The Role of Neurologists and Neuro-ophthalmologists in the ......May 27, 2020 · spectrum...

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Supported by an educational grant from Genentech.

WEDNESDAY, MAY 27, 2020

The Role of Neurologists and Neuro-ophthalmologists in the Diagnosis and Management of

NEUROMYELITIS OPTICA SPECTRUM DISORDER

The Role of Neurologists and Neuro‐ophthalmologists in the Diagnosis and Management of Neuromyelitis Optica Spectrum Disorder

FACULTY

Brian G. Weinshenker, MD, FRCP(C) Consultant, Department of Neurology

Professor of Neurology, College of Medicine Mayo Clinic

Rochester, MN PROGRAM OVERVIEW This case‐based live activity will cover the treatment and management of patients with NMOSD. TARGET AUDIENCE This activity is designed to meet the educational needs of US‐based neurologists, neuro‐ophthalmologists, and emergency physicians who treat patients with NMOSD. Learning Objectives

• Describe dysfunctional immunologic factors, such as IL‐6, and pathways of clinical importance for NMOSD therapy

• Discuss best practices for early diagnosis of NMOSD, including differential diagnosis and AQP4‐IgG testing • Review the novel mechanisms of action of emerging treatments for NMOSD and clinical trial data on their

safety and efficacy profiles ACCREDITATION STATEMENT Med Learning Group is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. This CME activity was planned and produced in accordance with the ACCME Essentials. CREDIT DESIGNATION STATEMENT Med Learning Group designates this live activity for a maximum of 1.25 AMA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the live activity. NURSING CREDIT INFORMATION Purpose: This program would be beneficial for nurses involved in the long‐term treatment and management of patients with NMOSD. CNE Credits: 1.25 ANCC Contact Hour(s). CNE ACCREDITATION STATEMENT Ultimate Medical Academy/CCM is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Awarded 1.25 contact hour of continuing nursing education of RNs and APNs. DISCLOSURE POLICY STATEMENT In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Med Learning Group must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, staff, and planning committee members participating in a MLG‐sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturers of any commercial products and/or providers of commercial services that are discussed in an educational activity.

DISCLOSURE OF CONFLICTS OF INTEREST Brian G. Weinshenker, MD, FRCP(C) receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO‐IgG as a diagnostic test for neuromyelitis optica spectrum disorders, served on adjudication committee for clinical trials in neuromyelitis optica spectrum disorders being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi‐Tanabe regarding clinical trials for neuromyelitis optica spectrum disorders. CME Content Review The content of this activity was independently peer‐reviewed. The reviewer of this activity has nothing to disclose. CNE Content Review The content of this activity was peer‐reviewed by a nurse reviewer. The reviewer of this activity has nothing to disclose. The staff, planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Matthew Frese, General Manager of Med Learning Group has nothing to disclose. Christina Gallo, SVP, Educational Development of Med Learning Group has nothing to disclose. Ashley Whitehurst, Program Manager of Med Learning Group has nothing to disclose. Chris Drury, Medical Director of Med Learning Group has nothing to disclose. Lauren Welch, MA, VP of Accreditation and Outcomes of Med Learning Group has nothing to disclose. Russie Allen, Accreditation and Outcomes Coordinator of Med Learning Group has nothing to disclose.

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AGENDA

I. NMOSD: An Overview

A. Case study B. Diagnostic criteria C. Symptoms D. Clinical course E. Effects on patients’ quality of life A. 2006 versus 2015 NMOSD criteria B. Epidemiology C. Role of AQP4‐IgG and IL‐6/IL‐6R

III. Current Management of NMOSD and Emerging Agents A. Therapeutic strategies B. Relationship between new pathophysiological findings and new drug targets C. Review of MOAs of emerging agents D. Review of efficacy and safety data from clinical trials of emerging agents

‐ Complement C5 inhibitor ‐ IL‐6 receptor inhibitor ‐ CD19 inhibitor

E. Additional targets of interest IV. Case Study/Conclusions V. Questions and answers

May 27, 2020 7:00 pm ET

1

The Role of Neurologists and Neuro‐Ophthalmologists in the Diagnosis and Management of Neuromyelitis Optica

Spectrum Disorder

Brian Weinshenker MDNeurologist and Professor of Neurology

Department of NeurologyMayo Clinic College of Medicine

Rochester, MN

Disclosures• Dr. Brian Weinshenker—

– Receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO‐IgG as a diagnostic test for neuromyelitis optica spectrum disorders (NMOSD);

– Served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/Viela Bio and Alexion; and

– Consulted for Chugai/Roche/Genentech and Mitsubishi‐Tanabe regarding clinical trials for NMOSD.

• The presentation includes off‐label therapy discussions of methylprednisolone, plasma exchange, azathioprine, mycophenolate mofetil, rituximab, tocilizumab, inebilizumab, satralizumab, and other immunological therapies used for NMOSD.

This program is supported by an educational grant from Genentech.

2

Learning Objectives

• Discuss best practices for the early diagnosis of NMOSD including differential diagnosis andAQP4‐IgG testing

• Describe the immunologic factors and pathways of clinical importance for NMOSD therapy

• Review the novel mechanisms of action of emerging treatments for NMOSD and clinicaltrial data on their safety and efficacy profiles

Case Example

• A 44‐year‐old woman presents with 5 days of mid‐thoracic pain and progressive difficultywalking.

• She reports being healthy, but 2 years ago she had a 9‐day episode of persistent vomitingand hiccups with a negative GI evaluation.

• Exam shows:– Moderate paraparesis with bilateral extensor plantar responses– Impaired vibratory and joint position sense at great toes– Sensory level at T11– Abnormal gait—wide based, slow, cannot walk with tandem gait

GI = gastrointestinal.

3

• MRI spine with contrast • Her serum AQP4‐IgG is positive (1:1000)

MRI = magnetic resonance imaging; AQP4 = aquaporin‐4; IgG = immunoglobulin‐G.

Case Example: Testing

Audience Response Question

What preventive treatment do you recommend?

1) Preventive treatment is not needed because she has had only 1 attack.2) Eculizumab3) Azathioprine4) Mycophenolate mofetil5) Rituximab

4

NMOSD: Overview and Diagnostic Criteria

What Is NMOSD?

• NMOSD is a CNS inflammatory/autoimmune disease that primarily affects the optic nerves and spinal cord.

• The autoimmune target is the astrocyte water channel aquaporin‐4 (AQP4).– 70% seropositive for AQP4‐IgG

– 20–50% of AQP4‐IgG seropositive for myelin oligodendrocyte glycoprotein (MOG)‐IgG

• AQP4 antibodies (AQP4‐IgG) are highly specific for NMOSD.

• AQP4‐IgG has a wide spectrum of clinical and neuroimaging disease features.

NMOSD = neuromyelitis optica spectrum disorder; CNS = central nervous system; IgG = immunoglobulin G.

5

Development of International Consensus Diagnostic Criteria

Wingerchuk DM, et al. Neurology. 2015;85:177‐189.

• NMOSD: unified term

• Stratified by serostatus– NMOSD with AQP4‐IgG– NMOSD without AQP4‐IgG (or testing unavailable)

• Allows for future revisions– Discovery and validation of other antibodies associated with NMOSD

clinical phenotype

NMOSD With AQP4‐IgG• Requirements

– At least 1 core clinical characteristic– Positive test for AQP4‐IgG– No better explanation

• Clinical and MRI red flags

• Core clinical characteristics– Optic neuritis– Acute myelitis– Area postrema syndrome, ie, otherwise unexplained nausea/vomiting and/or hiccups– Other brainstem syndrome– Symptomatic narcolepsy or acute diencephalic syndrome with MRI lesion(s)– Symptomatic cerebral syndrome with MRI lesion(s)


6

NMOSD Without AQP4‐Ig (or Unavailable)

• At least 2 core clinical characteristics all satisfying:– At least 1 must be ON, acute myelitis with LETM, or area postrema syndrome– Dissemination in space

• Isolated recurrent ON or recurrent TM do not qualify

– Additional MRI requirements • AP syndrome: dorsal medulla lesion

• Myelitis: LETM

• ON: normal brain MRI OR >1/2 ON OR chiasm lesion

– Negative test(s) for AQP4‐IgG using best available assay, or testing unavailable

• No better explanation for the clinical syndrome

ON = optic neuritis; LETM = longitudinal extensive transverse myelitis; AP = area postrema; TM = transverse myelitis.Wingerchuk DM, et al. Neurology. 2015;85:177‐189.

Spinal Cord and Optic Nerve Lesions


A. Sagittal T2W MRI of thoracic spinal cordB. Axial T2W MRI of central cordC. Axial T1W MRI with Gd of central cordD. Sagittal T2W MRI showing cervical LETM

extending into medullaE. Sagittal T1W MRI with Gd of cervical LETM

extending into medullaF. Sagittal T1W MRI of intralesional hypointensityG. Sagittal T2W MRI of spinal cord atrophyH. Axial MRI of atrophic spinal cordI. Fast spin echo fat‐suppressed T2W MRI in

axial planeJ. Fast spin echo fat‐suppressed T2W MRI in

coronal planeK. Axial T1W MRI with Gd shows enhancement of

optic chasm.

T2W = T2‐weighted; T1W = T1‐weighted; Gd = gadolinium.

7

Area Postrema Lesions


A. Sagittal T2W FLAIR MRI of lesion in dorsal medulla

B. Sagittal T2W MRI of acute lesion associated with APCS

C. Sagittal T1W MRI with Gd of acute lesion associated with APCS

D. Axial T2W FLAIR MRI of dorsal medulla involvement in patient with APCS

E. Axial T1W MRI with Gd of dorsal medulla involvement in patient with APCS

FLAIR = fluid‐attenuated inversion recovery; APCS = area postrema clinical syndrome.

Brainstem Lesions


Axial T2W FLAIR MRI of periependymal lesions involving

the pons

Axial T2W FLAIR MRI of periependymal lesions involving

dorsal midbrain

Sagittal T2W FLAIR MRI shows increased signal surrounding fourth

ventricle

8

Diencephalic Lesions


Axial T2W FLAIR MRI of lesions of right thalamus

Axial T2W FLAIR MRI of lesions of hypothalamus

Cerebral Lesions


A. Axial T2W FLAIR MRI of subcortical WML

B. Axial T1W MRI with Gdof subcortical WML

C. Sagittal T2W FLAIR MRI of corpus callosum lesions

D. Coronal T2W FLAIR MRI of cerebral peduncle and pons

E. Sagittal T2W FLAIR MRI of acute PCLs

F. Axial T2W FLAIR MRI of acute PCLs

G. Axial T1W MRI with Gdof acute PCLs

WML =‐white‐matter lesion; PCL = periependymal cerebral lesion.

9

“Red Flags” for NMOSD DiagnosisClinical/Laboratory

1. Clinical features and laboratory findings• Progressive overall clinical course : MS• Atypical time to attack nadir:

– less than 4 hours: cord infarction;

– Worsening over >4 weeks : sarcoidosis or neoplasm

• Partial transverse myelitis not associated with LETM MRI lesion: MS

• CSF oligoclonal bands: MS

2. Comorbidities associated with neurologic syndromes that mimic NMOSD

• Sarcoidosis (mediastinal adenopathy, fever and night sweats, elevated serum ACE or IL‐2 receptor)

• Cancer: consider lymphoma or paraneoplastic disease (eg, collapsin response mediator protein‐5 associated optic neuropathy and myelopathy or anti‐Ma‐associated diencephalic syndrome)

• Chronic infection: HIV, syphilis• *Myelin oligodendrocyte glycoprotein (MOG)‐

associated disease: predilection for rON, younger, male, consistently good recovery and resolution of MRI abnormalities


MS = multiple sclerosis; CSF = cerebrospinal fluid; ACE = angiotensin‐converting enzyme; IL = interleukin; HIV = human immunodeficiency virus.

“Red Flags” for NMOSD DiagnosisConventional Neuroimaging

1. Brain• Imaging features (T2‐weighted MRI) suggestive

of MS – perpendicular to lateral ventricles (Dawson

finger)– adjacent to temporal horns– juxtacortical lesions – cortical lesions– central vein sign

• Imaging characteristics suggestive of diseases other than MS and NMOSD– persistent (>3 mo) Gd enhancement

2. Spinal cord• Characteristics more suggestive of MS

than NMOSD–

10

What Is the Best AQP4‐IgG Assay?

• Sensitivity = 60–80%

• ELISA kit:– Potential for false positives

• Cell‐based assays appear most sensitive and specific.

• AQP4‐IgG seronegative cases– Check MOG‐IgG

Waters P et al, Neurology 2012ELISA = Enzyme‐linked immunosorbent assay. Waters PJ, et al. Neurology. 2012;78:665‐671.

NMO = neuromyelitis optica; BSD = brainstem demyelination; DS = diencephalic syndrome; OSD = optic neuritis with short segment demyelination; TM = transverse myelitis.

Conclusion: Application of the 2015 criteria led to a rise in diagnosis of NMOSD by 76%. The rise in the AQP4 IgG‐positive group contributed 62% and the seronegative group contributed 14%.

2006 NMO criteria176 All patients

63 NMO (ON +LETM)

113Unclassified

42AQP4 IgG+

21AQP4 IgG–

• AQP4 IgG+ TM (n = 35)• AQP4 IgG+ ON (n = 3)• AQP4 IgG+ DS (n = 1)• OSD (n = 17) • TM (n = 26)• ON (n = 13)• BSD (n = 2)• Cerebral demyelination (n = 1)• Other combination of clinical events (n = 15)

2015 International Panel for NMO Diagnosis (IPND) criteria

176 All patients

65Unclassified

111NMOSD

30AQP4 IgG–

81AQP4 IgG+

42 (2006 criteria, ON +LETM)

39 (new)TM 35ON 3DS 1

21(2006 criteria, ON +LETM)

9 (new)TM + BSDON + BSDDS + TM

• OSD (n = 17)• TM (n = 26 )• ON (n = 13)• BSD (n = 2)• Cerebral demyelination (n = 1)

• Combination of clinical events (n = 6)

NMOSD Criteria and Diagnostic Rates

Hamid SH, et al. Mult Scler. 2017;23:228‐233.

11

Pediatric Diagnosis

Chitnis T, et al. Neurology. 2016;86:245‐252.

• IPND criteria 97% sensitive for consensus NMO diagnosis

• 2006 NMO criteria only 49% sensitive (most did not have ON + TM)

IPND Criteria Benefits

• Increased sensitivity

• Increased specificity versus MS

• Earlier confirmed diagnosis– AQP4‐IgG seropositive diagnosis with 1 attack

• Earlier initiation of treatment

• Clinical trials

• Epidemiologic studies


12

Clinical Pearls: NMOSD Diagnosis

• No single clinical manifestation establishes the diagnosis.

• Beware of making the diagnosis exclusively based on serology– Need compatible symptoms/MRI findings

• Beware of false positive AQP4‐IgG– Especially low‐titer ELISA assay and clinical course is atypical– Confirm with cell‐based assay

• NMOSD vs MS: when in doubt, treat as NMOSD

NMOSD Worldwide Prevalence(per 100,000 population)

Mori M, et al. J Neurol Neurosurg Psychiatry. 2018;89:555‐556.

*2006 NMO diagnos c criteria, †IPND 2015 diagnos c criteria

13

NMO Epidemiology

• Incidence:>1–4 per million/year• Prevalence: 2.0–4.4 per 105• Asia, Latin America, Africa—relatively greater proportion of CNSDD is NMO• >3% familial• 90% female• Median onset at age 40 years• 90% relapse• More severe than MS but has highly variable course

Pandit L, et al. Mult Scler. 2015;21:845‐853.

CNSDD = central nervous system demyelinating disorders.

NMOSD with AQP4‐IgG: Disease Mechanisms

14

Pathophysiology of NMOSD

Plasma exchange

TocilizumabSatralizumab

Complement inhibitors

CetirizineSivelestat

AquaporumabDeglycosylation of AQP4‐IgG

Small molecule competitive inhibitors

Modified from Weinshenker BG, Wingerchuk DM. Mayo Clin Proc 2017;92:663‐679.

APC = antigen‐presenting cell; IL‐6R = interleukin 6 receptor; M1, M23 = dominant isoforms of AQP4; mAb = monoclonal antibody; EAAT2 = excitatory amino acid transporter 2; MHC‐1 = major histocompatibility complex 1 protein; TcR = T‐cell receptor.

Tolerance induction Immunosuppression B‐cell mAb: Anti‐CD20, CD19

Anti‐AQP4 NMOSD: An Astrocytopathy

1. Fujihara K, et al. Clin Exp Neuroimmunol. 2012;3:58‐73. 2. Hinson SR, et al. Neurology. 2007;69:2221‐2231. 3. Misu T, et al. Brain. 2007;130:1224‐1234. 4. Misu T, et al. J Neurol Neurosurg Psychiatry. 2009;80:575‐577.

Activ

e C’

Inactiv

e C’

Activ

e C’

Inactiv

e C’

Activ

e C’

Inactiv

e C’

Control NMOMerge GFP‐AQP4

C9neo

NMO serum

Control serum

Merge GFP‐AQP4

C9neo IgG1

IgG3

IgG2

IgG4

Membranolytic attack complex of complement Is assembled after IgG binds to surface AQP4.2

NMOrel

ng/m

L

NMOrem

MS ADEM SI OND

CSF GFAP4100,000

10,000

1000

100

10

1

0.1

C’ = complement.

Loss of AQP4 and glial fibrillary acidic protein (GFAP)

and relatively preserved myelin basic protein3 ADEM = acute disseminated encephalomyelitis; SI

= spinal cord infarction; OND = other neurological disease.

1

15

Mechanisms of Astrocyte Injury

Bennett J L, Owens GP. J Neuroophthalmol. 2017;37:291‐299/

CDC = complement‐dependent cytotoxicity; AP = alternate pathway; CP = classical pathway; MAC = membrane attack complex; NK natural killer.

Current and Emerging Management Options for NMOSD

16

Therapeutic Strategies: Attack PreventionExpected impact on natural history• Low risk of secondary progressive NMO• Attack prevention key to maintaining function


Actuarial survival

Years

NMO

0 10 20 30 40 50

1.00

0.80

0.60

0.40

0.00

0.20

Actuarial survival analysis for endpoint of conversion to secondary progressive clinical course

MS

Therapeutic Strategies: Attack Prevention(continued 1)

• Some MS disease‐modifying therapies are ineffective.

• IFN‐beta likely aggravates NMOSD.– Increased B‐cell activating factor?

• NMO worsening reported with:– Natalizumab– Fingolimod– Alemtuzumab

Weinshenker BG, Wingerchuk DM. Mayo Clin Proc. 2017;92:663‐679. Wingerchuk DM, et al. Neurology. 2015;85:177‐189.

IFN = interferon.

17

Therapeutic Strategies: Attack Prevention(continued 2)

• Unapproved therapies based on observational evidence– Rituximab– Mycophenolate mofetil– Azathioprine– Corticosteroids

• Approved therapy (as of June 2019): eculizumab

• Under regulatory review– Inebilizumab– Satralizumab

“Flash News”

• 4 phase 3 clinical trials of 3 agents are now completed.– Eculizumab– Inebilizumab– Satralizumab

• First drug FDA‐approved for prevention of NMOSD attacks in AQP4‐IgG seropositivepatients– Eculizumab (June 2019)

18

Summary of Phase 3 Clinical Trials

• All are placebo‐controlled.

• Outcome in all is time to first attack, expressed as reduction in relapse frequency.

• The studies VARY in:– Enrollment criteria– Whether or not AQP4‐IgG seronegative patients were admitted– Allowance for continuing background immunosuppression– Definition of attack (operationally)– Duration of the randomized, controlled phase

Summary of Key FindingsPREVENT1Eculizumab

Anti-C5

N-MOmentum2Inebilizumab

Anti-CD19

SAkura Sky3Satralizumab

Anti-IL6R

SAkura Star4Satralizumab

Anti-IL6RSubjects (n) AQP4+ only

143AQP4+/-

(212+18)=230AQP4+/-

(55+28)=83AQP4+/-

(64+31)=95Placebo Arm Background IST

allowedPlacebo only Background IST

allowedPlacebo only

Relapsereduction

94.2% 73% overallAQP4+: 77.3%

62% overallAQP4+: 79%

AQP4-: 34% (NS)

55% overallAQP4+: 74%

AQP4-: 34% (NS)

Relapse-free28 weeks

NR AQP4+ 87.6% (56.6% PBO)

AQP4-NR

NR NR

Relapse-free48 wks

97.9%(63.2% PBO)

NR AQP4+ 91.5% (59.9% PBO)

AQP4-84.4% (75.5% PBO)

AQP4+ 82.9% (55.4% PBO)

AQP4-63.3% (77.8% PBO)

Relapse-free96 wks

96.4%

(51.9% PBO)

NR AQP4+ 91.5% (53.3% PBO)

AQP4-56.3% (67.1% PBO)

AQP4+ 76.5% (41.1% PBO)

AQP4-63.3% (77.8% PBO)

Disability NS OR=0.371P=0.007

NR NR

Safety No major/unexpected

No major/unexpected

No major/unexpected

No major/unexpected

1. Pittock SJ, et al. N Engl J Med. 2019;381:614‐625 (plus supplement). 2. Cree BAC, et al. Lancet. 2019;394:1352‐1363. 3. Yamamura T, et al. N Engl J Med. 2019;381:2114‐2124. 4. Traboulsee A, et al. Lancet Neurol. 2020;19:402‐412.

19

What’s Next: Future NMO Therapeutic Strategies

• Complement inhibition—anti‐C5—eculizumab• Cytokine‐targeted therapy—anti‐IL6R—satralizumab• B cell depletion/modulation—anti‐CD19—inebilizumab• Other B cell‐related targets• T cell strategies, including tolerization• Immunoablation/stem‐cell therapy• Sivelestat (neutrophil protease inhibitor)• Antibody removal• Anti‐glutamate therapy• Inhibition/blocking of AQP4‐IgG binding

Summary

• NMOSD diagnostic criteria are sensitive and useful in practice and research.

• NMOSD with AQP4‐IgG is an autoimmune channelopathy/astrocytopathy.

• Eculizumab, a complement‐inhibiting monoclonal antibody, is the first approved therapy for NMOSD with AQP4‐IgG.

• Inebilizumab (B cell depletion) and satralizumab (IL‐6R blocker) also show strong efficacy for relapse prevention in NMOSD with AQP4‐IgG.

20

Case Example

• A 44‐year‐old woman presents with 5 days of mid‐thoracic pain and progressive difficulty walking.

• She reports being healthy, but 2 years ago she had a 9‐day episode of persistent vomiting and hiccups with a negative GI evaluation.

• Exam shows:– Moderate paraparesis with bilateral extensor plantar responses– Impaired vibratory and joint position sense at great toes– Sensory level at T11– Abnormal gait—wide based, slow, cannot walk with tandem gait

GI = gastrointestinal.

• MRI spine with contrast • Her serum AQP4‐IgG is positive (1:1000)

Case Example: Testing

21

Selected Questions About Pathogenesis

• How are lesions initiated?

• What influences the distribution of CNS lesions?

• Why are extra‐CNS organs that express AQP4 often not affected?

Lesion Initiation

1. Binding of GRP78 autoantibodies to cell surface GRP78 2. Induction of nuclear factor (NF)‐κB nuclear translocation 3. Enhancement of macromolecular permeability and

penetration of AQP4 antibodies into the brain 4. Binding of AQP4 antibodies to AQP4 on astrocytes 5. Production of IL‐6 by astrocytes.6. Activation of IL‐6 signaling in endothelial cells and further

induction of blood‐brain barrier breakdown.

Vessel diameter (µ

M)

Control‐IgG ON‐12‐2‐46

100

80

60

P

22

Aquaporin‐4 Structure

• AQP4 is expressed in two isoforms: – M1

– M23

• M23‐AQP4 tetramers and M1‐AQP4 tetramers can form mixed arrays on the cell surface.

Badaut J, et al. J Cereb Blood Flow Metab. 2002;22:367‐378. Matiello M, et al. JAMA Neurol. 2013;70:1118‐1125.

Extracellular

Intracellular

H2O

H2O

H2NHOOC

P

P

AN

NA

Aquaporin‐4 mRNA and Protein ExpressionHighest in Optic Nerve and Spinal Cord

Matiello M, et al. JAMA Neurol. 2013;70:1118‐1125.

M1M23

Relativ

e AQ

P4:HPR

T mRN

A expressio

n (SYB

R‐Green)

Liver Kidney Brain—frontal lobe

Brainstem Spinal cord Optic nerve

0.045

0.040

0.035

0.030

0.035

0.020

0.015

0.010

0.005

0.000

HPRT = hypoxanthine guanine phosphoribosyl transferase (reference gene); mRNA = messenger ribonucleic acid.

23

Expression of AQP4 and RCAs in Human TissuesTissue AQP4 CD46 CD55 CD59 AQP4-RCA coexpressionNormal brain Astrocyte end-feet Endothelium GFAP– cell processes Endothelium NoNMO brain lesion No No No No —NMO brain perilesion Astrocyte end-feet

Reactive astrocytesEndothelium GFAP– cell processes Endothelium No

Normal kidney Distal tubulesCollecting ducts

Widely expressed Widely expressed Endothelium AQP4 with CD46AQP4 with CD55

Normal skeletal muscle Sarcolemma Sarcolemma No Endothelium AQP4 with CD46Normal stomach Gastric gland cells Gastric gland cells No Endothelium AQP4 with CD46

Complement Regulatory Proteins in NMOSD

Saadoun S, Papadopoulos MC. Mult Scler. 2015;21:1644‐1654.

Complement regulatory proteins appear to protect peripheral but not CNS tissue from complement‐mediated injury.

RCA = regulator of complement activation.

AQP4 and RCAs in Normal Peripheral Organs

Thank you!

Toolkit

Additional Reading

1. Bennett J, et al. Neuromyelitis optica: Deciphering a complex immune‐mediated astrocytopathy. J Neuroophthalmol. 2017;37:291–9.

2. Chang V, et al. Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder. Neuropathol Appl Neurobiol. 2019. [Epub ahead of print]

3. Chitnis T, et al. Clinical features of neuromyelitis optica in children: US Network of Pediatric MS Centers report. Neurology. 2016;86:245‐52.

4. Collongues N, et al. Pharmacotherapy for neuromyelitis optica spectrum disorders: Current management and future options. Drugs. 2019;79:125‐42.

5. Cree B, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N‐MOmentum): a double‐blind, randomised placebo‐controlled phase 2/3 trial. Lancet. 2019;394:1352‐63.

6. Huda S, et al. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19:169‐76. 7. Hyun J, et al. Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder. Neurology.

2016;86:1772‐9. 8. Mori M, et al. Worldwide prevalence of neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry.

2018;89:555‐6. 9. Pittock S, et al. Eculizumab in aquaporin‐4–positive neuromyelitis optica spectrum disorder. N Engl J Med.

2019;381:614‐25. Pittock S, et al. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin‐4 channelopathies: a decade later. Ann N Y Acad Sci. 2016;1366:20‐39.

10. Saadoun S, et al. Role of membrane complement regulators in neuromyelitis optica. Mult Scler. 2015;21:1644‐54.

11. Waters P, et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin‐4‐IgG assays. Neurology. 2012;78:665‐71.

12. Weinshenker B, et al. Neuromyelitis spectrum disorders. Mayo Clin Proc. 2017;92:663‐79. 13. Wingerchuk D, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.

Neurology. 2015;85:177‐89. 14. Wingerchuk D, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6:805‐15. 15. Yamamura T, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med.

2019;381:2114‐24. Neurology/Neuromyelitis optica Associations and Foundations

American Academy of Neurology https://www.aan.com/

National Institutes of Health https://www.ninds.nih.gov/Disorders/All‐Disorders/Neuromyelitis‐Optica‐Information‐Page

National Multiple Sclerosis Society https://www.nationalmssociety.org/What‐is‐MS/Related‐Conditions/Neuromyelitis‐Optica‐(NMO)

National Organization for Rare Disorders https://rarediseases.org/rare‐diseases/neuromyelitis‐optica/

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The Role of Neurologists and Neuro-ophthalmologists in the Diagnosis and Management of

NEUROMYELITIS OPTICA SPECTRUM DISORDER

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