Neuromyelitis optica spectrum disorders

1. NEUROMYELITIS OPTICA
SPECTRUM DISORDERS
DR. SUMIT KAMBLE
SENIOR RESIDENT NEUROLOGY
GMC, KOTA
MODERATOR
DR. BHARAT BHUSHAN
ASS. PROFESSOR NEUROLOGY

2. 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.

3. • 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.

4. 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%
Neurology 2010;75:310–15

5. 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

6. 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.

7. PATHOGENESIS

8. Pathological and immunopathological findings in NMO
Jacob A, et al. J Neurol Neurosurg Psychiatry 2013

9. CLINICALFEATURES
• 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.

10. 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.

11. 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

12. 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.

13. 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
neuritis
3. Optic neuritis or transverse myelitis in isolation

14. • 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)

15. 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

16. 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.
Neurology 2015;85:177–189

17. 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.

18. 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

19. 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

20. 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

21. REVISED DIAGNOSTIC CRITERIAFOR NMOSDWITH
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 neuritis
2. Acute myelitis
3. Area postrema syndrome:
episode of otherwise
unexplained hiccups or nausea
and vomiting
4. Acute brainstem syndrome
5. 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

22. Diagnostic criteria forNMOSD withoutAQP4-IgG orNMOSD
with unknownAQP4-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 syndrome
b) 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

23. Additional MRI requirements forNMOSD withoutAQP4-IgG and
NMOSD with unknownAQP4-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

24. 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
a) Sarcoidosis
b) Cancer (lymphoma or CRMP-5 associated ON/myelopathy)
c) Infection with potential neurologic involvement (e.g., HIV,
syphilis)

25. 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 NMOSD
I. 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)

26. 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.

27. Seropositive versus
seronegative: More
likely to be/have:
• Woman
• Systemic autoimmune
disease
• Unilateral ON
• ON OR myelitis
• Relapses

28. 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

30. 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).

31. 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

32. NEUROIMAGING
Spinal cord MRI
• LETM lesion associated with acute TM
Increased signal on sagittal T2-weighted extending over 3 or more
complete vertebral segments
Central 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 detected
Rostral extension of the lesion into the brainstem
Cord expansion/swelling
Decreased signal on T1-weighted sequences corresponding to region
of increased T2-weighted signal

34. 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

36. 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

37. ACUTEAREAPOSTREMACLINICALSYNDROME

38. DIENCEPHALIC MRI LESIONS

39. CEREBRALMRI LESIONS

40. 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.

41. 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

42. 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

43. 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.

44. DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY
Corticosteroids Bind to
glucocorticoid
receptor,
Induce gene
expression
and modulates
immune function
Acute attack:
methylprednisolone
1,000 mg, 3–5 days
Prophylaxis:
prednisone
2.5–20 mg/d
Insomnia, mood
changes, 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
to
0.40–0.60
EDSS was
stable

45. DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY
Mycophenolate Reversible inhibitor of
inosine monophosphate
dehydrogenase 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, joint
pain, stomatitis, nausea,
diarrhea
Reduced
ARR from
1.39 to 0.18
EDSS was
stable

46. DRUG MECHANISM DOSE SIDE EFFERCTS EFFICACY
Mitoxantrone Intercalates with DNA
and inhibits
topoisomerase II
Suppresses development
of T and B lymphocytes
and macrophages
max. cumulative
doses 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 from
5.6 to 4.4
Rituximab Chimeric anti-CD20
monoclonal antibody
Depletes B cells from
pre-B cells through
memory lineages
Initiation with 375
mg/m2 weekly
for 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 elevati
on, PML
Reduced
ARR from
1.7–2.6 to
0.0–0.93
EDSS
stabilized or
improved

47. CommonimmunosuppressivemedicationsusedinNMO

48. EFNS guidelines

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

50. EMERGING NEUROMYELITIS OPTICATHERAPY
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.

51. 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

52. 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.

53. Current and emergingtherapeutic strategies forNMO

55. THANKYOU

56. 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

57. • 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