Neuromyelitis spectrum disorder : an overview

1. AQP4 ANTIBODY DISEASE : NMOSD
AN OVERVIEW
BY
Dr (Prof ) Sandhya Manorenj
MBBS,DNB (Gen Medicine),DNB ( Neurology)
FNR, MRCP Neurology (SCE), FEBN , FRCP (London)
PROFESSOR & HOD, NEUROLOGY
PRINCESS ESRA HOSPITAL
DECCAN COLLEGE OF MEDICAL SCIENCES
MS meet Jan 21 2024 NIMS
Sandhya Manorenj

2. FOCUSSED QUESTIONS: WHATS THE EVIDENCE ?
• Can we diagnose NMOSD in patient with negative or without AQP4 Ab test ?
• Is the disease common in India in terms of other demyelinating disease?
• Which subclass of AQP4 Ig G causes NMOSD ? G1, G2,G3,G4
• What is the recent diagnostic criteria for NMOSD ?
• Is there any difference in Pediatric NMOSD?
• Is there any role of monoclonal antibodies in the management of NMOSD ?
• Which immunosuppressant's are safe in pregnancy ?
• When should I repeat AQP4 antibody test ?
Sandhya Manorenj

3. WHAT IS AQP4? ITS LOCATION IN BRAIN
• Water channel protein
(integral membrane protein)
• Encoded by the AQP4 gene
• Conduct water through the
cell membrane rich in CNS
• facilitating water movement
near cerebrospinal fluid and
vasculature
Whittam D et al. What's new in neuromyelitis optica? A short review for the clinical neurologist. J Neurol 2017;264:2330-44
Sandhya Manorenj

4. THE EVOLUTIONS IN AQP4 ANTIBODY ASSOCIATED DISEASE OR ILLNESS:
• Early 19th
Century
1894 Over many
years
1999
2004 2005 & 2006 2015
• Coexistence Of
ON & TM
• Aberchromie-
intractable
vomiting & asso
with medulla
Eugène Devic
and his student
Fernand Gault
reviewed
published cases
of optic
neuritis with
myelitis.
DEVIC’ S
DISEASE
• Considered
as overlap
syndrome
with MS
• (optico-
spinal MS)
with later
being more
severe .
• Wingerchuk
s diagnostic
criteria
Lennon and
colleagues.
Discovery of
circulating
IgG antibody
in
opticospinal
forms
Antibodies are
directed to
astrocyte AQP4
Revised
Wingerchuks
diagnostic
criteria 2006
where AQP4
antibody was
added to
diagnostic
criteria .
NMO
IPND
Dean M.
Wingerchuk et
al.
NMOSD
New diagnostic
criteria with 6 core
clinical features.
Encompass:
association ;
SLE,sjogrens,
Myasthenia gravis.
Increases
specificity and
sensitivity from
mimics
NMOSD
2023
International
Delphi
(Friedemann
Paul et
al)(consensus
on
Management
of AQP4
positive IgG
NMOSD using
4mab
Eculizumab
Inebilizumab
Satralizumab
Ravalizumab.
Disease
biomarkers ?
Sandhya Manorenj

5. EVIDENCE ON ETHNICITY OF NMOSD : World wide prevalence
Jyh Yung Hor et.al Prevalence of neuromyelitis optica spectrum disorder in the multi-ethnic Penang Island, Malaysia, and a review of worldwide prevalence,Multiple
Sclerosis and Related Disorders, Volume 19,2018
Highest incidence & prevalence ?
Afro Caribbeans
(0.73 & 10 per 100000)
Among Asians
East Asia ( china and Japan) higher
prevalence
India : prevalence 2.4/100000
incidence 11/419306
Lowest incidence & prevalence?
Australia & New Zealand
(0.037 & 0.7 per 100000)
Sandhya Manorenj

6. PATHOPHYSIOLOGY OF NMOSD
AQP4-IgG G1
subclass
Extrathecal
space/periph
erl
Defects
in BBB
Triggers
in Host
Silvia C et.al Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health
and Autoimmune Disease.Volume 27, Issue 13, 25 June 2019
Systemic infection,
immunity tolerance
breakdown & oxidative
stress
Sandhya Manorenj

7. Complement dependent cytotoxicity (CDC)
by assembling complexes for complement
C1q (C1q) binding.
AQP4-IgG also activates
Antibody-dependent cell-mediated
cytotoxicity (ADCC) by natural killer (NK)
cells
PATHOPHYSIOLOGY CASCADES IN NMOSD
AUTOIMMUNE ASTROCYTOPATHY
Sandhya Manorenj

8. EVIDENCE ON SEX PREDILECTION AND AGE IN NMOSD.
More common in female sex : 3: 1 to 9:1 (female prevalence is especially significant in patients
seropositive to AQP4-IgG)
1:1 in NMOSD & MOG- IgG
Occurs in all age. Mean age is ~ 40 years in AQP4-Ig G positivity.
Tendency of earlier onset in non whites . Late onset NMOSD> 70 years
Is there any genetic association ?
Association of NMOSD with different alleles of the human leukocyte antigen (HLA) system, including
HLA DRB1*03:01, DRB1*04:05, and DRB1*16:02
Hor J Y,et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol.
2020;11:501 Sandhya Manorenj

9. CLINICAL FEATURES OF NMOSD : Neurologic, systemic,and psychiatric syndromes
Fiona costello.Continuum (minneap minn) 2022;28(4), multiple sclerosis and related disorders): 1131–1170.
Sandhya Manorenj

10. CLINICAL FEATURES OF NMOSD : Neurologic, Systemic,and psychiatric syndromes
Fiona costello.Continuum (minneap minn) 2022;28(4), multiple sclerosis and related disorders): 1131–1170.
Sandhya Manorenj

11. INTERNATIONAL CONSENSUS DIAGNOSTIC CRITERIA FOR NEUROMYELITIS OPTICA SPECTRUM DISORDERS
2015
NMOSD with AQP4-IgG
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
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 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
Wingerchuk DM et al. International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica
spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. Sandhya Manorenj

12. 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 (SIADH)with NMOSD-typical
diencephalic MRI lesions
6.Symptomatic cerebral syndrome with NMOSD-
typical brain lesions
WHAT ARE THE NEW 6 CORE CLINICAL
CHARACETERISTICS ?
ABCD
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
Wingerchuk DM et al. International Panel for NMO Diagnosis. International consensus diagnostic criteria forneuromyelitis optica spectrum disorders. Neurology.
2015 Jul 14;85(2):177-89.
Sandhya Manorenj

13. Eslam Shosha,et al. Area postrema syndrome .Frequency, criteria, and severity in AQP4-IgG–positive NMOSD. Neurology October 23, 2018 issue
Sandhya Manorenj

14. Clinical features and laboratory findings
Progressive overall clinical course (neurologic deterioration unrelated to attacks;
consider MS)
Atypical time to attack nadir: less than 4 hours (consider cord ischemia/infarction);
continual worsening for more than 4 weeks from attack onset (consider sarcoidosis
or neoplasm)
Partial transverse myelitis, especially when not associated with LETM MRI lesion
(consider MS)
Presence of CSF oligoclonal bands (oligoclonal bands occur in <20% of cases of
NMO vs >80% of MS)
WHAT ARE THE RED FLAGS ? FINDINGS ATYPICAL FOR NMOSD
Wingerchuk DM et al. International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology.
2015 Jul 14;85(2):177-89. Sandhya Manorenj

15. BRAIN
Imaging features (T2-weighted MRI) suggestive of MS
(MS-typical)
1.Lesions with orientation perpendicular to a lateral
ventricular surface (Dawson fingers)
2.Lesions adjacent to lateral ventricle in the inferior
temporal lobe
3.Juxtacortical lesions involving subcortical U-fibers
4.Cortical lesions
Imaging characteristics suggestive of diseases other than
MS and NMOSD
1.Lesions with persistent (>3 month) gadolinium
enhancement
SPINAL CORD
Characteristics more suggestive of MS than
NMOSD
1.Lesions <3 complete vertebral segments on
sagittal T2-weighted sequences
2.Lesions located predominantly (>70%) in
the peripheral cord on axial T2-weighted
sequences
3.Diffuse, indistinct signal change on T2-
weighted sequences (as sometimes seen with
longstanding or progressive MS
WHAT ARE THE RED FLAGS FOR NEUROIMAGING?
Wingerchuk DM et al. International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology.
2015 Jul 14;85(2):177-89. Sandhya Manorenj

16. WHAT INVESTIGATION TO BE ORDERED IN SUSPECTED CASE OF NMOSD?
EVIDENCE
MRI
SERUM
AQP4 IgG
CBA
OTHER
LAB
TESTS
MRI Brain spine ,
orbit with contrast
Additional OCT
Sensitivity 80-100 %
Specificity 86-100%
Basic blood tests
Serology for Connective
tissue disorder, Autoimmune
encephalitis, paraneoplastic
Infection.
CSF Study : OCB in 20%
Neutrophil or eosinophilic
predominant pleocytosis
If AQP4 Ig G Negative : MOG
IgG to be tested
75% cases are positive
25-30% negative
Sandhya Manorenj

17. RADIOLOGICAL FEATURES IN NMOSD
Optic neuritis (LEON)
Area postrema syndrome
LETM
Cerebral syndrome -Marbled pattern,bridge arch pattern
Diencephalon syndrome
Bright spotty sign
Brainstem
syndrome
Sandhya Manorenj

18. HOW TO DIFFERENTIATE CEREBRAL SYNDROME (SUBCORTICAL WM) OF NMOSD FROM MS LESION ?
NMOSD
• Corpus callosal(CC) lesion show bridge arch or
marbled pattern. Subcortical lesion .Absence of
combined justacortical/cortical lesion .
• Lesions are rounded in a ground glass like
heterogenous appearance in body of CC
• Central vein sign seen in 20%
• Diffuse leptomeningeal enhancement noted. Cloud
like, linear enhancement .
MS
• CC lesion show dawson finger on sagittal section.
Juxtacortical/cortical lesion
• Lesion are ovoid, well circumscribed and oriented
perpendicular to body of lateral ventricle
• Central vein sign in 80%
• Diffuse leptomeningeal enhancement is rare
Sandhya Manorenj

19. EVIDENCE ON EMERGING BIOMARKERS IN NMOSD
Biomarker is a marker of pathogenic process and responses to therapeutic intervention. Good biomarker
shows strong association with the disease process and the outcome after treatment
AQP4-IgG does not decide the severity , response to treatment and positive in remission phase too .
Useful only for diagnosis of NMOSD- DIAGNOSTIC BIOMARKER & play role in pathogenicity
GFAP is a principal intermediate filament that forms the astrocyte cytoskeleton. Patients with NMOSD
have elevated GFAP levels in the CSF and serum, owing to astrocyte injury. Higher serum and CSF GFAP
levels have been reported during NMOSD attacks and predicts future disease activity and severity -
STRONG BIOMARKER
Serum neurofilament light chain are increased in NMOSD and MS relapse , but decreases in MS after
DMT and a correlates with future relapse in MS. While in NMOSD it remains higher for longer period
even after relapse. A higher serum GFAP/serum neurofilament light chain quotient at relapse may help
differentiate NMOSD from MS.
Ma X etal. Risk of relapse in patients with neuromyelitis optica spectrum disorder: recognition and preventive strategy. Mult Scler Relat Disord 2020;46:102522.
Sandhya Manorenj

20. ALGORITHM FOR DIAGNOSIS OF NMOSD
History and clinical presentation / physical examination
Suspected NMOSD
General and
immunological
lab works
CSF
analysis
Imaging
(MRI,OCT)
CHECK RED FLAGS
CHECK ALTERNATIVE DIAGNOSIS
Testing for AQP4
IgG (CBA)
Check
alternative
diagnosis
Testing for MOG
IgG (CBA)
Consider MOGAD
IPND CRITERIA FOR NMOSD MET ?
+
+
-
-
Ringelstein M, et al.; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) - revised recommendations of
the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis. J Neurol. 2023 Jul;270(7):3341-3368
Sandhya Manorenj

21. WHAT ARE THE DIFFERENTIAL DIAGNOSIS for NMOSD?
Especially in patients
with seronegative
NMOSD.
MOG-Encephalomyelitis
MS,Neurosarcoidosis,
Paraneoplastic
neurological syndromes,
Infectious diseases.
Ringelstein M, et al.; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) - revised recommendations of
the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis. J Neurol. 2023 Jul;270(7):3341-3368
Sandhya Manorenj

22. 0
1
2
3
4
5
6
7
0 10 20 30 40 50 60 70 80
EDSS
Time in hours
ATTACK
Temporal profile of NMOSD
Relapse rate ?
92% of seropositive NMOSD experience relapse
Relapse rate is average of 1.3 times per year .
Female ,young and Africans are at risk.
What is the initial event ?
Transverse Myelitis in 50 %
ON in 35%,Both in 10% ,Other clinical syndrome 4%
ON relapse tend to occur frequently before age 30 years while
myelitis relapses occur more often in older
Sandhya Manorenj

23. Relapse versus pseudo relapse ?
Relapse :New symptoms or an exacerbation of
preexisting deficits lasting longer than 24
hours and not otherwise explained by fever or
infection.
Area postrema syndrome : attacks of NVH
should last for more than 48 hours or be
supported by MRI.
Some studies defines : Increase of at least 0.5
points in EDSS, an increase of at least 1 point
on two functional system scales, or an
increase of at least 2 points on one functional
scale
Pseudorelapse is a clinical exacerbation of
preexisting neurologic symptoms that
worsen because of systemic metabolic
factors. The most common causes of
pseudorelapse were infection, pain, mood
changes and dysautonomia.
Pseudorelapses are not accompanied by
new MRI findings, and they resolve with
treatments targeting the underlying cause
Fiona costello.Continuum (minneap minn) 2022;28(4), multiple sclerosis and related disorders): 1131–1170.
Sandhya Manorenj

24. Neuroimmunological stroke
DISABILITY IN NMOSD ? Every relapse matters
Legally blind (20/200 or 6/60)
in 41 % in 5 years of disease onset
Require walker in 22 % at
5 years of disease onset
World wide mortality 9-32 % (2018)
Mealy MA, Kessler RA, Rimler Z, Reid A, Totonis L, Cutter G, Kister I, Levy M. Mortality in neuromyelitis optica is strongly associated with
African ancestry. Neurol Neuroimmunol Neuroinflamm. 2018 Jun 7;5(4):e468.
Sandhya Manorenj

25. DISABILITY SCALE : KURTZKE EDSS
Rabadi MH, Vincent AS. Comparison of the Kurtkze expanded disability status scale and the functional independence measure: measures of multiple sclerosis-related disability. Disabil
Rehabil. 2013;35(22):1877-84.
Sandhya Manorenj

26. TREATMENT OF ACUTE ATTACK OF NMOSD
Kümpfel T et al; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of
the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management. J Neurol. 2024 Jan;271(1):141-17
Severe myelitis : Apheresis
is recommended as first line
therapy
Immunoadsorption using
using TRYPTOPHAN
IA-Tr
Oral steroids : 1 mg/kg/day
or 20–30 mg/day and then
tapered to 10–15 mg/day
within 2–3 weeks till 3-6
months .
Sandhya Manorenj

27. WHAT ARE THE TREATMENT AVAILABLE FOR PREVENTION OF ATTACKS OF NMOSD ?
Classical
immunosuppresants
Azathiprine
Mycophenolate
Mofetil
Low dose oral steroids
Monoclonal Antibody
Compliment
inhibition
Eculizumab 
Ravulizumab 
ER
IL6 receptor
blockade
Tocilizumab
Satralizumab 
S
ERIS Satralizumab is only drug approved for
adolescent≥12 yrs
Experimental
therapy
Intermittent PE, IA
Stem cell therapy
IVIG, methotrexate
tacrolimus
B cell
depletion
Rituximab 
Inebilizumab
RI
Sandhya Manorenj

28. 1-alphatical order ERIS
2- consider only after second
attack (Eculizimab)
3 Hypothetical option ,no clinical
data
4 In developing countries where
MAB not available
5 Intermittent PE/
immunoadsorption or Stem cell
therapy
In children or in case of
contraindications to other
therapies intravenous
immunoglobulins may be used;
methotrexate and tacrolimus
may be used if other therapies
are not available
LONG-TERM THERAPY FOR AQP4-IGG-POSITIVE NMOSD
Sandhya Manorenj

29. LONG-TERM THERAPY FOR DOUBLE-NEGATIVE NMOSD
Kümpfel T et al; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group
(NEMOS). Part II: Attack therapy and long-term management. J Neurol. 2024 Jan;271(1):141-17
Sandhya Manorenj

30. EVIDENCE ON MANAGEMENT OF NMOSD IN SPECIAL CIRCUMSTANCES
C0-ASSOCIATION with Connective
tissue disorder : SLE & Sjogrens
Multidisciplinary collaboration
Rituximab is used for preventive
therapy .
PEDIATERIC NMOSD : Paediatric onset NMOSD accounts 3-5% of all NMOSD. Accounts 10% in less than 18 yrs. First
report in 1927 <18 years .Cerebral lesion are more in children. . Thalamic and Internal capsule lesion are more common
in ADEM than NMOSD. Mog IgG is more frequent than NMOSD.
Imaging features and new diagnostic criteria IPND (2015) are similar to adults .
Acute attack : IV MP first line, second line PE is safe in children
Prevention od attack : First line Rituximab well tolerated in children, Satralizumab only approved for adolescent ≥ 12
years. Second line Azathiprine and Mycophenolate mofetil are effective, IV immunoglobulin , intermittent PE
maintenance.
PREGNANCY may precipitate disease onset for some women and exacerbate
disease activity for those with an established diagnosis Third trimester and
peripartum period are vulnerable for relapses .Miscarriages can occur.
Azathioprine, rituximab, eculizumab, and glucocorticoid therapy are
relatively safe in pregnancy; moreover, tocilizumab can be considered for
women with more severe NMOSD. Avoid Mycophenolate abortion in 45 %,
fetal malformation in 26%
Sandhya Manorenj

31. LITERATURE OF RECENTLY APPROVED MONOCLONAL ANTIBODY (Biological therapy) FOR AQP4 POSITIVE
NMOSD
PICO Eculizumab
(PREVENT&OLE)
Ravalizumab
(CHAMPION)
Inebilizumab
(N Momentum)
Satralizumab
Sakurasky,
Sakurastar
Population 143 patients (≥ 2 attacks in 1
year months or 3 in 2 y r/ 33
cases no immunosuppressant
58 positive cases
≥ 2 attacks in 1 year months or 3
in 2 y
230/213 positive
17 megative
≥ 18 yrs age
55 positive, 23 neg
63 positive , 21 neg
≥ 1 attack in 1 yr or ≥2 attack in
2 yrs ≥ 12 yrs age
Intervention IV Eculizumab monotherapy X
2.8 yrs. Assementat 4 yr.
No IS.
IV Ravalizumab
Concomittant IS Yes
No concomitant IS except
tapering steroids plus
Inebizumab
Satralizumab ±commitant IS
treatment exposure for 4.4 yrs
IS yes in sky
No in star
Comparison 2:1
(USA) placebo
1:1
placebo
3: 1 1:1Sky
1:2Star
International Multicentre study
Outcome 96% free from relapse
95 % no disability worsening
Relapse risk reduction 98% 12% vs 39% attacks No AVR or infection
Sandhya Manorenj

32. Sandhya Manorenj

33. CONCLUSION
NMOSD is an Autoimmune Astrocytopathy and its relapse has been likened to Neuro-immunological stroke.
75% NMOSD are AQP4 IgG positive while 25% are sero negative ;
Diagnosis of NMOSD is based on IPND criteria 2015, applicable for both adults and children.
The treatment for acute attack of NMOSD both seropositive, and seronegative patient remains same with high dose
IVMP as first line drug in adults, children and in pregnancy.
Apheresis therapy has been recommended recently as the first line of choice in acute attack of severe myelitis and in
those with poor response to pulse steroids in previous attack in adults, children and pregnancy .
First line of choice in prevention of attack in AQP4 Ig G positive NMOSD has changed from past . 4 Monoclonal antibody
are approved : ERIS (Eculizumab, ravalizumab, ,inebilizumab, Satriluzumab) and rituximab approved in Japan. In
Pediateric and pregnancy: Rituximab is safe. Satrilizumab is approved in adolescent ≥12 yrs. Second line therapy drugs for
paediatrics and pregnancy is Azathioprine . Mycophenolate should be avoided in pregnancy.
First line of choice in prevention in seronegative NMOSD is Rituximab or Azathiorprine /mycophenolate and indicated
only after second attack or first severe attack.
There is no role of repetition of AQP4 Ig G antibody titre once it is positive as it is only a diagnostic marker.
In NMOSD with co existence SLE,sjogrens, MG, first line in prevention of NMOSD relapse should be early initiation
biological therapy – B cell depleters MAB preferred. And requires multidisciplinary approach
Sandhya Manorenj

34. Thank you
Sandhya Manorenj