This document provides an overview of neuromyelitis optica (NMO), including its clinical presentation, pathogenesis, diagnostic criteria, treatment, and biomarkers. Some key points: - NMO predominantly targets the optic nerve and spinal cord, often causing severe vision loss or paralysis. It was previously considered a variant of multiple sclerosis but is now recognized as a distinct condition. - The discovery of antibodies against aquaporin-4 helped establish NMO as a separate autoimmune disease, with these antibodies detected in around 70-80% of cases. - In addition to optic neuritis and transverse myelitis, NMO can involve other areas of the CNS and cause a range of neurological and non-

1. Neuromyelitis Optica- An Update
21 Jan 2016

2. Introduction

3. • NMO is an autoimmune chronic inflammatory
disorder of CNS.
• Till recently was thought to be a variant of MS.
• The mean age at onset (32.6-45.7yrs) and
median time to first relapse (8-12 months) is
similar in different populations studied.
• It targets the spinal cord and optic nerve
predominantly, is most often relapsing and
has a female preponderance.

4. Its a Spectrum

5. • The discovery of a novel biomarker anti aquoporin 4
immunoglobulin G (anti AQP4IgG) vastly improved the
specificity of diagnosis.
• In nearly 70-80% of cases, anti AQP4IgG is associated
with NMOS.
• A variety of conditions were discovered with anti
AQP4IgG positive state necessitating the term NMO
spectrum disorders (NMOSD).
• The spectrum of NMO disorders is likely to constitute
approximately 20% of all demyelinating disorders in
India.
• Brain MRI features and additional biomarkers are
being identified, which may produce an "NMO
phenotype" disorder.

6. Etiopathogenesis

7. • Nearly a third of attacks in NMOSD are
preceded by fever or vaccination.
• However no specific environmental agent has
been associated with NMOS.
• Most cases of NMOSD are sporadic in
occurrence though familial forms have been
rarely reported.
• Genetic susceptibility studies have shown that
HLADRB1*03 may be associated with NMOS.

8. About Anti AQP4IgG

9. • Aquoporin 4 is a water transport protein highly expressed
at the astrocyte end feet at the blood brain barrier.
• It is expressed widely in all neural tissues with the highest
concentration in optic nerves and spinal cord.
• Anti AQP4IgG is produced mainly by plasma cells in the
peripheral blood by unknown mechanisms and gains access
to CNS through a blood brain barrier breach.
• They target the aquoporin rich astrocyte foot processes and
the subsequent antigen antibody interaction leads to
activation of complement cascade with complement
dependent cellular cytotoxicity.
• Granulocytes (neutrophils, eosinophils) migrate to the
region by chemotaxis and there is antibody dependent
cellular cytotoxicity. When unchecked, the inflammation is
severe and associated with necrosis.

10. Diagnostic Criteria

11. • Original criteria was
proposed by Wingerchuk
et al., in 1996.
• The 2006 criteria included
– 2 absolute criteria
• optic neuritis (OPN),
• acute myelitis
– at least two out of three
supportive criteria:
• Contiguous spinal cord MRI
lesion extending over ≥ 3
vertebral segments;
• brain MRI not meeting MS
diagnostic criteria; and
• seropositivity for NMOIgG.
• Currently a revision of
diagnostic criteria is
underway. Some of the
salient features include-
– the addition of area
postrema syndrome
(presentation with nausea,
vomiting and hiccups),
– other brain stem
syndromes,
– symptomatic narcolepsy
– symptomatic cerebral
syndrome with MRI
findings.

12. • Seropositive patients may manifest as limited
forms of the disease
– isolated unilateral/bilateral recurrent OPN,
– recurrent transverse myelitis,
– myelitis associated with collagen vascular
disorders etc.
• Loosely termed as NMOSD.

13. Clinical Features

14. • The classical features of NMO are
– acute severe OPN
– longitudinally extensive transverse myelitis (LETM)-
longitudinal cord lesions extending >3 vertebral
segments.
• First attack is often monosymptomatic. The
concomitant appearance of both OPN and TM is
seen in 15-40% of cases.
• Optic Neuritis-
– Severe visual impairment
– difficult to differentiate OPN associated with NMOSD
from that seen in MS.
– bilateral simultaneous or sequential OPN in rapid
succession is suggestive of NMOSD rather than MS.

15. • Spinal cord lesions typically present as
– Complete transverse myelitis
– Occasionally seropositive patients have been noted to have
spinal lesions <3 segments.
– Extension of cervical spinal cord lesions into the brainstem-
cause hiccups, vomiting and respiratory failure.
– Asymptomatic lesions in patients presenting with OPN.
• Neuropathic pain, Lhermitte's sign and painful tonic spasms
are common.
• The timing of MRI is very crucial- in early or resolving
disease, the classical tumefactive and longitudinal lesion
may be missed.
• It is to be remembered that not all long cord lesions are
NMOSD (other causes- idiopathic transverse myelitis, acute
disseminated encephalomyelitis or rarely infective causes).

16. Extra Optico Spinal Manifestations

17. • The clinical manifestations of NMOSD may involve sites
outside the spinal cord and optic nerve, sometimes in
isolation.
• Brain stem involvement is seen in up to one third of the
patients. Brainstem involvement is more common in anti
AQP4IgGpositive patients and particularly among non
Caucasians. It manifests as
– intractable vomiting (area postrima syndrome),
– intractable hiccups due to periaquiductal lesions in the midbrain
– narcolepsy,
– hypothermia and
– hypersomnolence due to diencephalic involvement.
– oculomotor dysfunction,
– deafness,
– facial palsy, trigeminal neuralgia and other cranial nerve signs
– vertigo.

18. • Other symptoms/syndromes that have been
reported include
– seizures,
– hyposmia,
– posterior reversible encephalopathy syndrome (PRES),
– meningoencephalitis,
– myeloradiculopathy,
– cognitive dysfunction,
– ophthalmoplegia,
– skeletal and smooth muscle involvement in the form
of muscle edema and myocarditis
– HyperCKemia has been detected during attacks.

19. Non-neurological Manifestations

20. • Anti AQP4IgG antibodies may target extra neural
tissues that express aquoporin thus leading to
– placentitis with risk of abortion,
– internal otitis
– gastritis.
• Nearly 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 B 12 deficiency,
– autoimmune encephalitis.

21. Investigations

22. MRI of the spine
• Spinal cord MRI is crucial
especially since brain
lesions indistinguishable
from MS in up to 27% of
patients.
– The hallmark lesion is
LETM.
– It is edematous in the
acute phase
– Most often centrally placed
– Involves the thoracic and
cervical cord commonly.
• Spinal cord lesions in MS
– are short,
– situated posteriorly
– most often in the cervical
cord.

23. • NMOSD lesions show patchy enhancement in
33-71% of cases and during an acute relapse.
• After steroid therapy lesions tend to fragment
into shorter segments, chronic lesions may
show cavitation and cord atrophy.
• It is to be noted that failure to enhance
sometimes prevents the distinguishing of a
recent attack from a pseudo relapse.

24. MRI of the Brain
• Brain lesions are present in more than half of the patients
• MRI brain may show lesions indistinguishable from MS.
• Absence of Dawson's finger, "U" fibre lesions, paucity of
lateral ventricle and inferior temporal lobe lesions are
strongly suggestive of NMOSD.
• In doubtful situations the cord lesions should be carefully
scrutinized to obtain additional supportive evidence.
• The so called NMO specific lesions are seen at sites of high
AQP4 expression
– the diencephalon,
– the hypothalamus and
– the aqueduct and are present in <10% of NMOS.

25. • NMOSD lesions are frequent in
– the corpus callosum.
– Infratentorial lesions-medulla, contiguous with
cervical cord lesions.
– in the pons,
– cerebellar peduncles
– midbrain.
• Tumefactive brain lesions, periependymal lesions
involving third, fourth and lateral ventricles and
involvement of corticospinal tracts have been
described.
• Brain lesions in NMOSD may show variable
enhancement.

26. MRI of the orbit
• It is important to include optic nerve imaging
as part of the MRI protocol for investigation of
a suspected case of CNS demyelinating
disorder.
• Optic nerve lesions are
– frequently extensive,
– bilateral,
– involving intracranial portions of the nerve and
frequently the optic chiasm

27. Paraclinical tests
• CSF shows
– a variable degree of
pleocytosis
– raised proteins
– Oligoclonal bands
(restricted to CSF) in 20%
– eosinophils.
• Histopathologically,
NMO is characterized
by
– astrocytic damage,
– demyelination,
– neuronal loss, and
– often pronounced
necrosis.

28. Optical coherence tomography (OCT)
• Noninvasive method that shows thinning of
the unmyelinated retinal axons otherwise
called retinal nerve fiber layer (RNFL) and their
neurons (retinal ganglion cells).
• The role of OCT in differentiating NMOSD
from MS and other inflammatory diseases, its
role in monitoring disease progress and
therapy is currently being investigated.

29. Electrophysiology- VEPs
• Visual evoked potentials are frequently altered
in NMO - prolonged P100 latencies in around
40 % and reduced amplitudes or missing
potentials in around 25 % of patients.

30. Biomarkers in NMOSD
• Antiaquaporin 4 antibody
– In 2004 antiaquaporin 4 antibody was discovered.
– Immunosuppressive therapy dramatically reduces its serum levels.
– Retesting may be necessary and preferably at the onset of a relapse in
such situations.
• AntiMOG antibody
– positive antimyelin associated oligoglycoprotein (antiMOG) may be
seen in Seronegative patients. MOG localizes to the outer surface of
oligodendrocytes and the myelin sheath
– They have a monophasic course
– Affect males equally as females.
– OPN, simultaneous and recurrent, may be more commonly associated.
– Myelitis involving the caudal portions of the cord is more likely.
• Other auto antibodies such as antiCV2/ CRMP5 and NMDA receptor
antibody have been shown to mimic NMOSD in isolated cases

31. • The search for additional biomarker
candidates in NMO has resulted in several
interesting leads, though they remain to be
further validated

33. B Cells
• B cell dysregulation appears to be at the core of
NMO/NMOSD pathogenesis.
• B cells expressing anti- AQP4 antibodies in the CSF and
elevated levels of circulating plasmablasts are found in
patients with acutely active NMO.
• Specific B cell subsets have been implicated as
potential biomarker candidates during relapses in
patients with NMOe.g. CD138+HLA-DR+ plasmablasts.
• Future focused analyses of B cell subsets (surface
biomarkers, idiotype, and affinity maturation) will be
necessary to identify and validate a prognostic or
therapeutic B cell biomarker in NMO.

34. CYTOKINES, CHEMOKINES, MOLECULAR
MARKERS OF INFLAMMATION
• Increased levels of additional inflammatory mediators have also been detected in
the serum or CSF of patients with NMO, including
– IL-1 receptor antagonist,
– IL-6,
– CCL8 (IL-8),
– IL-13,
– granulocyte colony-stimulating factor (GCSF),
– High Mobility Group Box 1 Protein,
– CXCL13 (BLC),
– CXCL10 (IP-10), and
– IL-13–responsive chitinase.
• In addition, cytokine and chemokine profile differences between NMO/NMOSD
and MS have been examined and may prove useful as future diagnostic
biomarkers.
• Despite the differential expression of these inflammatory markers in the serum of
patients with NMO, these markers are also observed in other systemic and
inflammatory conditions; thus, the specificity and utility of these biomarkers in
NMO remain to be investigated further.

35. MARKERS OF BBB BREAKDOWN
• Circulating AQP4-IgG may enter the CNS via the
disrupted BBB or may be generated intrathecally.
• Factors indicative of BBB integrity may serve as
surrogate markers of NMO disease activity e.g.
– matrix metalloproteinase-9 (MMP-9)- in degradation of
collagen IV.
– vascular endothelial growth factor-A (VEGF-A),
counterregulates claudin-5 and occludin at vascular tight
junctions and promotes BBB breakdown in demyelinating
disorders.
– intercellular adhesion molecule- 1 (ICAM-1) and
– vascular cell adhesion molecule- 1 (VCAM-1), which
support lymphocyte migration into the CNS

36. Th LYMPHOCYTE RESPONSE IN NMO
• There appears to be a direct relationship
between T activation, expansion, and enhanced
expression of TH1, TH17 cytokines, and APQ4-
specific T cells.
• Furthermore, presence of APQ4-specific T cells
has been observed.
• Elevation of IL-17 (from TH17 cells), CXCL8 IFN-g,
and GCSF levels in CSF were also observed in
patients.
• Recent findings also suggest that CD41: CD81 T
cell ratios may be of interest.

37. CNS PROTEINS AS BIOMARKERS
• Elevated levels of CNS proteins are detected in
sera and CSF of patients with NMO/NMOSD,
likely as part of compromised BBB and tissue
damage e.g.
– Neurofilament (NF) heavy-chain levels,
– GFAP and S100B (astrocytic markers),
– CSF and serum levels of S100B,
– CSF haptoglobin levels.

38. GENETIC BIOMARKERS
• There is no direct relationship between any
individual gene or gene locus and NMO/NMOSD,
suggesting multifactorial etiology with interplay
from environmental triggers.
• Genetic susceptibility loci include HLA-DPB1,e52
HLADRB1* 03:01, PD-1.3A allele of PTPN22, and
CD226 Gly307Ser.
• Although all of the above examples offer
reasonable insights, additional studies in larger
cohorts are necessary to explore potential
genetic contributions to NMO/NMOSD.

39. Treatment
Acute treatment

40. • Steroids are applied on 3-6 consecutive days with 1 g
methylprednisolone per day i.v. in combination with a proton pump
inhibitor and thrombosis prophylaxis-no evidence based study.
• In the case of a confirmed diagnosis of NMO, and depending on
severity of the attack, an oral steroid tapering period should be
considered.
• If the patient’s condition does not sufficiently improve or the
neurological symptoms worsen, therapeutic plasma exchange (5-7
cycles) can be performed-effective both in seropositive and in
seronegative patients.
• A second course of steroids can be applied at a higher dosage of up
to five times 2 g MP if Plasma exchange is contraindicated.
• Intravenous immunoglobulins 0.4 gm/kg for acute relapses shows
improvement- In contrast to evidence of a positive effect of PE, the
efficacy of intravenous immunoglobulin (IVIg) has not been
demonstrated in patients with severe demyelinating events such as
optic neuritis with severe visual impairment.

41. Treatment
Long-term treatment of NMO

42. • Long term treatment may be planned with
– Azathioprine
– Rituximab
– Mycophenolate mofetil
– Mitoxantrone
– Cyclophosphamide
– Methotrexate
– Natalizumab
– Eculizumab
– Fingolimod

43. Anti-IL-6 therapy and new therapies
• IL-6 plays a role in NMO, contributing to the
persistence of NMO-IgG-producing
plasmablasts in patients with NMO.
– A favorable effect of the IL-6 receptor-blocking
antibody tocilizumab, already licensed for therapy
of rheumatoid arthritis, in NMO patients who
have failed to respond to other therapies may be
another therapeutic option.

44. • The monoclonal antibody eculizumab is directed against the
complement component showed considerable efficacy in
NMO/NMOSD patients with disease activity. Patients will receive
eculizumab at a dose of 500mg IV each week for 4 weeks, 900mg IV
the fifth week, and thereafter 900mg every 2 weeks for 48 weeks.
• Some beneficial effect in animal models in vitro and in vivo, include
the use of
– competitive, non-pathogenic AQP4-specific antibodies (e.g.,
aquaporumab),
– neutrophilelastase inhibitors,
– antihistamines with eosinophil-stabilizing actions, and
– enzymatic AQP4-IgG deglycosylation or cleavage.
• Alemtuzumab, a B- and T-cell depleting antibody previously used in
MS trials with favorable outcome, did not show beneficial effects
when used in individual NMO patients

45. • Autologous hematopoietic stem cell transplantation
(AHSCT) trial involving NMO patients is expected to shed
light on whether some patients do benefit from the
therapy- ongoing in Australia.
• Serping 1 is a serine protease inhibitor that controls
bradykinin generation and prevents the initiation of
classical and lectine pathway activation. Recent findings
show that the carbohydrate moieties of serping 1 can
interact with E- and P-selectin on leukocyte and endothelial
cells and in future should prove interesting for use in
inflammatory diseases. In hereditary angioedema, current
IV infusion of serping 1 needs to be repeated every 34 days,
and is unlikely to prove useful in chronic conditions.

47. Azathioprine
• Prodrug form of 6-
mercaptopurine.
• Works as a purine antagonist
that gives negative feedback
on purine metabolism and
inhibits DNA and RNA
synthesis.
• Azathioprine reduces the
relapse rate and ameliorate
the neurological disability.
• Dose- 2 to 3 mg/kg/day p.o
• Treatment may only take full
effect after 3–6 months.
• Blood cell count and liver
enzyme monitoring are
mandatory.
Rituximab
• B cell depletion leads to effective
treatment of NMO in both
treatment-naıve patients and as a
second line therapy.
• RX treatment can be initiated using
one of two different regimens:
– four weekly 375 mg/m2 body surface
area (BSA)
– two 1 g infusions of RX at
an interval of 2 weeks or
• Premedication ( 1 g paracetamol,
100 mg prednisolone) should be
dispensed.
• Most patients remain B-cell
deficient for 6 months after RX
treatment, re-dosing every 6
months is considered to be an
adequate retreatment frequency.
• CD19/20-positive B cells and/or
CD27?memory cells may be used as
surrogate markers for treatment
monitoring and re-dosing

48. Cyclophosphamide
• Treatment is applied in
immunoablative doses
(2,000 mg/day for 4 days) or
• dose of 600 mg/m2 BSA per
administration (together
with uromitexan).
• The dose should be
adjusted according to
changes in the TLC.
Methotrexate
• Mainly prescribed as a
second line drug
• Reduces median relapse
rates
• Well tolerated.
• Disability stabilized or
improved.
• May be given as a
monotherapy or in
combination.

49. Mycophenolate mofetil
• MMF indirectly depletes the
guanosine pool in lymphocytes
and inhibits T- and B-cell
proliferation, dendritic cell
function and immunoglobulin
production, and inhibits B- and
T-cell transendothelial
migration and antibody
response
• Treatment reduces relapse
frequency and reduces
disability.
• Median dose 2,000 mg/day,
ranging between 750 and
3,000 mg.
• Response is quicker than
azathioprine.
Mitoxantrone
• Interacts with the enzyme
topoisomerase-2 and causes single- and
double-strand breaks by intercalating
the DNA through hydrogen bonding,
thereby delaying cell-cycle progression
by preventing ligation of DNA strands.
– MITO also inhibits B-cell functions,
including antibody secretion,
– abates helper and cytotoxic T-cell activity,
– decreases the secretion of Th1 cytokines
• There is a 75-80% reduction in relapse
rate.
• A dose of 12 mg/m2 BSA of
mitoxantrone administered i.v. monthly
for 3–6 months, followed by infusions
of 6–12 mg/m2 every 3 months.
• The maximum dose of mitoxantrone
was 100–120 mg/m2 BSA.
• Due to the side effects (cardiotoxicity,
therapy-related acute leukemia) and
the limited duration of the therapy, its
recommend as a second-line therpay.
maximum cumulative
• Dose should not exceed 100 mg/m2
BSA

50. Immunoglobulins
• High-dose IVIg are
potentially beneficial.
• Bimonthly IVIg treatment
(0.7 g/kg body weight/day
for 3 days) for up to 2 years.
Interferon-beta
• Interferon (INF)-beta should
not be used in patients with
NMO, it is shown to result in
NMO disease exacerbation.
• Interferon b (IFN b) induces an
inhibitory effect on the
proliferation of leukocytes,
antigen presentation and T-
cell migration across the blood
brain barrier and enhances
anti-inflammatory cytokine
production.

51. Natalizumab
• Treatment may cause
disease exacerbation in
NMO patients.
Fingolimod
• Clinical deterioration and
increased MRI activity was
found after initiation.

52. Prognosis

53. • The clinical course of the disease and
particularly mortality has improved from 30%
at 5 years to 9% at 6 years.
• It is likely due to
– greater awareness of the disease,
– access to anti AQP4IgG testing and
– use of longterm immunosuppressants.

55. References

56. • Lekha Pandit. Neuromyelitis optica spectrum disorders: An
update. Annals of Indian Academy of Neurology 2015; 18
(5):11-15.
• Corinna Trebst, Sven Jarius, Achim Berthele, Friedemann
Paul,Sven Schippling, Brigitte Wildemann et al. Update on
the diagnosis and treatment of neuromyelitis optica:
Recommendations of the Neuromyelitis Optica Study
Group (NEMOS). J Neurol 2014;261:1–16.
• Esther Melamed,Michael Levy, Patrick J. Waters, Douglas
Kazutoshi Sato, Jeffrey L. Bennett, Gareth R. John et al.
Update on biomarkers in neuromyelitis optica. Neurology:
Neuroimmunology & Neuroinflammation 2015;2; DOI
10.1212/NXI.0000000000000134.
• Nicolas Collongues , Je´roˆme de Seze. Current and future
treatment approaches for neuromyelitis optica.
Therapeutic Advances in Neurological Disorders 2011; 4(2)
:111-21.

57. THANK YOU