This document discusses the history, epidemiology, diagnostic criteria, immunopathology, laboratory findings, and treatment of neuromyelitis optica spectrum disorder (NMOSD). It provides details on the distinctive clinical, MRI, and serological features that differentiate NMOSD from multiple sclerosis. It also outlines the diagnostic criteria for NMOSD with and without aquaporin-4 antibodies. For treatment, it recommends aggressive immunotherapy for relapses followed by immunosuppressants such as azathioprine or mycophenolate to reduce relapse rates. Rituximab is noted as a second-line therapy, and certain DMTs used to treat MS are avoided due to risk of exacerbating NMOSD.

2. Why ?

3. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

4. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

5. Western Countries
Asia
1894: Devic’s NMO :
bilateral optic
neuritis and
myelitis
1900-1990:
monofasic
bilateral optic
neuritis and
myelitis
1999-2006:
monofasic or relapsing
illness dominated by
bilateral optic neuritis
and myelitis,
associated with NMO-IgG
2007- present: NMO-SD
spectrum of conditions
.
1960-2003: Unique Asian Form of MS: OSMS
Primary confined to optic nerve and spinal cord,
usually no OCB in CSF
2004 - present: Growing Recognition of NMO
(The term “OSMS” is disappearing)

6. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

7. Prevalence of MS:
- Western Countries 1/ 1000
- Asia < 5/100000
- Japan 8-16/100000
NMO : MS ratio
- Western Countries 1/100
- Asia 1/2 – 1/10
Prevalence of NMO
- (Western) Countries ~1-4,4/100000

8. Woman vs man ratio 9 : 1
Median age at onset 39y
Relapsing vs monofasic course 8-9:1
Frequently + with other autoimmune diseases
In up tot 20-30% preceded by infection or
vaccination

9. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

10. Wingerchuk et al, Neurology 2006
• Optic neuritis
• Acute myelitis
+ at least 2 out of the following:
- Brain MRI at onset
not meeting Paty’s
criteria for MS
Contiguous lesion
extending over
≥ 3 vertebral
segments on spinal
MRI
- - NMO-IgG
seropositive
status

11. • Discovery of NMO-IgG
NMO can be recognized reliably at an earlier point
• Limited versions of NMO
recurrent myelitis or recurrent optic neuritis
• Brain lesions may occur
may be the presenting manifestations
may be highly suggestive or diagnostic
• Co-association of other autoimmune conditions
Do they exclude NMO?

14. Cortical oscillopsia without nystagmus, an isolated symptom of
neuromyelitis optica spectrum disorder
with anti-aquaporin 4 antibody
Sung-Min Kim1,2, Ji-Soo Kim1,2, Young Eun Heo1,2, Hye-Ran Yang1,2 and Kyung Seok
Park1,2. Multiple Sclerosis Journal 2012, 18(2) 244–247
45 y,female

15. A case of cerebral aquaporinopathy
A Tanaka1, T Yoshida1, T Yamada1, R Isayama1, Y Fujiwara1, K Shiga1, K Yamada2, K
Tanaka3 and M Nakagawa1. Multiple Sclerosis 201016(10) 1252–1254
35 y, female,
fever, headache
Left INO,
Left facial palsy,
impaired
consciousness

17. •Convened October, 2011
•Co-chairs: Dean Wingerchuk
Brian Weinshenker
•Overall objective:
“To revise NMO diagnostic criteria
to reflect advances in
Clinical and radiological spectrum Serological testing”

19. 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:
nausea/vomiting/hiccups
• Other brain stem syndrome
• Symptomatic narcolepsy or acute
diencephalic syndrome with MRI lesion(s)
• Symptomatic cerebral syndrome with MRI
lesion(s)

20. NMOSD without AQP4-IgG
(or unavailable)
At least 2 core clinical characteristics all satisfying:
• 1 of optic neuritis, myelitis, or area postrema syndrome
• Dissemination in space
Isolated recurrent optic neuritis or recurrent myelitis 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
• No better explanation

22. Overlapping CNS inflammatory diseases: differentiating features of NMO and MS. Juryńczyk M, et al.
Neurol Neurosurg Psychiatry 2014;0:1–6.

27. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

28. The spectrum of neuromyelitis optica. Dean M Wingerchuk et al. Lancet Neurol 2007; 6: 805–15

29. MS NMO
Clinical onset and course 85% remitting-relapsing
15% primary progressive
Not monophasic
Onset always with relapse
80-90% relapsing course
10-20% monophasic
Secondary progressive
course
common rare
CSF white-blood-cell
number and differential
count
Mild pleiocytosis
Mononuclear cells
Occasional prominent
pleiocytosis
Polymorphonuclear cells
and mononuclear cells
CSF oligoclonal bands 85% 15-30%

30. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

31. Factors to influence sensitivity in AQP4-Ab assay:
- specificity varies between 90 and 100%*
- sensitivity of 60-90%* (FACS assay 88%**)
- Seropositive conversion at relapse in some cases
- Seronegative conversion by immunosuppression
- Sero-negative but CSF-positive in rare instances
*Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the NEMOS,
C.Trebst, Neurol. 2014; 261(1): 1–16.
**Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica, Y.Jiao,
Neurology. October 1, 2013 vol. 81 no. 14 1197-1204
Cell-Based-Assay
Mouse Tissue-
Based AssayELISA

32. MOG-Ab present in some anti-AQP4-Ab-seronegative NMOSD
Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Sato et al.
Neurology2014;82:474–481
Neuromyelitis Optica Spectrum Disorders With AQP-4 and MOG Antibodies: A Comparative Study. Kitley et al.
JAMA Neurol. 2014;71(3):276-283
No NMOSD patients were
double-positive
No female predominance
Fewer attacks & better recovery

33. A little bit of history
Epidemiology
Diagnostic criteria of NMO
Comparative immunopathological hypothesis for MS
and NMO
Laboratory: AQP 4 AB, MOG-Ab …
Treatment

34. aggressive relapse treatment
reduce permanent disability
poor response
significant disability
4-10 days
Urgent IV Methylprednisolone
1g 3-5 days
Prompt plasma exchang
5-7 days or
IVIG
Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the
NEMOS. Corinna Trebst et al. J Neurol. 2014; 261(1): 1–16.

35. Prednisolone
and/or
Azathioprine
or
Mycophenolate
or
Methotrexate
or
Rituximab
2nd LINE
Rituximab
Ciclosporin / Tacrolimus
Cyclophosphamide
Mitoxantrone
Regular plasma exchange/IVIG
Relapse
adequate dose
3-6 months
NMO treatments and trial design.Dr Jackie Palace. AAN 2014 Boston
Watanabe S, Misu T, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica:
a retrospective analysis. Mult Scler. 2007;13(8):968–974. [PubMed]

36. NMO treatments and trial design.Dr Jackie Palace. AAN 2014 Boston

37. Avoid: Interferon-beta,
Natalizumab,
Alemtuzumab,
Fingolimod

38. relapsing seronegative NMO
 DMTs options for overlap syndromes:
•Azathioprine
•Methotrexate
•Mycophenolate
•Glatiramer acetate
•Mitoxantrone
•Rituximab

39. One more thing…

41. - Azathioprine: 2-3mg/kg/d,
absolute lymphocyte count < 1500µL
+ prednisone 1 mg/kg/d the first 6 m
- Mycophenolate: 750-3000 mg
absolute lymphocyte count < 1500µL
- Methotrexate: 7.5 mg 1/w untill 17.5 mg 1/w
+ low dose prednisone 5–10 mg at least 6 m
- Rituximab regime:
1000 mg twice at a 2-w interval or 375mg/m2 wkly for 4w.,
every 6 months or when B cell count starts to rise (eg.
CD19/20 and/or CD27 memory cc > 0.05-0.1% )