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-
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.
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.
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.
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.
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.
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).
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.
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.
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
32.
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.
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.
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.
46.
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.
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.
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