: S. Fredrikson (Stockholm, SE)
A. Siva (Istanbul, TR)
15 Diagnostic and differential diagnostic aspects in MS
S. Fredrikson (Stockholm, SE)
16 MRI – possibilities and pitfalls in diagnosis of MS
A. Siva (Istanbul, TR)
17 Heterogeneity of idiopathic inflammatory demyelinating
disease
S. Vukusic (Lyon, FR)
19/08/2015 Name Surname 1
Diagnostic and differential diagnostic
aspects of multiple sclerosis
Teaching course 8, ECTRIMS 2015
Sten Fredrikson
Professor of Neurology
Division of Neurology
Department of Clinical Neuroscience
Karolinska Institutet
Stockholm, Sweden
”Multiple sclerosis is what a good
clinician would call multiple
sclerosis”
John Kurtzke, 1970
”Nothing shuts off critical
neurological thought processes
faster than a diagnosis of
multiple sclerosis”
Semin Neurol 1985:5:94-98
Key Steps in the Diagnostic Process
§ History:
à Previous episodes
à Other diseases
à Family history
§ Comprehensive physical examination:
à ‘Objective evidence’
à Other lesions
§ Additional tests:
à MRI
à CSF
Megacystic MS
Balo-like MS
Infiltrative
MS
Benign MS
RIS
Tumefactive
MS
PPMS SPMS
RRMS
Devic
Schilder
Marburg
NMO AHL
ADEM
CIS
Idiopathic inflammatory
demyelinating lesion
The evolution of MS
Clinical
Threshold
MRI Activity
Total lesion load
CIS RRMS SPMS RIS
McDonald
MS Poser
CDMS
First clinical
event
Adapted from Trapp BD et al. Neuroscientist. 1999;5(1):48-57
Figure 3. Overview of the indications for MRI
in published cohorts, n=394. 4,6 –12,23,26 ...
Granberg T et al. Mult Scler 2012;19:271-280
Copyright © by SAGE Publications
RIS
Radiologically isolated syndrome
§ Approximately two-thirds of persons with RIS show radiological
progression and one-third develop neurological symptoms
during mean follow-up times of up to five years. Cervical cord
lesions are important predictors of clinical conversion.
Mult Scler Jour 2013 Mar;19(3):271-80..
Radiologically isolated syndrome--incidental magnetic resonance imaging
findings suggestive of multiple sclerosis, a systematic review.
19/08/2015 Name Surname 8
What is a Clinically Isolated Syndrome?
§ A clinically isolated syndrome (CIS) is a first acute or subacute
episode of neurological dysfunction with a high suspicion of
development of multiple sclerosis
§ A CIS is usually the first clinical event in an MS patient
§ Magnetic resonance imaging (MRI) findings compatible with:
à No or minimal oedema/mass effect
à T2-hyperintense lesions
à Contrast enhancing lesions
à Location of lesion
§ Spontaneous or steroid responsive remissions
To exclude other pathologies that may underly the same syndrome
(Always look for RED FLAGS, Miller DH, Mult Scler 2008:14:1157-74)
10 Tobias Granberg
Multiple sclerosis and diagnosis
§ The main principle: dissemination in time (DIT) and space (DIS)
§ Schumacher 19655
§ Poser 19836
§ McDonald 20017
§ Reviderade McDonald 2005 (Polman)8
§ Reviderade McDonald 2010 (Polman)9
§ Demonstration of DIS and DIT with MRI:
§ Paty 198810
§ Barkhof 199711
§ Reviderade Barkhof (Tintoré) 200012
§ Swanton 200613
5. Schumacher GA, et al. Problems of Experimental
Trials of Therapy in Multiple Sclerosis: Report by the
Panel on the Evaluation of Experimental Trials of
Therapy in Multiple Sclerosis. Ann N Y Acad Sci.
1965;122(1):552–68.
6. Poser CM, et al. New diagnostic criteria for multiple
sclerosis: Guidelines for research protocols. Ann
Neurol. 1983;13(3):227–31.
7. McDonald WI, et al. Recommended diagnostic criteria
for multiple sclerosis: guidelines from the International
Panel on the diagnosis of multiple sclerosis. Ann
Neurol. 2001;50(1):121–7.
8. Polman CH, et al. Diagnostic criteria for multiple
sclerosis: 2005 revisions to the “McDonald
Criteria.”Ann Neurol. 2005;58(6):840–6.
9. Polman CH, et al. Diagnostic criteria for multiple
sclerosis: 2010 Revisions to the McDonald criteria. Ann
Neurol. 2011;69(2):292–302.
10. Paty DW, et al. MRI in the diagnosis of MS: a
prospective study with comparison of clinical
evaluation, evoked potentials, oligoclonal banding, and
CT. Neurology. 1988;38(2):180–5.
11. Barkhof F, et al. Comparison of MRI criteria at first
presentation to predict conversion to clinically definite
multiple sclerosis. Brain. 1997;120(11):2059–69.
12. Tintoré M, et al. Isolated demyelinating syndromes:
comparison of different MR imaging criteria to predict
conversion to clinically definite multiple sclerosis. Am J
Neuroradiol. 2000;21(4):702–6.
13. Swanton JK, et al. Modification of MRI criteria for
multiple sclerosis in patients with clinically isolated
syndromes. J Neurol Neurosurg Psychiatry.
2006;77(7):830–3.
20 mars 2014
Ann Neurol 2011:69:292-
Recent radiological classifications
for MS lesions
19/08/2015 Name Surname 12
Tintoré M, et al. Isolated demyelinating syndromes: comparison of different MR
imaging criteria to predict conversion to clinically definite multiple sclerosis. Am J
Neuroradiol. 2000;21(4):702–6.
Swanton JK, et al. Modification of MRI criteria for multiple sclerosis in patients with
clinically isolated syndromes. J Neurol Neurosurg Psychiatry. 2006;77(7):830–3.
Diagnostic criteria for Multiple Sclerosis:
2010 Revisions to the McDonald Criteria Ann Neurol 2011:69:292-302
Oligoclonal bands
Nature Rev Neurol 2013:9:267-276
Frequencies of abnormal CSF
variables in clinically definite MS
Oligoclonal IgG in CSF >95%
Increased IgG index 70-80%
Increased cell count 50%
Abnormal albumin ratio 12%
Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report
J Neurol Neurosurg Psych 1994:57:897-902
Andersson M, Alvarez-Cermeno J, Bernardi G, Cogato I, Fredman P, Frederiksen J,
Fredrikson S, Gallo P, Grimaldi LM, Gronning M, Keir G, Lamers K, Link H, Magalhaes
A, Massaro AR, Ohman S, Reiber H, Rönnbäck L, Schluep M, Schuller E, Sindic CJM,
Thompson EJ, Trojano M, Wurster W.
Differential diagnosis based on
presenting symptoms from the brainstem,
spinal cord, optic nerves or cerebrum.
Mult Scler 2008:14:1157-74
MS Less common Atypical
Internuclear
ophthalmoplegia
Facial palsy,
facial myokymia
Ataxia and
multidirectional
nystagmus
Deafness Vascular territory
syndrome, e.g.,
lateral medullary
Sixth nerve palsy One-and-a-half
syndrome
Third nerve palsy
Facial numbness Trigeminal
neuralgia
Progressive
trigeminal sensory
neuropathy
Paroxysmal
tonic spasms
Focal dystonia,
torticollis
Brain stem presentation
MS Less common Atypical
Unilateral optic
neuritis
Bilateral
simultaneous
optic neuritis
Progressive optic
neuropathy
Pain on eye
movement
No pain Severe, continuous
orbital pain
Partial and mainly
central visual
blurring
No light
perception
Persistent
complete loss of
vision
Normal disc or
mild disc swelling
Severe disc
swelling
Neuroretinitis
(optic disc swelling
with macular star)
Uveitis (mild,
posterior)
Uveitis (severe,
anterior)
Optic nerve presentation
MS Less common Atypical
Partial myelopathy Complete transverse
myelitis
Anterior spinal artery
territory lesion (sparing
posterior columns only)
Lhermitte’s symptom Radiculopathy,
areflexia
Cauda equina
syndrome
Deafferented hand Segmental loss of
pain and
temperature
sensation
Sharp sensory level to
all modalities &
localised spinal pain
Numbness Partial Brown-
Sequard syndrome
(sparing posterior
columns)
Complete Brown-
Sequard syndrome
Urinary urgency,
incontinence, erectile
dysfunction
Faecal incontinence Acute urinary retention
Progressive spastic
paraplegia
(asymmetrical)
Progressive spastic
paraplegia
(symmetrical)
Progressive sensory
ataxia (posterior
columns)
Spinal cord presentation
Cerebral presentation
MS Less common Atypical
Mild subcortical
cognitive
impairment
Epilepsy Encephalopathy
(obtundation,
confusion,
drowsiness)
Hemianopia Cortical blindness
Hemiparesis Chorea,
myoclonus
Generalized
movement disorder
or Parkinsonian
syndrome
Some differential diagnosis to MS
§ ADEM, NMO, AHL, PML, Balo
§ Systemic: Sarcoidosis, SLE, Behcet, Sjögren, Wegener
§ Vascular: Stroke, Vasculitis, CADASIL, anti-phospholipid
syndrome, AV-malformations, hemangioma
§ Metabolic: Leukodystrophies (metachromatic/adreno-),
mitochondrial disorders (MERFF, MELAS, Leber), B12-
deficiency
§ Genetic: SCAs, Friedreich, HSP
§ Neoplastic: Lymphomas, paraneoplastic syndromes
§ Infection: HIV, syphilis, Borrelia, herpes, Whipple
§ Psychiatric
§ Others (toxic, compression, neuromuscular (MG) etc)
RED FLAGS § Lung involvement
§ Multiple cranial neuropathies or polyradiculopathy
§ Peripheral neuropathy
§ Tendon xanthomas
§ Cerebral venous sinus thrombosis
§ Cardiac disease
§ Myopathy
§ Renal involvement
§ Cortical infarcts
§ Haemorrhages/microhaemorrhages
§ Extrapyramidal features/ Movement disorders
§ Livedo reticularis
§ Retinopathy
§ Calcifications on CT scans
§ Bone lesions
§ Diabetes insipidus
§ Increase serum lactate level
§ Selective involvement of the anterior temporal and inferior frontal lobe
§ Hematological manifestations
§ Lacunar infarcts
§ Mucosal ulcers
§ Myorhythmia
§ Hypothalamic disturbance
§ Recurrent spontaneous abortion or thrombotic events
§ Simultaneous enhancement of all lesions
§ Rash
§ Arthritis, polyarthalgias, myalgias
§ Amyotrophy
§ Headache or meningismus
BUT REMEMBER:
§ Age?
§ Abrupt onset?
§ Lack of typical symptoms?
§ Family history?
§ Normal examination?
§ Normal MRI/CSF?
What differ age related changes on MRI from MS?
19/08/2015 Name Surname 23
Red flags on MRI
§ Persistent Gd-enhancement and continued enlargement of
lesions
§ Persistently unifocal manifestations
§ Large and infiltrating brainstem lesions
§ Predominance of lesions at the cortical/subcortical junction
§ Meningeal enhancement
§ T2-hyperintensity in the dentate nuclei
§ No "black holes“
§ Large lesions
§ Marked asymmetry of WM lesions
§ No enhancement
Blood tests in MS diagnosis???
19/08/2015 Name Surname 25
In conclusion…
MS remains a diagnosis requiring an
expert neurologist
Differential diagnosis are many, but they can
usually be excluded by considering “red flags”
Although a disease specific marker does not exist, a
robust diagnosis can usually be established early
after onset in most cases after weighing
clinical-, CSF- and MRI-data
References
§ Miller DH, et al: Differential diagnosis of suspected multiple
sclerosis: a consensus approach. Mult Scler 2008:14:1157-1174
§ Rolak LA, Fleming JO: The differential diagnosis of multiple sclerosis. The neurologist. 2007:13:57-72
§ Stangel M et al: The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nature Rev Neurol 2013:9:267-276
§ Hahn JS, et al: Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology 2007:68 (suppl 2):S13-S22
§ Polman CH et al: Diagnostic criteria for Multiple Sclerosis:2010 revisions to the McDonald Criteria. Ann Neurol 2011:69:292-302
§ Lublin F et al: Defining the clinical course of multiple sclerosis. The 2013 revisions. Neurology 2014:83:278-286
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Multiple Sclerosis Differential diagnoses and diagnostic dilemmas
MRI - possibilities and pitfalls in diagnosis of MS
Aksel Siva, M.D. MS Clinic & Department Of Neurology
Istanbul University Cerrahpaşa School Of Medicine [email protected]
ECTRIMS 07 October 2015, Barcelona
Diagnostic criteria in “MS”
• Schumacher et al, 1965 "a clinical disease disseminated in time and space"
• Poser et al, 1983 "additional paraclinical and / or laboratory evidence: neuroimaging, neurophysiology & CSF (↑IgG/OCB)"
• McDonald et al, 2001 & • revised McDonald; Polman et al, 2005 “evidence for dissemination in time and space supported by MRI”
No better explanation to account for symptoms and signs (no alternative neurological disease)
"dissemination in time and space"
Diagnostic criteria in “MS” Diagnosing MS
MS is a neuro-inflammatory demyelinating disease with neurodegeneration of the CNS, in which there is
• Evidence of dissemination in space (multifocality)
• Evidence of dissemination in time (recurrent attacks or steady progression)
• No better explanation to account for symptoms and signs (no alternative neurological disease)
Multiple Sclerosis
The basis of diagnosis is to clinically establish that • disease activity has affected more than one part of the CNS "dissemination in space" and • on more than one occasion "dissemination in time" However, we now know that • MS is an ongoing disease and • MS involves more widely – diffusely the CNS
…and, how do we now
that?
Clinical Hx Neuro-exam and, by MRI!
Clinical Hx Neuro-exam and, by MRI!
Clinical Symptoms & Signs suggestive of ”MS”
Imaging Cranial & Spinal MRI suggestive of “MS”
Clinical & Imaging findings suggestive of MS
Diagnosis and Differential Diagnosis of MS
Patients are admitted to neurology outpatient clinics because of...
RIS CIS RRMS PMS MS variants, mimics or not so rarely something else!
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A first concern!
• What should be our first concern in the general neurology out-patient clinic?
• Could it be MS?
• What should be our first concern in the MS out-patient clinic?
• Could it not be MS
In a patient who is admitted with symptoms and/or MRI findings suggestive of MS or MS Spectrum / related disorders
Difficulties in MS diagnosis
Evaluation of diagnostic outcomes in patients referred to a university-based MS center for possible MS
(University of Colorado Multiple Sclerosis Center, Denver)
*Carmosino et al. Arch Neurol. 2005
Difficulties in MS diagnosis
Evaluation of diagnostic outcomes in patients referred to a university-based MS center for possible MS
# 281 pts → Final MS diagnosis: 33% (McDonald-I)
pts referred on the basis of clinical dx: MS in 46% pts referred on the basis of MRI dx: MS in 11%
Non-MS dx: Other neurologic disorders: 31.5 %
Probable psychiatric diagnoses: 22.5 % No clear diagnosis made: 12.5 %
*Carmosino et al. Arch Neurol. 2005
Difficulties in MS diagnosis
*Solomon et al. Neurology, 2012
For MS experts & in MS centers it is relatively common to see patients diagnosed as MS, who in fact don’t have MS, with a significant number of these misdiagnosed cases being on DMD!
Difficulties in MS diagnosis
*Solomon et al. Neurology, 2012
The most common alternative diagnoses in patients misdiagnosed with MS* NSWMA - nonspecific white matter abnormalities 81 % SVID - small vessel ischemic disease 78.5 % Migraine 50 % Psychiatric disease 44.8 % Fibromyalgia 31 % NMO - Neuromyelitis optica 40.5 % Misdiagnosed patients on DMD for MS 26 %
Difficulties in MS diagnosis
Diagnosing MS may be challenging!
Vague neurologic symptoms in young people Insignificant neurological findings
Nonspecific white matter abnormalities on brain MRI
False neuroimaging (MR) reports The urge (!) to diagnose MS early
MS and its masquerades
May cause over / false – diagnosis of MS!!!
3
MS diagnosis
Steps to MS Dx
• Clinical history
• Neurological examination
• Neuroimaging - MRI
• aother laboratory testing (CSF & EP)
MRI - possibilities and pitfalls in diagnosis of MS
The diagnostic spectrum of MRI in MS • RIS • CIS • Clinical MS • MS variants • NMOSD and other autoimmune
neuroinflammatory-neurodegenerative CNS diseases
• Non-MS CNS disseases
The Spectrum of Multiple Sclerosis
MS phenotypes • RIS • CIS • SAMS • SAPMS • RRMS • 20 PMS • PPMS
MS variants • Tumefactive MS • Balo’s • Marburg’s • Schilder’s?
MS related disorders (once upon a time ago MS!) • ADEM • NMO / NMOSD • aMOG-related
syndromes • Others – yet Antb
unknown - atypical CNS inflammatory disorders?
MRI - possibilities and pitfalls in diagnosis of MS
In a patient who has been referred with a “clinical diagnosis” of probable MS
• MRI may confirm the clinical diagnosis of MS • MRI may be suggestive of an alternative diagnosis • MRI sometimes may cause further diagnostic confusion!
MRI - possibilities and pitfalls in diagnosis of MS
In a patient who has been referred with an “MRI diagnosis” of probable MS (radiology report/non-expert reading)
A proper MRI reading; • may confirm the clinical diagnosis of MS • may be suggestive but not confirmative, necessitating
further w/up & f/up for MS • may not be conclusive and leads for further work-up for
non-MS other neuro-inflammatory demy. diseases • may exclude the clinical diagnosis of MS and offer an
alternative diagnosis
confirmative
suggestive
explorative
eliminative
MRI - possibilities and pitfalls in diagnosis of MS
In a patient who is diagnosed and followed with a diagnosis of MS, MRI may assist the clinician to, • Decide to start long term treatment • Decide whether the patient is a treatment responder • Decide to change a DMD • Predict the clinical course and prognosis (to a certain
extent)
4
Defining the clinical course of multiple sclerosis - the 2013 revision*
*Lublin et al Neurology, 2014
This new definition is highly
MRI-dependent
Neuroimaging in MS diagnosis
CT in MS diagnosis – its first years!
Acta Neurol Scand 53; 386-389, 1976
Department of Neuroradiology, Rigshospitalet, Copenhagen, Denmark
Computer Tomography of the Brain in Multiple Sclerosis A radiological study of 110 patients with special reference to demonstration of cerebral plaques
Carsten Gyldensted
Computerised Axial Tomography in Multiple Sclerosis L.A. Cala and F.L. Mastaglia
Department of Radiology, Perth Medical Centre, Perth, Western Australia
University Department of Medicine, Perth Medical Centre Lancet, March 27, 1976
MRI in MS diagnosis – its first years!
MS 2010 diagnostic criteria MRI (CIS!)
What’s new? …and
today!
McDonald 2010 - MRI diagnostic criteria
DIS – Dissemination in space ≥ 1 T2 lesions in ≥ 2 regions of the following CNS areas • juxtacortical • periventricular • infratentorial • spinal cord DIT – Dissemination in time • ≥ 1 asymptomatic Gd enhancing lesion/s in the initial MRI • New T2 lesion/s (Gd+Ø) on follow-up MRI
*Polman et al, Ann. Neurol 2011
5
McD 2010 MS diagnostic MR findings periventricular & juxtakcortical areas
Sub-cortical
periventricular Juxta-cortical
pv Posterior fossa lesions
McD 2010 MS diagnostic MR findings posterior fossa lesions
Posterior fossa lesions
McD 2010 MS diagnostic MR findings posterior fossa lesions
MS suggestive MR findings corpus callosum lesions
Spinal cord lesions
McD 2010 MS diagnostic MR findings spinal cord lesions
McD 2010 MS diagnostic MR findings spinal cord lesions
Spinal cord lesions
multiple Gd +
lesions
6
MS suggestive MR findings Gadolinium enhancing lesions
Ring pattern Nodular
enhencement
Open ring pattern
MS suggestive MR findings Gadolinium enhancing lesions
MR findings in MS "black holes!"
(T1) black holes
Clinically MS & MR consistent with MS
Not all white spots seen on MRI are MS!!!
32, Male (seen in another center) Admitted because of dizziness, starting a year ago following an upper resp infec. He describes that his dizziness worsen at times, but is not directly related to cranio-cervical movements. Sometimes in association with dizziness he experiences a mild nausea and mild visual blurring, but has no headaches, no instability and doesn't vomit. Physical exam: normal Neurological exam: unremarkable Past medical history: Smokes a pack a day, otherwise insignificant Family history: insignificant
A young man with dizziness and numbness in hands
7
32, M admitted because of dizziness with normal exam. The patient is referrred for an MRI study – which shows bilateral mostly subcortical T2 hyperintensities, these were read as being
“nonsignificant” WM hyperintensities in the radiology report
The consultant neurologist doesn’t think MS or other neurological disorder and prescribes an SSRI!
A young man with dizziness, numbness in hands and T2 lesions on MRI
32, M admitted because of dizziness – MRI initially read as nonsignificant neuro-exam normal; first neurologist doesn’t think MS!
A year later he is re-admitted to another center, he reports now numbness in hands and dizziness, he has a repeat an MRI study in
another center where this MRI, although unchanged from the initial MRI done a year ago is read as suggestive of MS
A young man with dizziness, numbness in hands and T2 lesions on MRI
32, M admitted because of dizziness and numbness in hands, his MRI was read as suggestive of MS
However, these MRI studies are not fulfilling the MRI criteria for MS (McDonald 2010)
• There are bilateral multiple subcortical T2 hyperintensities • Despite a relatively high number of subcortical lesions, juxtacortical and
periventricular lesions are hardly seen • There are no posterior fossa (and no corpus callosum) lesions
(at this stage there was not a spinal cord MRI)
• There is neither symptomatic nor asymptomatic “Gad-enhancing” lesion • There was no change compared with the MRI done about a year ago • No new or enlarging T2 lesions; no Gadolinium enhancing lesion
A young man with dizziness, numbness in hands and T2 lesions on MRI
“Dissemination in space” criteria not fulfilled!
“Dissemination in time” criteria not fulfilled!
32, M admitted because of dizziness – MRI initially read as nonsignificant neuro-exam normal; first neurologist doesn’t think MS!
A year later another neurologist makes a diagnosis of MS and starts DMT! One year later continues to describe same symptoms – no change on MRI
Accepted as a non-responder, DMD switched
About another year later he comes for another opinion to our center... Neuroexam normal; MRI unchanged!
Work up – including vasculitis/collagen disease panel & serology all normal CSF: normal, no OCB
A young man with dizziness, numbness in hands and T2 lesions on MRI
Lesions are bilateral - semisymmetrical – largely subcortikal – no gadolinium enhancement
No posterior fossa lesion
No corpus callosum lesion
Follow up MRIs: no change in any MRI – no enhancement in any – no atrophy – no T1 Black holes
Not MS
A young man with dizziness, numbness in hands and T2 lesions on MRI
First MRI 2004
Second MRI 2005 DMD initiated
Third MRI 2006 DMD switched!
MRI 2008 Pt self-admitted to our MS center
No spinal cord lesion
A young man with dizziness, numbness in hands and T2 lesions on MRI
Patient was seen again about 3 years later in Apr 2014 because of dizziness and tension type headache - he was fine over the years with the
exception of a few episodes of dizziness closely related to life events! He was given duloxetine in 05.2014 and responded well.
His neuro-exam was normal and a f/up MRI done on 08/14 was unchanged.
Follow up MRI: no change – no enhancement – no atrophy – no T1 Black holes No posterior fossa and no spinal cord lesions
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A young man with dizziness, numbness in hands and T2 lesions on MRI
His final diagnosis is not MS or any other significant neurologic disease
This individual is someone who turns out to have “NSWMA - nonspecific white matter abnormalities” on his MRI He also has an anxiety disorder and a tendency for somatization
His MRI changes are unlikely to be related to his symptoms or to any other disorder
He was overdiagnosed with MS and received unnecessary & toxic treatments
.
Differential Diagnosis in MS – Imaging (MRI)
• UBOs ! • Enlarged Wirchow-Robin (perivascular) spaces • Migraine • Antiphosfolipid antibody syndrome • Vasculitic (primary/secondary) syndromes & CTD
– PACNS; NBS; SLE, Sjogrens syndrome; neuro-Behcet’s • Fabry disease • CADASIL • Leber hereditary optic neuropathy • Adult onset leukodistrophies • Ischemic-degenerative changes in the elderly
Difficulties in MS diagnosis by MRI
• Never rely on a radiologist’s report (whom you don’t know)!
• A clinical neurologist should understand neuro-imaging and be able to read what MRI abnormalities may say…
• When you are not sure about what MRI abnormalities may mean, then find a good neuroradiologist (whom you trust) to consult…
MS diagnosis by MRI clinical diagnosis should come first!
• All MRI abnormalities, in which MS turns out to be a
diagnostic possibility, the imaging differential diagnosis should be based on “clinical grounds”
• The clinical impression and diagnosis comes first! Ø imaging/MRI and all other lab tools should be used to
confirm or to exclude a clinical diagnosis!
• The MRI may lead you to a clinical diagnosis, only when it’s highly suggestive of a certain disease (i.e. MS!) and when your mind isn’t clear clinically!
Pink Flags!!!
MRI - possibilities and pitfalls in diagnosis of MS differential diagnosis
Neuro-imaging In a patient, in whom the clinical symptoms are suggestive of MS The MRI may disclose • A normal study • Atypical findings • MS suggestive findings • Findings fulfilling MS criteria • Non-MS pathology (i.e.vasculopathies; neoplastic disorders...)
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MRI - possibilities and pitfalls in diagnosis of MS differential diagnosis
Neuro-imaging In a patient, in whom the clinical symptoms are not suggestive
of MS The MRI may disclose • MS suggestive findings
– incidental – it may be RIS! – consider re-taking a detailed Hx – it may be MS!
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with MRI abnormalities suggestive of MS! Demographic possibilities and pitfalls !
• Childhood-onset (age << 16) [consider the probability of dysmyelinating diseases] • Late-onset (age >> 50) [consider the probability of ischemic-demyelinating changes] • (+) Strong family history ≥ 2 family members have identical MRI abnormalities [consider genetic diseases]
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with MRI abnormalities suggestive of MS! Clinical possibilities and pitfalls • (+) Patient have systemic symptoms suggestive of a
connective tissue disorder or a vasculitic syndrome [consider systemic inflammatory autoimmune diseases] • (+) Patient have systemic symptoms suggestive of an
infectious disease [consider infectious diseases such as Lyme, HIV, HTLV I&II, tbc] • (+) Patient have systemic psychiatric symptoms!
[consider somatoform disorders; anxiety & depression; fibromyalgia! in the setting of NSWMA]
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with MRI abnormalities suggestive of MS! MRI findings atypical for MS – less likely to be MS • Very small lesions (<3 mm) • Absence of ovoid lesions • Absence of posterior fossa & corpus callosum lesions • Peripheric – subcortical - localization of white matter
lesions rather than periventricular • Symmetrical/semi-symmetrical lesions • Unproportionaly large corpus callosum lesions
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with MRI abnormalities suggestive of MS! Neurological imaging – MRI – atypical / unexpected in MS • No change in succesive MRIs – all MRIs are the same! • No gadolinium enhancement in any MRI • Lesions with prominent mass effect • Up/downward (edematous) extension of large brainstem les. • Longitudinally extensive spinal cord lesions (LECL) • Family members with similar MRIs! All possible in MS, but other diseases should be R/o first!
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with parenchymal (intra-axial) spinal MRI abnormalities suggestive of inflammatory pathology...possibilities;
When it is a “small spinal cord lesion” [<3 segments] • MS • Transverse myelitis • Atypical or recovering NMO / NMOSD – myelitis • Myelitis assoiated with systemic vasculitides & collagen tissue disorders • Tumors (i.e.astrocytoma; ependymoma) • Infectious disorders
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MRI - possibilities and pitfalls in diagnosis of MS “think twice”
MS Brain MR+
Spinal lesion Small
Lateral Gd+
Recovering NMO-myelitis
Transverse myelitis?
MRI - possibilities and pitfalls in diagnosis of MS “think twice”
In an individual with parenchymal (intra-axial) spinal MRI abnormalities suggestive of inflammatory pathology...possibilities;
When it is a “longitudinally extensive spinal cord lesion” [>3 segments] • MS – multiple small lesions in contiguity suggestive of a single LETM-lesion • Transverse myelitis • NMO / NMOSD – myelitis • Myelitis assoiated with systemic vasculitides & collagen tissue disorders • Spinal venous dural fistula • Tumors (i.e.astrocytoma; ependymoma) • Infectious disorders (i.e. viral, tbc, lyme) • Granulomatous disorders (i.e. Sarcoidosis)
Longitudinally extensive spinal cord lesions suggestive of NMO
Longitudinally extensivespinal cord lesions LETM / NMO / NMOSD
widespread Gd enhancement
Spinal cord lesions
peri-cordial vascular abnormalities spinal venous dural fistula
Gd + enchancing
vasc structures
Longitudinally extensive lesions 2o to dural fistules
Subclinical lesions on MRI in young people what to think?
Subclinical lesions on MRI and migraine
ZC, 26 yrs old F Attacks of visual & sensorial aura, followed by a migrainous headache
In some aura without headache •
Past family Hx: Mother alive/well&HT Father A/Well – has migraine Sister A/W - has migraine
Work-up ? TTE / TEE to R/o - PFO & ASA Doppler R/o embolic showers?
11
Tumefactive lesions when they may be MS and when not?
Tumefactive lesions
What could they be? • Brain neoplasms • CNS lymphoma • Abscesses • PML! • Vasculitic disorders & NBS! • Tumefactive demyelinative lesions (TDL)
Clues to the diagnosis of TDL include* • Less mass effect than
expected for their size • open ring enhancement • no increased perfusion • visualisation of veins
coursing through the lesion
*Kaschka et al 2014
Tumefactive lesions – MS or not?
Tumefactive demyelinating lesions are well-demarcated, hyperintense on T2, hypointense on T1-wMRI. Ring enhanc with Gd is characteristic, >open ring, the open portion abuts the GM of the cortex (or BG). Size of the lesion (>20mm), the relative lack of mass effect, and edema are helpful radiological findings
Biopsy proven acute demyl
Tumefactive lesions – MS
“Tumefactive MS” lesions may be seen with other MS suggestive lesions when the diagnosis becomes easier,
However, it should be kept in mind that MS and brain tumors although highly unlikely may be seen together in an unfortunate individual!
MS and its MRI mimics – multifocal tumors
18 02 09
MS and its mimics – multifocal tumors
06 03 09
12
MS and its MRI mimics multifocal high grade glioma
18 02 09
...we biopsied the most superficial lesion last week. Although the lesion is quite odd looking, our neuropathologist is convinced that it is a high-grade glioma. The reason it appears to be unusual is that there is a great deal of inflammation and fibrosis. I think this is a result of the hemorrhage into the tumor, rather than the tumor itself
MS and its MRI masquerades
MS and its clinical and MRI masquerades
• PCNSA • Neuro – Behcet • SLE • Sjogren • CADASIL • Susac • Fabry
Cerebral vasculapathies, which may mimic MS both clinically and on MRI!
These are disorders seen uncommonly either some of their clinical or MRI features will be atypical for MS!
MS and its mimics Primary CNS vasculitis
Diagnostic criteria
1. recent history or presence of an acquired neurologic deficit unexplained by other causes; encephalopathy
Various symptoms and findings at diagnosis of PCNSV* (Most with multiple manifestations) headache, altered cognition, visual symptoms, focal neurologic manifestations, persistent neurologic deficit or stroke
2 evidence of vasculitis in a CNS biopsy specimen; or
3. a cerebral angiogram with changes characteristic of vasculitis
*Calabrese and Mallek, Medicine, 1988 & Salvarini et al Ann Neurol 2007
• Systemic vasculitides and connective tissue diseases may involve either the CNS or PMS, or both
• In most instances this involvement is the result of inflammation of the blood vessels and less commonly due to thrombotic vasopathies - nervous system involvement secondary to different form of vasculopathies.
• Other vasculopathic disorders (i.e. lymphoproliferative diseases and other malignancies, some infections and related conditions, drugs and substance abuse) may also affect the CNS and may result in clinical and MRI features that may mimic MS!!!
Systemic vascular inflammatory diseases with nervous system involvement – do they cause confusion with
MS diagnosis???
Behcet’s disease Uygunoğlu & Saip & Siva
13
Neuro - Behçet Syndrome
Neurological involvement directly related to BS*
• Headache (non-structural) • Cerebral venous sinus thrombosis (extra-axial NBS) • Central nervous system involvement (intra-axial NBS) • Neuro-Psycho-Behçet Syndrome • Peripheral nervous system involvement • Subclinical NBS
*Siva & Saip. J Neurol, 2009
MS and its mimics - intraaxial (CNS) NBS
NBS • Neurological involvement
is unlikely prior to the onset
of systemic signs & Sx of BD
• Neuroimaging is highly,
suggestive of NBS
MS and its mimics - intraaxial (CNS) NBS
Spinal involvement in NBS is
in the form of LETM AQP4-Abs are absent
the major CNS region to be involved in NBS is the brainstem lesions are large and extend to deep hemispheric strutures
uncommonly subcortical lesions may be seen
Gd enhancement may be seen
in acute lesions
MS and its mimics - intraaxial (CNS) NBS
14
MS and its mimics - intraaxial (CNS) NBS MS vs NBS – differential diagnosis I*
MS • F > M Sx/S common at onset • ON; sensory; motor; spinal
cord; BS; Cblr Sx/S uncommon at onset • Headache,
cranial neuropathies
CNS – NBS • M > F Sx/S common at onset • Headache; motor;
Cblr; BS (INO rare) Sx/S uncommon at onset • ON; sensory;
spinal cord
*Siva & Saip. J Neurol, 2009
MS vs NBS – differential diagnosis II*
MS MRI • PV & SC lesions (+++)
BS lesions: small, discrete, extension (–) spinal cord lesions (++) CSF • Inflammatory changes (-)
OCB (+) [>90%]
CNS – NBS MRI • PV & SC lesions (±)
BS lesions: large, diffuse, extension (+) spinal cord lesions (±)
CSF • Inflammatory changes (+)
OCB (–) [<20%]
* Siva & Saip. J Neurol, 2009
MS and its mimics Systemic lupus erythematosus 30 yrs F with SLE & neuro complication
SLE diagnosis known Systemic involvement prior to nervous system involvement
CADASIL
Cerebral Autosomal Dominant Arteriopathy
with Subcortical Infarcts and Leukoencephalopathy
AA 64 F, (28.01.2004)
Semi-specific white matter lesions – CADASIL*
Characteristic MRI lesions in the ant.temporal & frontal poles, U-fibres, the basal ganglia, external capsule, insular regions and lacunar like infarcts within the corona radiata and SC regions.
Frequent sparing of corpus callosum and cerebellum
(
*Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
15
CADASIL
• The primary disease process is a vasculopathy a (nonatheromatous, nonamyloid angiopathy)
• Although the disease manifests itself as brain dysfunction,
this vasculopathy is systemic
• The clinical spectrum of CADASIL is heterogeneous
• inherited in an autosomal dominant pattern (19q13)
• Characteristic MRI lesions in the ant.temporal lobes, frontal poles, the basal ganglia, capsula extrema and lacunar like infarcts within the corona radiata and SC
Susac’s Syndrome
*Rennebohm et al. / J Neurol Sci 2010
It is an autoimmune endotheliopathy affecting the precapillary
arterioles of the brain,retina, and
inner ear
*Rennebohm et al. / Journal of the Neurological Sciences 299 (2010)
MRI possibilities and pitfalls in diagnosis of MS WRAP-UP
MRI possibilities and pitfalls in diagnosis
*Rovira et al. Nature Reviews – Neurology, 2015
MRI possibilities and pitfalls in diagnosis The MAGNIMS study group guidelines*
Shortcomings of MRI studies in general practice • Nonstandardized MRI examinations are often of inadequate quality • MRI reports are likely to be read by people lacking expertise in the field
of MS and without consideration of relevant clinical and laboratory data • These can lead to erroneous diagnoses The MAGNIMS study group guidelines* • to better define and optimize the use of brain and spinal cord MRI in the
diagnostic process for MS • recommendations to promote standardized strategies that apply to the
planning, performance and interpretation of MRI for clinical use *Rovira et al. Nature Reviews – Neurology, 2015
16
McD 2010 MS diagnostic MR findings – DIT*
DIS – Dissemination in space ≥ 1 T2 lesions in ≥ 2 regions of the following CNS areas • juxtacortical • periventricular • infratentorial • spinal cord
*Polman et al, Ann. Neurol 2011
McD 2010 MS diagnostic MR findings – DIS juxtacortical & periventricular & post fossa & spinal cord
Sub-cortical periventricular Juxta-cortical
Spinal cord lesions Posterior fossa lesions
Corpus callosum lesions
Sub-cortical
1
3
4
2
McD 2010 MS diagnostic MR findings – DIT*
DIT – Dissemination in time • ≥ 1 asymptomatic Gd enhancing lesion/s in the initial MRI • New T2 lesion/s (Gd+Ø) on follow-up MRI
*Polman et al, Ann. Neurol 2011
Not likely to be MS!
Normal CSF: (-) OCBs → think twice! Normal MRI* → unlikely to be MS
Normal MRI & CSF → can’t be MS!!!
*MRI of brain and spinal cord
The other side of the coin!
Abnormal CSF → (+) OCBs not always MS! Abnormal MRI → not always MS or not clinically significant “MS!”
The diagnosis of MS by MRI is not always an easy task!
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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Heterogeneity of idiopathic inflammatory demyelination
ECTRIMS Teaching Course #8 “Differential diagnosis and diagnostic dilemma”
Wednesday 7 October 2015
Sandra VUKUSIC1-4
1 Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques,
Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, F-6977, France; 2 Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et
Neuro-inflammation, Lyon, F-69003, France; 3 Université de Lyon, Lyon, F-69003, France;
4 Université Lyon 1, Lyon, F-69003, France;
Correspondance to: Prof. Sandra VUKUSIC – Service de Neurologie A – Hôpital Neurologique Pierre Wertheimer 59 boulevard Pinel – 69677 BRON cedex – France e-mail: [email protected] Tel: +33 4 72 35 75 22 – Fax: +33 4 72 35 75 25 Financial Disclosure Statement
Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from Bayer-
Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma.
None of these relationships results in a conflict of interest in the scope of this paper.
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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Idiopathic inflammatory demyelinating disorders of the central nervous system (CNS) represent a wide
range of clinical phenotypes. They exclusively affect the CNS and their immunopathogenesis remains
poorly understood.
In the last decade, advances in clinical descriptions, imaging techniques, immunological testing and
pathology have allowed defining new disease entities. However, it remains unclear whether these
entities represent different diseases or part of a wide spectrum of idiopathic inflammatory
demyelinating disorders of the CNS.
Multiple sclerosis (MS) is the most frequent of these disorders. Its diagnostic criteria have clearly
improved in the recent years, although we still miss a specific diagnostic test. In particular, early
clinical stages (so-called clinically isolated syndromes (CIS), optic neuritis, myelitis or other focal
lesions) might be difficult to classify without temporal data.
Thus, a similar initial presentation of optic neuritis or myelitis might remain isolated and monophasic,
or evolve either to MS or to neuromyelitis pptica (NMO). A relapsing brainstem involvement could be
MS, but also CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement
Responsive to Steroids) and even NMO spectrum disorders (NMOSD).
By contrast, a very “noisy” clinical and radiological presentation, especially in children, might be an
acute disseminated encephalomyelitis (ADEM) that is supposed to be a monophasic condition…
unless new and more typical neurological episodes, sometimes several years after, lead to a final
diagnosis of MS… or NMO.
In 2005, the description by Lennon et al. of anti-aquaporin 4 autoantibodies (AQP-4) has been a major
step in our comprehension of the immunopathogenesis of inflammatory CNS demyelination. It allowed
delineating a particular clinical phenotype, affecting specifically the optic nerves and the spinal cord,
which was previously considered and treated as MS. But more interestingly, it also lead later to extend
the clinical spectrum of what are now called “aquaporinopathies” or NMOSD, including a much wider
range of clinical and/or radiological presentations.
Is history about to be repeated with anti-myelin oligodendrocyte glycoprotein (MOG) auto-antibodies?
Are anti-MOG positive patients representing a new entity or is it just a prognostic markers?
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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The objective of this lecture will be to discuss the spectrum of idiopathic inflammatory demyelinating
disorders of the central nervous system.
The presentation will be based on typical case reports, followed by an overview of the current state of
knowledge about each clinical phenotype.
In particular, the following disorders will be discussed:
- Acute demyelinating encephalomyelitis (ADEM) and related disorders
- Neuromyelitis optica spectrum disorders and anti-MOG autoantibodies associated disorders
- Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids
(CLIPPERS)
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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Selected references
Acute disseminated encephalomyelitis
Krupp LB, Tardieu M, Amato MP et al. International Pediatric Multiple Sclerosis Study Group
criteria for pediatric multiple sclerosis and immune-mediated central nervous system
demyelinating disorders : revisions to the 2007 definitions. Mult Scler 2013;19:1261-1267.
Krupp LB, Banwell B, Tenembaum S for the International Pediatric MS Study Group.
Consensus definition proposed for pediatric MS and related disorders. Neurology 2007;68:S7-
12.
Ketelslegers IA, Neuteboom RF, Boon M, Castman-Berrevoets CE, Hintzen RQ for the Dutch
Pediatric MS Study Group. A comparison of MRI criteria for diagnosing pediatric ADEM and
MS. Neurology 2010;74:1412-1415.
Callen D, Shroff MM, Branson HM et al. Role of MRI in the differentiation of ADEM from MS in
children. Neurology 2009;72:968-973.
Mikaeloff Y, Adamsbaum C, Husson B et al for the KIDSEP Study Group on Radiology. MRI
prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain
2004;127:1942-1947.
Neuromyelitis optica spectrum disorders
Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm
2015;21:e110.
Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune
aquaporin-4 channelopathies: a decade later. Ann N Y Acad Sci 2015. doi:
10.1111/nyas.12794. [Epub ahead of print]
Wingerchuk DM, Banwell B, Bennett JL et al. International consensus diagnostic criteria
for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89.
Panel C
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to
Steroids (CLIPPERS)
Pittock SJ, Debruyne J, Krecke KN et al. Chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids (CLIPPERS). Brain 2010;133:2626-2634.
Simon NG, Parratt JD, Barnett MH et al. Expanding the clinical, radiological and
neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids (CLIPPERS). J Neurol Neursurg Psychiatry 2012;83:15-
22.
Kira J. The expanding phenotype of CLIPPERS: is it a disease or a syndrome? J Neurol
Neurosurg Psychiatry 2012;83:2-3.
Taieb G, Duflos C, Renard D et al. Long-term outcome of CLIPPERS (chronic lymphocytic
inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive
series of 12 patients. Arch Neurol 2012;69:847-855.
Dudesek A, Rimmele F, Tesar S et al. CLIPPERS: chronic lymphocytic inflammation with
pontine perivascular enhancement responsive to steroids. Review of an increasingly
recognized entity within the spectrum of inflammatory central nervous system disorders. Clin
Exp Immunol 2014;175:385-396.
Taieb G, Renard D, Labauge P. Should CLIPPERS be considered a prelymphoma state ir a
new inflammatory disease? JAMA Neurol 2013;70:1200-1201.
Relapsing Inflammatory Optic Neuropathy (RION)/Chronic Relapsing Inflammatory Optic
Neuropathy (CRION)
Petzold A, Plant GT. Diagnosis and classification of autoimmune optic neuropathy. Autoimm
Rev 2014;13:539-545.
Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of
122 cases reported. J Neurol 2014;261:17-26.
Kidd D., Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy
(CRION). Brain 2003;126:276-84.
Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course
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Anti-MOG autoantibodies associated disorders
Cobo-Calvo Á, Sepúlveda M, Bernard-Valnet R et al. Antibodies to myelin oligodendrocyte
glycoprotein in aquaporin 4 antibody seronegative longitudinally extensive transverse myelitis:
Clinical and prognostic implications. Mult Scler 2015 Jul 24. pii: 1352458515591071.
Waters P, Woodhall M, O'Connor KC et al. MOG cell-based assay detects non-MS patients
with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm 2015;2:e89.
Hacohen Y, Absoud M, Deiva K et al. Myelin oligodendrocyte glycoprotein antibodies are
associated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm
2015;2:e81.
Zamvil SS, Slavin AJ. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory
disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm
2015;2:e62.
Baumann M, Sahin K, Lechner C et al. Clinical and neuroradiological differences of paediatric
acute disseminating encephalomyelitis with and without antibodies to the myelin
oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry 2015;86:265-72.
Kitley J, Waters P, Woodhall M et al. Neuromyelitis optica spectrum disorders with aquaporin-
4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol
2014;71:276-83. Sato DK, Callegaro D, Lana-Peixoto MA et al. Distinction between MOG
antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology
2014;82:474-81.