NEUROMYELITIS OPTICA SPECTRUM DISORDERSDR. SUMIT KAMBLESENIOR RESIDENT NEUROLOGYGMC, KOTA

MODERATORDR. BHARAT BHUSHANASS. PROFESSOR NEUROLOGY

INTRODUCTION

• Neuromyelitis optica (NMO, Devic disease) and neuromyelitis optica spectrum disorders (NMOSD) are inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord.

• First clinical descriptions of NMO given century ago in 1894 by Devic and Gault

• Previously it was believed that NMO and multiple sclerosis represented one disease entity, with variable phenotypes and expression.

• NMO is distinct from classic relapsing-remitting multiple sclerosis with respect to pathogenesis, imaging features, biomarkers, neuropathology, and response to treatment.

EPIDEMIOLOGY• Prevalence - 0.5 to 10 per 100,000

• Female: male ratio - 10:1 • In monophasic NMO (1 to 10 percent of patients) men and

women are affected equally.

• Median age of onset is 32 to 41 years• Influence of pregnancies - increase in relapse rate in the first 3

months post partum.• Familial NMO has been reported in 3%

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India• Prevalence - 2.6/100,000• NMO Spectrum disorders constitute approximately 20% of all

demyelinating disorders• Mean age at onset - 32.6 to 45.7 years• Median time to first relapse – 8 to 12 months

Ann Indian Acad Neurol 2015;18

ETIOPATHOGENESIS• No specific environmental agent has been associated with

NMOS. • Third of attacks in NMOSD are preceded by fever or

vaccination.

• Genetic susceptibility studies have shown that HLA-DRB1*03 may be associated with NMOS in Indian population.

PATHOGENESIS

Pathological and immunopathological findings in NMO

Jacob A, et al. J Neurol Neurosurg Psychiatry 2013

CLINICAL FEATURES• Hallmark features of NMO include acute attacks of bilateral or

rapidly sequential optic neuritis (leading to severe visual loss) or longitudinally extensive transverse myelitis defined as longitudinal cord lesions extending >three vertebral segments with a typically relapsing course.

• Most often the first attack is monosymptomatic.• Concomitant appearance of both OPN and TM is seen in 15-

40% of cases.

Optic neuritis- • While the majority of optic neuritis attacks in NMO are

unilateral, sequential optic neuritis in rapid succession or bilateral simultaneous optic neuritis is highly suggestive of NMO

• Severe visual impairment, bilateral simultaneous or sequential OPN in rapid succession is suggestive of NMOSD rather than MS.

Transverse myelitis- • Typically have a longer extent of spinal cord demyelination

than patients with multiple sclerosis, often involving three or more vertebral segments on MRI

• Minority of patients with NMO or NMOSD present with a shorter extent of spinal cord involvement

Brainstem syndromes• Medullary involvement in particular area postrema - clinical

syndrome of nausea and vomiting or hiccups, sometimes intractable, with associated medullary lesions on MRI occurs with an incidence of 16 - 43 %.

• Occulomotor dysfunction, deafness, facial palsy, vertigo, trigeminal neuralgia

• May lead to acute neurogenic respiratory failure and death.• More common in anti AQP4 IgG positive patients and

particularly among non Caucasians.

NMO spectrum disorders• Limited or partial forms of NMO:1. Single or recurrent episodes of myelitis, usually but not

always involving longitudinally extensive spinal cord lesions 2. Single or recurrent unilateral or simultaneous bilateral optic

neuritis3. Optic neuritis or transverse myelitis in isolation

• Asian optic-spinal multiple sclerosis

• Optic neuritis or longitudinally extensive spinal cord lesions associated with systemic autoimmune disease

• Optic neuritis or myelitis associated with distinct brain MRI lesions typical of NMO (ie, with hypothalamic, corpus callosal, periventricular, or periependymal brainstem lesions on T2 images)

Other manifestations — • encephalopathy, myeloradiculopathy• fulminant cerebral demyelination, • posterior reversible leukoencephalopathy • hypothalamic lesions - symptomatic narcolepsy or excessive

daytime sleepiness, and various autonomic manifestations such as hypotension, bradycardia, and hypothermia .

• Skeletal and smooth muscle involvement in the form of muscle edema and myocarditis

• In rare cases, fulminant diffuse vasogenic edema can lead to brain herniation and death

Non-neurological manifestations of NMO

• Placentitis with risk of abortion, internal otitis and gastritis

• 30-40% of patients with NMOSD have coexisting autoimmune disorders such as Sjögren’s syndrome, systemic lupus erythematosus, autoimmune thyroid disease, myasthenia gravis, autoimmune-mediated vitamin B12 deficiency, autoimmune encephalitis.

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Pediatric NMOSD• Female preponderance is lower (3:1 female: male ratio

compared with up to 9:1 for adults),• Greater proportion of children may have monophasic disease

• Detection of LETM MRI lesion may be less specific for NMOSD.

• Approximately 15% of children with MS may have LETM during relapse.

Monophasic NMOSD• Approximately 5%–10% cases are monophasic• associated with a more equitable sex distribution, relatively

younger age at disease onset, tendency to present with simultaneous myelitis and bilateral optic neuritis, lower frequency of other autoimmune diseases, and lower prevalence of serum AQP4-IgG compared to relapsing NMO.

• Fraction of these patients may have other serum antibodies such as MOG-IgG.

• At least 5 years of relapse-free after the index events is required

Disease patterns• Has a relapsing course in > 90%• Relapse occurs within first year in 60 percent of patients and

within three years in 90 percent• Unlike multiple sclerosis, a secondary progressive phase of the

disease is rare. • Patients with cerebral presentations may have continued brain

attacks without involvement of optic nerves or spinal cord.

• Severe residual deficits follow initial and subsequent attacks, leading to rapid development of disability due to blindness and paraplegia within five years 

• Mortality rates - improved from 30% at 5 years to 9% at 6 years

DIAGNOSTIC CRITERIA• Original criteria proposed by Wingerchuk et al., in 1996 was

revised in 2006 after the discovery of anti AQP4-IgG.

Absolute Criteria• Transverse myelitis and optic neuritis Supportive Criteria• At least two of the following features:

1. MRI brain negative/nondiagnostic for MS 2. MRI spinal cord lesion extending over ≥3 vertebral segments (LETM) 3. NMO-IgG seropositivity

REVISED DIAGNOSTIC CRITERIA FOR NMOSD WITH AQP4-IGG

Requirements

1. At least 1 core clinical characteristic

2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended)

3. Exclusion of alternative diagnoses

Core Clinical Characteristics

1. Optic neuritis2. Acute myelitis3. Area postrema syndrome:

episode of otherwise unexplained hiccups or nausea and vomiting

4. Acute brainstem syndrome5. Symptomatic narcolepsy or acute

diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions

6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions

Neurology 2015;85:177–189

Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status

• 1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:a) At least 1 core clinical characteristic must be optic neuritis, acute

myelitis with LETM, or area postrema syndromeb) Dissemination in space (2 or more different core clinical

characteristics)c) Fulfillment of additional MRI requirements, as applicable

• 2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable

• 3. Exclusion of alternative diagnoses

Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status

• 1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium enhancing lesion extending over .1/2 optic nerve length or involving optic chiasm

• 2. Acute myelitis: requires associated intramedullary MRI lesion extending over >3 contiguous segments (LETM) OR >3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis

• 3. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions

• 4. Acute brainstem syndrome: requires associated periependymal brainstem lesions

Red flags: Findings atypical for NMOSD

1. Clinical course/lab more typical of MS or other pathology a) Progressive course b) Rapid nadir (infarction) c) Continual worsening more than 4 weeks from onset d) Partial TM without LETM e) CSF oligoclonal bands

2. Comorbidity, established or suspected, that mimics NMOSD f) Sarcoidosis g) Cancer (lymphoma or CRMP-5 associated ON/myelopathy) h) Infection with potential neurologic involvement (e.g., HIV,

syphilis)

3. Red flags (conventional neuroimaging)1. Brain• a. Imaging features (T2-weighted

MRI) suggestive of MS (MS-typical)I. Lesions with orientation

perpendicular to a lateral ventricular surface (Dawson fingers)

II. Lesions adjacent to lateral ventricle in the inferior temporal lobe

III. Juxtacortical lesions involving subcortical U-fibers

IV. Cortical lesions

• b. Imaging characteristics suggestive of diseases other than MS and NMOSD

• Lesions with persistent (>3 mo) gadolinium enhancement

2. Spinal cord• Characteristics more suggestive of

MS than NMOSDI. Lesions < 3 complete vertebral

segments on sagittal T2-weighted sequences

II. Lesions located predominantly (>70%) in the peripheral cord on axial T2-weighted sequences

III. Diffuse, indistinct signal change on T2-weighted sequences (as sometimes seen with longstanding or progressive MS)

INVESTIGATIONS

NMO-IgG (AQP4 -antibody) • High specificity (91-100%) and varying sensitivity (83-91%)

with cell-based assays being the most optimal.• Immunosuppressive therapy dramatically reduces serum levels

of anti AQP4-IgG and hence testing has to be done prior to therapy.

• Anti AQP4-IgG positive patients- relapsing disease, female, have a strong association with other connective tissue disorders and have more severe clinical attacks.

• Seronegative - monophasic course and affect males equally as females.

Seropositive versus seronegative: More likely to be/have:• Woman • Systemic autoimmune

disease • Unilateral ON • ON OR myelitis • Relapses

Anti-myelin associated oligoglycoprotein (anti- MOG) - • anti AQP4-IgG negative disorders may be positive for anti-

myelin associated oligoglycoprotein (anti- MOG).

• Women = men, monophasic course.• OPN and particularly simultaneous and recurrent OPN more

common. • Myelitis involves caudal portions of the cord • Coexisting systemic autoimmunity is less common • More benign course

Other laboratory tests• CBC, ESR, vitamin B12 • Antibodies associated with connective disorders (ANA/ENA,

anti-ds-DNA antibodies, lupus anticoagulant, antiphospholipid antibodies, ANCA, etc.

• Treponema pallidum hemagglutination assay,• Paraneoplastic antibodies (in particular, anti-CV2/CRMP5 and

anti-Hu).

Cerebrospinal fluid (CSF) analysis

• Moderate pleocytosis (mostly lymphomonocytic) - more prominent than in MS, but less than in infectious myelitis.

• Cell counts are normal - 40 %• OCBs - positive in approximately 30 % of cases• Interleukin-6 (IL-6) and of the soluble IL-6 receptor (sIL-6R) -

higher in the CSF of NMO patients than of MS patients

NEUROIMAGINGSpinal cord MRI• LETM lesion associated with acute TMIncreased signal on sagittal T2-weighted extending over 3 or more

complete vertebral segmentsCentral cord predominance (more than 70% of the lesion residing within

the central gray matter)Gadolinium enhancement of the lesion on T1-weighted sequences (no

specific distribution or pattern of enhancement is required)

• Other characteristic features that may be detectedRostral extension of the lesion into the brainstemCord expansion/swellingDecreased signal on T1-weighted sequences corresponding to region of

increased T2-weighted signal

Optic nerve MRI• Unilateral or bilateral increased T2 signal or T1 gadolinium

enhancement within optic nerve or optic chiasm • Relatively long lesions (e.g., those extending more than half the

distance from orbit to chiasm) and • Involving the posterior aspects of the optic nerves or the chiasm

MRI of the Brain• Lesions involving the dorsal medulla (especially the area

postrema), either small and localized, often bilateral, or contiguous with an upper cervical spinal cord lesion

• Periependymal surfaces of the fourth ventricle in brainstem/cerebellum

• Lesions involving the hypothalamus, thalamus, or periependymal surfaces of the third ventricle

• Large, confluent, unilateral, or bilateral subcortical or deep white matter lesions

• Long (1/2 of the length of the corpus callosum or greater), diffuse, heterogeneous, or edematous corpus callosum lesions

• Long corticospinal tract lesions, unilateral or bilateral, contiguously involving internal capsule and cerebral peduncle

• Extensive periependymal brain lesions, often with gadolinium enhancement

ACUTE AREA POSTREMA CLINICAL SYNDROME

DIENCEPHALIC MRI LESIONS

CEREBRAL MRI LESIONS

TREATMENTS

Treatment of acute exacerbation

1. Steroids- • Intravenous methylprednisolone 1g for 5 days followed by oral

prednisone (1 mg per kg body weight) for a month, and then a gradual tapering off over a 6–12 month period.

2. Plasma exchange –

• Relapses that do not respond to intravenous steroids could benefit from plasma exchanges (PLEX); typically 5–7 exchanges over a 2-week period.

• If the patient is known to have responded well to TPE during earlier attacks and the present attack is severe, TPE can also be considered as a first measure.

• Improvement - 44%–75% of the NMO patients treated with PLEX . • Male gender, preserved reflexes and early initiation of treatment are

associated with moderate or marked improvement.• Efficiency of plasma exchange is independent of NMO-IgG

seropositivity

3. intravenous immunoglobulins (IVIg) –• No report concerning therapeutic efficacy of intravenous

immunoglobulin (IVIG) for acute exacerbation of NMO.• In a retrospective review of 10 patients treated with intravenous

immunoglobulins (IVIg) for acute relapses because of lack of response to steroids with/without TPE, improvement was noted in about 50 % of patients

4. Cyclophosphamide

Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, Jacob A(2013) Mult Scler. doi:10.1177/1352458513495938

Prevention of relapses

• Principle of management - quickly achieve and maintain remission with corticosteroids, choose an immunosuppressant, establish it, and then start a gradual withdrawal of corticosteroids aiming to minimise its side effects.

• Since the biological effects of many corticosteroid-sparing agents take months to have an effect, corticosteroids may be needed in many patients at doses 0.5–1 mg/kg for up to 3 months after an attack, and then slowly tapered off over further 6–12 months.

DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY

Corticosteroids Bind to glucocorticoidreceptor,Induce gene expressionand modulatesimmune function

Acute attack:methylprednisolone1,000 mg, 3–5 days

Prophylaxis: prednisone   2.5–20 mg/d

Insomnia, moodchanges, weight gain,glaucoma,osteoporosis,diabetes,hypertension, growth impairment, insomnia

Reduced ARR from 1.48 to 0.49

EDSS was stable   

Azathioprine Acts as immunosuppressive antimetabolite by  interfering with proliferation of T and B lymphocytes and alterations in antibody production

 2 mg·kg−1·d−1 Bone marrow suppression, leukopenia, nausea, hepatotoxicity, diarrhea, hair loss, fatigue

Reduced ARR from  2.20–1.13 to0.40–0.60

EDSS was stable

DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY

Mycophenolate Reversible inhibitor of inosine monophosphatedehydrogenase that is involved in guanosine nucleotide synthesis

Proliferation of T and B lymphocytes is impaired by interruption of guanosine synthesis

2,000 mg/d, range 750–3,000 mg

Leukopenia, skin malignancy,lymphoma, PML,headache, hair loss,diarrhea, constipation,bruising, anxiety

Reduced ARR from 1.28  to 0.09

EDSS was stable

Methotrexate Inhibitor of dihydrofolate reductase and purine and thymidine synthesis

Inhibits proliferation of T and B lymphocytes

 17.5–50 mg/wk

Leukopenia,pancytopenia, infections,hepatotoxicity, jointpain, stomatitis, nausea, diarrhea

Reduced ARR from 1.39 to 0.18

EDSS was stable

DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY

Mitoxantrone Intercalates with DNAand inhibits topoisomerase II

Suppresses development of T and B lymphocytes and macrophages

max. cumulativedoses 120mg/m2

3–6 monthly cycles of 12 mg/m2 followed by 6–12 mg/m2 maintenance doses

Cardiotoxicity, leukemia, hepatotoxicity, leukopenia, nausea,stomatitis, diarrhea

Reduced ARR from   2.8 to 0.7

Reduced EDSS from5.6 to 4.4

Rituximab Chimeric anti-CD20monoclonal antibody

Depletes B cells frompre-B cells throughmemory lineages

Initiation with 375 mg/m2 weeklyfor 4 wk, 1,000 mg twice biweekly, maintenance(1,000 mg) either fixed or upon recurrence of B cells

Infusion reactions,infections, (e.g. recurrent herpes zoster, respiratory infections, urinary tract infects), fatigue, transient leukopenia and transaminase elevation, PML

Reduced ARR from   1.7–2.6 to 0.0–0.93

EDSS stabilized or improved

Common immunosuppressive medications used in NMO

EFNS guidelines

Recommendation for starting immunosuppressive treatment in spatially limited NMO spectrum disorders RION/BON and LETM

EMERGING NEUROMYELITIS OPTICA THERAPY

1. Eculizumab• Humanized monoclonal antibody against complement C5 that

inhibits its cleavage by C5 convertase. • In NMO, eculizumab blocks AQP4-IgG–mediated CDCC. • In an open-label phase II study of 14 NMO patients with

refractory disease, eculizumab therapy significantly reduced attack frequency and stabilized or improved neurological disability .

• After 12 months of treatment, 12 of 14 patients were relapse free; however, 1 patient developed meningococcal sepsis and sterile meningitis but fully recovered after treatment.

2. B Cell and Plasma Cell Targeted Therapies: Anti-CD19• CD19-depleting antibody may offer a promising avenue to

directly deplete AQP4-IgG-producing B cells and reduce pro-inflammatory lymphocyte populations in NMO.

3. Cytokine Modulation: Interleukin-6 and Interleukin-17• Tocilizumab is a monoclonal antibody that binds to the IL-6

receptor and blocks binding of IL-6 signaling.

4. Competitive Inhibitors of NMO IgG: Aquaporumab

5. Neutrophil and Eosinophil Inhibitors• Sivelestat, a potent neutrophil elastase inhibitor, reduces lesion

formation in both animal and ex vivo slice models of NMO • eosinophil stabilizers cetirizine and ketotifen

6. Antibody Modulation: Deglycosylation of NMO IgG and Fc Cleavage• Endoglycosidase S (EndoS) and IgG-degrading enzyme (IdeS)

from Streptococcus pyogenes are 2 distinct enzymes that may be used to modify endogenous AQP4 autoantibody pathogenicity.

Current and emerging therapeutic strategies for NMO

THANK YOU

REFERENCES

• International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Neurology 85 July 14, 2015

• Current concept of neuromyelitis optica (NMO)and NMO spectrum disorders Jacob A, et al. J Neurol Neurosurg Psychiatry 2013

• Update on the diagnosis and treatment of neuromyelitis optica:Recommendations of the Neuromyelitis Optica Study Group (NEMOS) J Neurol (2014) 261:1–16

• Neuromyelitis optica spectrum disorders: An update Annals of Indian Academy of Neurology, September 2015, Vol 18

• EFNS guidelines on diagnosis and management of neuromyelitis optica European Journal of Neurology 2010, 17: 1019–1032

• The Treatment of Neuromyelitis Optica J Neuroophthalmol. 2014 March

• Current and future treatment approaches for neuromyelitis optica Ther Adv Neurol Disord (2011) 4(2) 111121

• Therapy of NMO spectrum disorders an Indian Acad Neurol 2015

• Neuromyelitis optica spectrum disorders Uptodate.com