Dr. Shubham Garg discusses neuromyelitis optica (NMO), an autoimmune condition where antibodies attack aquaporin-4 in the central nervous system. NMO predominantly affects women and has a median age of onset of 32-41 years. Key clinical features include transverse myelitis, typically longitudinally extensive, and severe optic neuritis. Treatment involves high-dose steroids for acute attacks and immunosuppressants like azathioprine to reduce relapse rates. Prognosis is generally worse than multiple sclerosis due to risk of cumulative disability, though relapse rates can be lowered with appropriate treatment.

1. Dr . Shubham Garg
SR Neurology
GMC Kota

3.  Prevalence of NMO in various studies ranges from 0.5 to 10 per
100,000
 India 2.7/100,000
 Female: male – 9:1
 Median age of onset is 32 to 41 years,
 NMO is usually sporadic, though a few familial cases have been
reported.
 Other population studies of HLA in NMO indicate that the
DRB1*0301 and DRB1*1037 alleles are associated with increased
risk.

4. T effector cells
T follicular helper

5. Cardinal Clinical Features
 Transverse myelitis, typically longitudinally extensive (≥3 vertebral segments;
often followed by tonic spasms and occasionally accompanied by pain or pruritus)
 Optic neuritis (often severe; may be bilateral)
 Episodes of intractable nausea and vomiting or hiccups from area postrema
involvement
Other Clinical Features
 Narcolepsy
 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
 Other hypothalamic presentations (eg, anorexia)
 Acute myopathy with hyperCKemia
 Brainstem syndromes (eg, ophthalmoplegia, hearing loss [possibly related to inner
ear damage] opsoclonus/myoclonus)
 Myeloradiculitis
 Encephalopathy (PRES-like; ADEM-like)
 Cognitive dysfunction (subcortical pattern [inattention, executive dysfunction,
reduced speed of processing])

6. Long Y et al, Different Phenotypes at onset in NMOSD patients Front. Neurol. 8:62. 2017

7.  Optic neuritis:-
 Severe
 May not respond to steroids
 Trend for recurrence
 Progression beyond 2 weeks
 Bilateral simultaneous or sequential
 Usually retro bulbar
 Papillitis and peripapillary hemorrhage
EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J
Neurol 2015; 17:1019.

8.  Transverse myelitis:-
 Symmetric/Asymmetric paraparesis or quadriparesis, bladder
dysfunction, and sensory loss below the level of the spinal cord
lesion.
 Accompanying symptoms may include paroxysmal tonic spams of
the trunk or extremities, radicular pain, or Lhermitte sign.
 Typically have a longer extent of spinal cord demyelination often
involving three or more vertebral segments , a condition termed
longitudinally extensive transverse myelitis (LETM)

9.  50 to 60% of NMOSD patient has brain involvement.
 40% brain lesions are symptomatic .
 15-20% brain lesions are present during first clinical attack.
 Common sites involved are:-
1. Medulla(34%)
2. Supratentorial (29%) and infratentorial white matter (23%)
3. Midbrain (21%)
4. Cerebellum(18%)
5. Thalamus (13%) and hypothalamus (5%).

10.  Common manifestations:-
1. Encephalopathy,
2. Seizures
3. Hemiparesis
4. Aphasia
5. Vomiting, or hiccups
 Extensive hemispheric lesions over white matter, basal ganglia, and
corpus callosum manifesting as limbic encephalitis, parkinsonism,
and coma respectively.

11.  Brainstem is rich in AQP4 ag.
 Involvement of the brainstem occurs in almost one-third of patients
 Common in AQP4 Ig G Ab positive patients.
 Mc brainstem symptoms :- vomiting and hiccups.
 Due to area postrema involvement.(10% as presenting symptom)
 Only Small percentage of NMOSD patients with this symptoms
have lesion in area postrema on conventional imaging.

12.  Sudden-onset dystonic posturing either uni- or bilaterally with
a stereotyped pattern
 Brief, lasting less than 2 min, several times/hour
 Incidence higher in the patients with NMO (10 patients
[25.0%]) than in those with multiple sclerosis (1 patient
[2.9%].
 Painful tonic spasm associated with myelitis had a specificity
of 98.7% for identifying the NMO group
Ostermann PO, Westerberg CE.Brain.1975;98(2):189-202.

14.  The dorsal root ganglion has a specific subpopulations of
neurons, which express gastrin-releasing protein (GRP), that
act to mediate pruritus.
 The gastrin-releasing protein receptor (GRPR)-bearing
neurons in the Lamina 1 of the dorsal horn seem highly
specific for the transmission of itch.
 Very rarely present as first symptom of relapse in NMO and
precedes the development of myelopathy by several days.
 Predict impending relapse of myelopathy
Elsone et al. Mult Scler. 2013 Apr;19(4):475-9
Ramasamy B et al Pruritus: Is it a predictor of relapse in neuromyelitisoptica spectrum disorder?.Neurol India 2014 ;62:333-4

17.  Previous LETM
 Preceding nausea, vomiting, hiccups, endocrine disturbance
 H/O Optic neuritis
 H/O Autoimmune diseases
 Poor recovery
 Other causes are unlikely/ruled out- inflammatory diseases,
infection, neoplastic, metabolic, vascular, post radiation
Kitley JL et al Mult Scler 2011

18.  Monophasic -10-20%
 Relapsing – 80-90%
 Cumulative disability is more severe than MS
 Secondary progressive disease course is uncommon
 Relapse occurs within first year in 60 percent of patients and
within three years in 90 percent
Wingerchuk et al. Neurology 2017; 68: 603–605.

22. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Neurology® 2015;85:177–189

23. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Neurology® 2015;85:177–189

24. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Neurology® 2015;85:177–189

25.  Cerebrospinal fluid (CSF) analysis:-
 CSF pleocytosis mainly neutrophils.
 CSF cell count is greater than 50 cells/ll in 13–35% of patients and in a
few cases up to 1000 cells/ll .
 CSF pleocytosis :- LETM > ON
 Increased protein levels are present in 46–75% of cases
 Transient presence of OCB in NMO. (20%)
 Neurofilament heavy chain (NfH) and glial fibrillary acidic protein
(GFAP) levels are significantly higher in the CSF of NMO than in
patients with MS .

26.  Aquaporin 4 antibody:-
 Aquaporin-4 (AQP4) is a water channel protein
highly concentrated in:-
1. spinal cord gray matter
2. periaqueductal and periventricular regions
3. astrocytic foot processes at the blood-brain barrier.
 Serum testing is generally more sensitive than CSF
testing.
Jacob A, et al. J Neurol Neurosurg Psychiatry 2013;84:922–930.

27. Gadolinium-enhanced fat-saturated T1-
weighted images show enhancement of the
bilateral posterior optic nerves
Axial T2-weighted image shows chiasmatic
involvement

32.  Steroids:-
 Initial or recurrent episodes
are usually treated with high-
dose IV MPS
 Acute NMO symptoms
respond to short courses of
high-dose intravenous
corticosteroids in up to 80%
of patients within 1–5 days
 Median ARR reduced from
1.48 to 0.49
 Plasma exchange:-
 Effective in patients with
severe symptoms that fail to
improve or progress despite
treatment with corticosteroids.
 Plasma exchange can be done
up to five-seven times every
other day. (1–1.5 ltr plasma
volume per exchange)
 In case of unresponsiveness to
steroids, early initiation of a
rescue therapy with
plasmapheresis is indicated.

33. 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 months.

35. Medication ARR
Prednisolone 1.48 to 0.49
Azathioprine 2.1 to 0.6
Mycophenolate 1.3 to 0.09
Rituximab 2.5 to 0
Mitoxantrone 2.4 to 0.4

36.  Interferon beta
 Natalizumab
 Fingolimod
 Glatiramer acetate

37. DRUG
(trade name)
APPROVAL MECHANISM COST AVAILABLE
IN INDIA
AVAILABLE
as
Inebulizumab
(Uplizna)
12/6/2020 anti-CD19
humanized
monoclonal
antibody
Rs 35lac NO Single dose
vial(100mg/1
0ml)
Satralizumab
(Enspryng)
16/8/2020 anti-IL-6R
monoclonal
antibody
Rs 11lac NO Single dose
prefilled
syringe
(120mg/ml)
Eculizumab
(Soliris)
June 2019 humanized
monoclonal
antibody against
complement
protein C5
Rs
2,10,000/
vial
YES 300mg/30ml
vial

40.  Exacerbations are not substantially
increased during pregnancy.
 Increases in the postpartum period
and during the year following
childbirth.
 Azathioprine, mycophenolate and
methotrexate are pregnancy category
D or X and should not be continued
during pregnancy.
 Although rituximab and prednisone
are pregnancy class C, the absence
of an increase in ARR during
pregnancy makes continued therapy
during pregnancy questionable
 Median age of children presenting
with the disease is 10–14 years
 Children with NMO -more likely to
be seronegative and have more brain
involvement.
 Therapies for children are similar to
those used in adults
Kim et al. Neurology. 2016; 78:1264–1267 n=54 Tillema et al. J Child Neurol. 2015; 27:1437–1447

42.  ON 41-63%
 TM 30%
 ADEM-like varies based on age(common in pediatric age)
 Brainstem syndromes (incl. area postrema) up to 30%
 Many do not fulfill 2015 diagnostic criteria for NMOSD

43.  Monophasic or relapsing
 50% relapse in first two years after presentation
 75% relapse by five years
 Titers higher at time of relapse
 Up to 50% become antibody negative after relapse
 Persistent positivity indicates higher risk of relapse

44.  Outcomes better than NMO
 Severity of relapse may be the same but relapse outcome
better than NMO
 Severe persistent disability in 40-75%
 Sphincter>cognitive>visual>mobility
 Disability driven by severity of first attack (70%) and
frequency of attacks.
 Progression not described to date

45.  Common in pediatric age group
 ADEM symptoms: systemic (fever, headache, nausea,
vomiting, malaise, altered mental status) and more specific,
which vary based upon the locations of the lesions within the
CNS (vision impairment, ataxia, hemiparesis, hemisensory
loss)
 Anti-MOG antibodies present in 40–68% of children with
ADEM diagnosis.
 In adults with the positive anti-MOG test, ADEM
presentation is less frequent, varies from a few up to 18% of
cases.

46.  Most frequent clinical phenotype in older age patients
 Disc swelling common and may be severe
 Often bilateral
 Chronic Relapsing form
 Longitudinally extensive, anterior part on MRI
 Optic nerve head swelling
 Perineuritis common
 Good outcome
Ciotti, J. et al A. Clinical and laboratory features distinguishing MOG antibody disease from multiple sclerosis and AQP4 antibody-positive
neuromyelitis optica. Mult. Scler. Relat. Disord. 2020, 45, 102399.

47.  Isolated transverse myelitis (TM) as initial presentation of
MOGAD in about 20% patients, but a combination of TM and
ON occurred in 8 to 15%
 80% longitudinally extensive
 Multiple lesions including conus (75%)
 Urinary retention/incontinence and/or bowel and/or erectile
dysfunction developed at least once in almost 70% patients
with TM
 Often confined to grey matter
 Usually enhance acutely, but less commonly than NMO and
MS

49.  More brainstem and cerebellar than supratentorial lesions.
 Area postema seen in about 15% of the anti-MOG positive
patients
 Thalamic and cortical lesions common
 Less demarcated and more fuzzy compared to NMO and MS
 Cortical inflammation associated with the MOGAD manifests
mostly with epileptic seizures (20 times more common then
NMOSD)
Shen, C.H.; et alSeizure Occurrence in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Systematic Review and Meta-
Analysis. Mult. Scler. Relat. Disord. 2020, 42, 102057

50. POST TREATMENT
(1 MONTH LATER)

51.  5% of MS patients are MOG-IgG positive
 Mostly severe, relapsing brainstem and spinal syndromes
 Atypical lesion
 May show evolution in space and time on MRI
M Spadaro et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e257.

52.  Pleocytosis 40-50%
 Neutrophil predominance
 Elevated protein 33-40%
 OCB rare(<15%), Ig index usually normal
 MOG IgG in CSF in 70% of seropositive subjects

53. 1. Clinical findings: any of the following presentations:
• ADEM
• Optic neuritis, including CRION
• Transverse myelitis (LETM or SSTM)
• Brain or brainstem syndrome compatible with demyelination
• Any combination of the above
2. Serum positive for MOG-IgG by cell-based assay
3. Exclusion of alternative diagnosis

58. Characteristics MS NMO MOG
Antecedent
infection/
immuninization
Rare Rare common
Epidemiology Prevalence : common
Ethnicity: whites more
predisposed
Geographic regions:
farthest from equator
Rare
African-Americans,
Afro-Caribbeans
Near to equator
Unknown
Unknown
Unknown
Clinical onset and
course
85% remitting-
relapsing/
15% primary-
progressive
Not monophasic
Typically relapsing, no
secondary progression
Monophasic or
relapsing ,
No secondary
progression

59. Characteristics MS NMO MOG
Gender (M:F) 1:2 1:9 M<F
Functional
outcome
variable poor good
Age of onset 3rd decade 4th decade 1st to 3rd decade
Optic Nerve
MRI
Uninalteral,
enhancement of
<50% of nerve
affected, middle of
optic nerve
Bialteral, enhancement of
>50% of optic nerve,
posterior optic pathway
involving chiasma
Bilateral, enhancement of
>50% of optic nerve,
anterior optic pathway with
optic nerve head swelling
MRI: BRAIN Oviod
Periventricular,
Dawson fingers,
juxtacortical,
cortical,
infratentorial
peripheral, ring/
open ring
enhancement
Usually normal or non-
specific WM lesions; if
present , area prostrema,
perithird/ fourth ventricle,
splenium, diffuse corpus
callosum, pencil thin
ependymal or cloud
enhancement.
ADEM like fluffy WM,
deep GM,
diffuse/confluent
brainstem including
cerebellar peduncles.

60. MS NMO MOG
MRI:SPINE Short-segment
peripheral WM
lesions
LETM (≥3 vertebral
segments) central GM
lesion. 85% LETM
Distributed in the lower
parts of the spinal cord,
conus involved, central
cord involved, 75%LETM
CSF:CELLS Mild pleocytosis
Lymphocyte
predominant
Occasional prominent
pleocytosis
PMN cells and
mononuclear cell
Pleocytosis 40-50%
neutrophil predominant
CSF:OCBs 85% 15-30% Rare(10-15%)
AB Absent AQ-4 Present in 70-80% MOG +ve in 70%
Acute t/t
Maintenance t/t
Prognosis
IV/ steroid; plasma
exchange(rarely
required)
Immunomodulation
Majority
Ambulatory after
20 yrs; most
disability occurs in
2nd progressive
phase
IV/ steroid; plasma
exchange (often required)
Immunosupression
Attack-related
accumulationof disability;
IV/ steroid; plasma
exchange (often required);
IVIG in children
Immunosupression
Most disability after 1st
attack; transient
seropositivity predicts
monophasic course;
persistent seropositivity
and high titre predict
relapsing disease

62. THANK YOU

63. Ramanathan S, et al, Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for
demylination,2015

64. Ramanathan S, et al, Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for
demylination,2015

65. 1. NMOSD
2. MS
3. CTD- SLE, Sjogren, Behcet
4. Sarcoidosis
5. Infections: TB, EBV, WNV, Mycoplasma
6. Nutritional – B12, Cu
7. Spinal cord infarction
8. Paraneoplastic
9. ADEM
10. Primary CNS angitis
11. Idiopathic – most common cause

67. FEATURE NMO MS
1. Involves White and gray matter Predominant white matter
2. Edema Striking Less
3. Necrosis + Not striking
4. Cavitations + -
5. Myelin Relatively preserved Severe demyelination
6. Axon damage + +
7. Leukocyte infiltrates Neutro/eosinophils T and B lymphocytes
8. Aquaporin 4 Loss Upregulation
9. GFAP Loss Upregulation
10. Complement deposits + Less marked
11. Vascularity + uncommon

68. FEATURE NMO MS
1. Demographics Mixed race Whites
2. Age at onset 40yr 30yr
3. Gender Female in AQP4+
Equal in sero-
Female
4. Clinical phenotype
• Relapse
• Recovery
• Progression
Severe
Poor
-
Mild
Generally good
+
5. Optic neuritis
• Simultaneous B/L
• Altitudinal defect
• RNFL thinness
Upto 20% cases
+
Widespread and more
thin
Rare
-
Temporal and less thin
6. Transverse myelitis LETM, centally located Small segment,
peripheral
7. Devic type presentation 4-6% in AQP4+
24-32% in sero-
Atypical
8. Intractable
nausea/vomiting/hiccough
and SIADH
Well described Atypical

69. FEATURE NMO MS
9. Autoimmune disorders 20-30% Rare
10. Autoimmune
antibodies
40-50% Rare
11. CSF cells ≥50 <50
12. DLC Neutrophillic/eosinophillic Lymphocytic
13. OCB 10-25% 95% in RRMS
14. GFAP Raised -

72.  Rapid and non invasive technique for imaging
unmyelinated CNS axons within the retina (the so-
called retinal nerve fiber layer, RNFL).
 A single acute attack of ON causes more severe
damage to the RNFL in NMO than in MS, reflecting
the poorer visual outcome in NMO-associated ON.
Ratchford et al. Neurology 2009;73:302–308

73. ASSAY SENSITIVITY SPECIFICITY
1. Indirect immunofluorescence 48.3 100
2. Cell based assay 73.3 100
3. ELISA 60.0 100
4. Fluorescence activated cell sorting 76.7 100
5. Fluorescence immunoprecipitation assay -
Oxford
53.3 100
6. Fluorescence immunoprecipitation assay -
Mayo
53.3 97.7
Waters et al. Neurology 2012;78:665-671

74. 1. Sera sampled immediately after or during plasmapheresis/high-
dose corticosteroid often lowers the titers of AQP4-Ab.
2. Sera sampled during B-cell-depleting treatment (e.g. rituximab) or
during remission stage may have lower titers of AQP4-Ab and be
tested false-negative.
3. Sera with lower titers of AQP4-Ab may be tested negative in a
fixed-CBA.
4. Sera with highly active AQP4-Ab can destroy AQP4-expressing
cells, and thereby may mask the binding of the AQP4-Ab in
assays using live cells (either live-CBA or FACS-assay).
5. Recently a case report showed that natalizumab can directly
interact with the AQP4-expressing cells, and thereby might cause
false-positive AQP4-Ab assay results in patients being treated
with natalizumab
Takahashi T, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre.
Brain 2007; 130: 1235–1243

77. Sherif M Hamdy et al Management Strategies of Patients with Neuromyelitis Optica Spectrum Disorder During the COVID-19 Pandemic Era.
Therapeutics and Clinical Risk Management 2020:16 759–767

78. Sherif M Hamdy et al Management Strategies of Patients with Neuromyelitis Optica Spectrum Disorder During the COVID-19 Pandemic Era.
Therapeutics and Clinical Risk Management 2020:16 759–767

80. n=76

81.  Creatine kinase leakage as a result of AQP4-IgG-induced,
complement-mediated sarcolemmal injury may be a potential
mechanism for hyperCKemia.
 The sCK levels of patients in the acute phase of NMOSD were
significantly higher.
 NMOSD-associated myopathy seems to be characterized by
mild muscle symptoms with prominent hyperCKemia and
minimal changes on conventional pathological staining
Int J Neurosci. 2016 Oct;126(10):863-6. doi: 10.3109/00207454.2015.1113175. Epub 2015
Nov 19.

82. Posterior reversible encephalopathy:-
 Patients with NMO predisposed to a higher frequency of posterior
reversible encephalopathy syndrome
 When subjected to blood pressure fluctuations or therapies causing
rapid fluid shifts,
 Manifests as reversible encephalopathy, seizures, headache, and
vision symptoms.

83.  Fulminant cerebral demyelination :-
 Large hemispheric confluent cavitary lesions, presumably due to a
large area of inflammation with necrosis, are also observed in NMO.
 The lesions were vasogenic edema associated with inflammation
 In rare cases, fulminant diffuse vasogenic edema can lead to brain
herniation and death

84.  Endocrinopathies:-
 NMO may initially be seen with endocrinopathies
 Hypothalamic dysfunction :-amenorrhea, galactorrhea, hyperphagia
and weight gain
 Diabetes insipidus
 Hypothyroidism,
 Due to lesions seen in the hypophysis and hypothalamus

85.  Brainstem lesion predominantly involve medulla and pons that
sometimes caused multiple cranial neuropathy.
 These symptoms are reversible in most cases but sequelae may be
observed especially in hearing loss and oculomotor dysfunction.
 Acute and subacute bulbar dysfunction with ataxia in the form of BE
can occur.
 May lead to acute neurogenic respiratory failure and death.

88. Organ specific
 Hypothyroidism
 Pernicious anemia
 Ulcerative colitis
 Primary sclerosing
cholangitis
 Seropositive MG
Non organic specific
 ITP
 SLE
 SS
 APLAS
 Sarcoidosis
• The frequency of association of NMO with autoimmune disorders is 10-40%
Wingerchuk DM et al.(1999) Neurology 53: 1107–1114

90.  Some cases of aquaporin-4-seronegative neuromyelitis optica:
(40%)
 Some cases of ADEM specially the recurrent ones and the
fulminant courses.
 Some cases of multiple sclerosis.(Spadaro et al., 2016)
 Isolated optic neuritis or transverse myelitis
 Recurrent optic neuritis.