Neuromyelitis optica spectrum disorder

NeuroMyelitis Optica
Spectrum Disorder
DR BHAVIN J PATEL
DM NEUROLOGY RESIDENT
MBS HOSPITAL, KOTA

Introduction
• Inflammatory disorders of the central nervous system characterized by
severe, immune-mediated demyelination and axonal damage
predominantly targeting optic nerves and spinal cord.
• The first clinical descriptions of NMO emerged over a century ago by
Devic and Gault
• Over time, significant variation in the presenting features, clinical course,
and the degree of accumulated disability in patients with presumed NMO
has been observed.

Introduction
• It was previously believed that NMO and multiple sclerosis represented
one disease entity, with variable phenotypes and expression.
• The discovery of a disease-specific serum NMO-IgG antibody has led to
increased understanding of a diverse spectrum of disorders.
• NMO is now recognized as a distinct clinical entity based on unique
immunologic features.

Introduction
• In 2007, the term NMO spectrum disorders (NMOSD) was introduced.
1. AQP4-IgG-seropositive patients with limited or inaugural forms of
NMO
2. Encompassed the cerebral, diencephalic, and brainstem lesions that
occur in a minority of patients
3. AQP4-IgG-seropositive patients with coexisting autoimmune disorders
4. Patients diagnosed with opticospinal MS

Epidemiology
• Prevalence of NMO in various studies ranges from 0.5 to 10 per 100,000
• India it was 2.7/100,000
• Female: male – 9:1 (recurrent NMO)
• In monophasic NMO:- men and women are affected equally
• Median age of onset is 32 to 41 years,

Epidemiology
• 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.

Pathogenesis
• An autoimmune inflammatory cascade leads to florid demyelination and
axonal injury.
• Necrosis and cavitation typically involve both gray and white matter.
• NMO is thought to be primarily mediated by the humoral immune system.
The spectrum of neuromyelitis optica, lancet neurology 2oo7; 6;805

(A)Extensive demyelination of the
grey matter and white matter at the
level of the thoracic cord (Luxol
fast blue-periodic acid Schiff)
(B) Extensive axonal injury, necrosis
and associated cavitation
(Bielschowsky silver impregnation)
(C) and (D) The inflammatory
infiltrate contains perivascular and
parenchymal eosinophils and
granulocytes

Histopathologic examination of NMO
lesions shows immunoglobulin and
complement deposits

Pathogenesis
• Several lines of evidence support an autoimmune pathogenesis for NMO:-
1. NMO disease-specific autoantibody, the NMO-IgG antibody, also
referred to as the aquaporin-4 (AQP4) autoantibody
2. NMO is frequently associated with systemic autoimmune disorders.
3. Antinuclear autoantibodies are common in patients with NMO patients
who lack evidence of a systemic disorder
4. Therapeutic plasma exchange and immunosuppressive therapies are
beneficial for treatment and prevention of acute NMO attacks

AQP4is expressed at the blood–brain barrier, on
the ‘‘foot-like’’ processes of astrocytes, whereas
MOG is expressed by oligodendrocytes and on the
outermost surface of myelin sheaths
AQP4-IgG is synthesised in the bloodstream by
mature B-cells. On crossing the blood–brain barrier
it activates complement-mediated astrocyte damage
MOG-IgG is also produced outside of the
CNS. It causes a demyelination

Clinical features
• Hallmark features of NMO include acute attacks of optic neuritis or
transverse myelitis with a typically relapsing course
• Attacks most often occur over days, with variable degrees of recovery
over weeks to months.
• Central nervous system involvement outside of the optic nerves and spinal
cord is recognized in patients with NMO and NMOSD.
• No clinical features are disease-specific, some are highly characteristic

Clinical features
Optic neuritis:-
• Optic neuritis presents with varying degrees of vision loss
• Associated with eye pain that worsens with movement of the eye.
• Visual loss is generally more severe in NMO
• Majority of optic neuritis attacks in NMO are unilateral, sequential optic
neuritis in rapid succession or bilateral simultaneous optic neuritis is
highly suggestive of NMO
EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010;
17:1019.

Clinical features
Transverse myelitis:-
• It is defined as spinal cord dysfunction developing over hours or days in
the absence of a structural spinal cord lesion
• Symmetric 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)

Brain Involvement
• 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%).

Brain Involvement
• 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.

Brain Involvement
• Large confluent lesions in frontal, parietal, and occipital lobes were
observed manifesting clinically as homonymous hemianopia, aphasia, and
cognitive impairment.
• 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.

Brain Involvement
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

Brain Involvement
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

Brainstem symptoms
• Involvement of the brainstem occurs in almost one-third of patients NMO
and NMOSD
• Brainstem is rich in AQP4 ag.
• Number and pattern of brainstem involvement has no difference in
pediatric and adult age group.
• Common in AQP4 Ig G Ab positive patients.

Brainstem symptoms
• Mc brainstem symptoms :- vomiting and hiccups.
• Due to area postrema involvement.
• Small percentage of NMOSD patients with this symptoms have lesion in
area postrema on conventional imaging.
• Lesion in this area do not progress to demyelination or necrosis.

Brainstem symptoms
• 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.

Muscle involvement
• 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.

Cutaneous manifestation
• Nonspecific cutaneous manifestations such as erythematous
rash, sclerodactyly, and bilateral edema of the hands have been
noted in the setting of NMOSD, although these have been
limited to isolated case reports

Nonspecific neurological symptoms

Paediatric NMOSD
• Most clinical, neuroimaging, and laboratory characteristics of pediatric
NMOSD are similar to those of adult-onset disease except:-
1. The female preponderance may be of lower magnitude
2. A greater proportion of children may have monophasic disease
3. Detection of a LETM MRI lesion associated with acute myelitis may be less specific
for NMOSD
• Children with an ADEM-like event that includes optic neuritis and LETM,
may be required observation of the clinical course and testing of AQP4-
IgG status to achieve confident diagnosis.
International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Neurology® 2015;85:177–189

 Organ specific Comorbid
conditions:-
 Subacute combined degeneration
 Autoimmune encephalitis
 Idiopathic intracranial hypertension
 Hashimoto thyroiditis
 Myasthenia gravis
 Hematological immune disease
 Hypertrophic pachymeningitis
 Postural orthostatic tachycardia
syndrome
 Osmotic demyelination syndrome
 Posterior reversible encephalopathy
syndrome
Non organ specific Comorbid
conditions
 Systemic sclerosis
 Systemic lupus erythematosus
 Sjögren’s syndrome
 Mixed connective tissue
 Dermatomyositis
 Bacterial meningomyelitis
 Celiac disease
 Spinocerebellar ataxia type 31
Neuropsychiatric Disease and Treatment 2017:13 2653–2660

NMOSD coexisting with subacute combined
degeneration
• AQP4 is also expressed in diverse organs such as the stomach, skeletal
muscle, inner ear, and kidneys.
• AQP4-IgG may inhibit the production of intrinsic factor and gastric acid
secretion by parietal cells with resultant vitamin B12 malabsorption.
• Ishii et al reported the case of a 36-year-old Japanese woman who
simultaneously had NMOSD with AQP4-IgG and subacute combined
degeneration

NMOSD coexisting with anti-NMDAR
encephalitis
• NMOSD overlapping anti-NMDAR encephalitis is increasingly noted, as
evidenced by the simultaneous detection of both NMDAR antibodies and
AQP4-IgG in serum samples
• In 2017, Ran et al succinctly summarized the clinical characteristics of 34
patients who presented with both NMOSD and anti-NMDAR encephalitis
• Further studies are still needed to thoroughly investigate the association
between NMOSD and anti-NMDAR encephalitis

Multisystem involvement in neuromyelitis optica
• 13-year-old girl initially presented with
nausea and intractable vomiting
• creatine kinase (CK) to 5,018, lactate
dehydrogenace (LDH) to 1000,
• 4 months later with blindness due to
left-sided optic neuritis
• Antibodies to aquaporin-4 (AQP-4) were
positive in the serum
• treated with methylprednisolone pulse
followed by rituximab
Langille MM, Desai J. Multisystem involvement in neuromyelitis optica. Ann Indian
Acad Neurol 2015;18, Suppl S1:56-8

Disease pattern
• The presenting symptom was usually either ON or TM, especially among
seropositive patients.
• Simultaneous TM and ON, bilateral ON, and monophasic course were
relatively more common presentations among seronegative patients
• Has a relapsing course in > 90%
• Relapse occurs within first year in 60 percent of patients and within three
years in 90 percent

Disease pattern
• Young-onset disease commonly presenting with ON and had a high risk of
visual disability.
• An older age of onset was significantly associated with motor disability.
• Seropositive and seronegative patients did not differ in terms of age of
onset, time to relapse, relapse rates and mortality rate.

Disease pattern
• Periaqueductal ,grey matter, hypothalamic, and area postrema lesions may
be more often seen in seropositive patients.
• Patients with cerebral presentations may have continued brain attacks
without involvement of optic nerves or spinal cord

Diagnostic criteria
• Original criteria proposed by Wingerchuk et al., in 1996 was revised in
2006 after the discovery of anti AQP4-IgG.
Absolute Criteria
• Transverse myelitis and optic neuritis
Supportive Criteria
• At least two of the following features:
1. MRI brain negative/nondiagnostic for MS
2. MRI spinal cord lesion extending over ≥3 vertebral segments (LETM)
3. NMO-IgG seropositivity

Diagnostic criteria
Neurology® 2015;85:177–189

Red flags: Findings atypical for NMOSD
Neurology® 2015;85:177–189

Investigations
Cerebrospinal fluid (CSF) analysis:-
• CSF pleocytosis can include or be dominated by 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. (30%)

Investigations
Cerebrospinal fluid (CSF) analysis:-
• Neurofilament heavy chain (NfH) and glial fibrillary acidic protein
(GFAP) levels are significantly higher in the CSF of NMO than in patients
with MS .
• Analysis of CSF provides supportive data for the diagnosis of NMO and
CSF should be obtained during or shortly after an acute attack.
• The findings are useful, but not highly sensitive or specific

Investigations
• Electrophysiological study:-
• VEP, SEP and BAEP examination in patients with NMO
frequently reveal abnormalities.
• peripheral nerve conduction studies are expected to be normal.

Investigations
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. doi:10.1136/jnnp-2012-302310

Investigations
• Most commonly used method:-Indirect immunofluorescence (IIF)
(sensitivity of 58–76% and a specificity of 85–99%)
• In addition, there are four other assay techniques:-
1. Cell-based assays (CBA), ( 80% sensitivity)
2. Radioimmunoprecipitation assays,
3. Fluoroimmunoprecipitation assays (FIPA) (53%)
4. Enzyme-linked immunosorbent assays (ELISA) (60%)

Investigations
• Prognostic marker for high-risk syndromes
• NMO-IgG/AQP4 antibodies can be present in patients years before and
after clinical disease activity.
• It also remains to be determined whether NMO-IgG/AQP4 antibodies are
a reliable marker of disease activity and treatment response.

Investigations
Anti-myelin associated oligoglycoprotein (anti- MOG):-
• A proportion of patients with AQP4-IgG seronegative NMOSD have been
found to have serum antibodies against myelin-oligodendrocyte
glycoprotein (MOG-IgG).
• In MOG-IgG disease the sex difference is less (M:F, 1:3) and only 9% of
patients have a second autoimmune disorder
• Complete recovery from attacks appears more common with MOG-IgG
J Neurol DOI 10.1007/s00415-017-8445-8

Investigations
Other laboratory tests:-
• CBC, ESR, vitamin B12
• Antibodies associated with connective disorders (ANA/ENA, anti-ds-
DNA antibodies, lupus anticoagulant, antiphospholipid antibodies, ANCA,
etc.
• Treponema pallidum hemagglutination assay,
• Paraneoplastic antibodies (in particular, anti-CV2/CRMP5 and anti-Hu).

Neuroimaging
Neurology® 2015;85:177–189

Treatment:- acute exacerbation
Steroids:-
• Initial or recurrent episodes are usually treated with high-dose intravenous
methylprednisolone (1 g daily for three to five consecutive days).
• Acute NMO symptoms respond to short courses of high-dose intravenous
corticosteroids in up to 80% of patients within 1–5 days
• Treatment is generally well tolerated
• Median ARR reduced from 1.48 to 0.49

Plasma exchange:-
• Therapeutic plasmapheresis was effective in patients with severe
symptoms that fail to improve or progress despite treatment with
corticosteroids.
• Plasma exchange should be done up to seven treatments every other day.
(1–1.5 ltr plasma volume per exchange)

IV Immunoglobulin:-
• Might be effective in NMO given the potential humoral
immunopathogenesis.
• However, there are only very few supportive data in the literature.
• A case series of eight Spanish NMO patients showed positive results using
bimonthly IVIg treatment (0.7 g/kg body weight/day for 3 days) for up to
2 years

• In case of unresponsiveness to steroids, early initiation of a rescue therapy
with plasmapheresis is indicated.
• Prior to escalation therapy, a repeated course of high-dose corticosteroids
may be considered

Prevention of relapse
• 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 6–12 months.

Azathioprine:-
• Purine synthesis inhibitor and interferes with the proliferation of cells,
especially leucocytes.
• Azathioprine (75–100 mg daily) in combination with oral prednisolone (1
mg/kg/ daily).
• Haematological evaluations are required every 2–4 weeks, the dosage may
be reduced in the course and treatment duration of up to 5 years may be
considered

• Side effects:-
• gastrointestinal complaints and leucopenia very common (>10%)
• infections, allergy and haematological disturbances were common (1–10%)
Mycophenolate mofetil:-
• Mycophenolate (p.o. 1–3 g/ day)
• The occurrence of treatment effect is more rapid for mycophenolate than for
azathioprine

Cyclophosphamide:-
• Non-specific immunosuppressant that affects both T-cell and B-cell
functions
• I.v. cyclophosphamide range from 7 to 25 mg/kg every month over a
period of 6 months.
• Uromitexan administration with every dose needs to be included for
prevention of haemorrhagic cystitis.
• Occurrence of amenorrhea and sepsis has to be taken into account

Methotraxate:-
• Inhibition of dihydrofolate reductase and has anti-inflammatory and
immunomodulatory effect
• Mainly prescribed as second-line drug, was associated with a significant
decrease in the median annualized relapse rate (ARR) and was relatively
well-tolerated.

Mitoxantrone;-
• An anthracenedione antineoplastic agent that intercalates with DNA and
inhibits both DNA and RNA synthesis
• 12 mg/m2 monthly for 6 months, followed by three more treatments, each
3 months apart.
• Bone marrow suppression, opportunistic infection and cardiomyopathy.
• Amenorrhoea is a major concern in the treatment of young women
• Therapy related acute leukaemia

Rituximab:-
• A chimeric anti-CD20 monoclonal antibody capable of depleting mature
and precursor B cells
• Dose:-(1)375 mg/m2 infused once per week for 4 weeks
(2) 1000 mg infused twice, with a 2-week interval between the infusions
• To date, no incidents of progressive PML have been reported in NMO.
• Whether long-term RX treatment at lower doses suppress disease activity
is requires further investigation to confirm.

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

Drugs that are ineffective or worsen NMO
• Interferon beta
• Natalizumab
• Fingolimod
• Glatiramer acetate is also not beneficial in NMOSD

• Long-term treatment options should be initiated as soon as the diagnosis of
NMO is made
• Prevention of attacks is the key issue for reducing permanent disability.
• Seronegative NMO is treated in the same way as seropositive NMO
• Immunosuppressants seem to work to varying degrees, and cost, convention,
convenience, availability, side effects and familiarity of the treating physician to
the drug are the guiding factors in its choice at present.
EFNS GUIDELINES/CME ARTICLE ,European Journal of Neurology 2010, 17: 1019–1032
doi:10.1111/j.1468-1331.2010.03066

EFNS guidelines
doi:10.1111/j.1468-1331.2010.03066

Treatment in spatially limited NMO spectrum disorders
RION/BON and LETM

Emerging therapy
• Combination therapies
• Stem cell trials are still in their infancy; three are in progress, two with
haematopoietic cells and one using mesenchymal umbilical cord cells
• Humanised anti-CD20 monoclonal antibodies, ofatumumab and
ocrelizumab
• specific protective monoclonal antibodies that bind AQP4
(Aquaporumab)
doi:10.1111/j.1468-1331.2010.03066

Emerging therapy
Serping 1
• serine protease inhibitor that controls bradykinin generation and prevents
the initiation of classical and lectine pathway activation
• A proof-of-concept trial has used purified human C1-esterase inhibitor
Cinryze as an adjunct to IVMP in the treatment of ten patients with acute
exacerbation.

Emerging therapy
Complement inhibitors:-
• Eculizumab is a C5-specific humanized monoclonal antibody that inhibits C5a
generation
• 14 AQP4-IgG seropositive patients with highly active disease were treated with
eculizumab for 12 months .12 patients became relapse-free and two had possible
relapses.
• Dose of 500mg IV each week for 4 weeks, 900mg IV the fifth week, and thereafter
900mg every 2 weeks for 48 weeks
doi:10.1111/j.1468-1331.2010.03066

Ongoing trials
doi:10.1111/j.1468-1331.2010.03066

Symptomatic treatment
Neuropathic pain:-
• Antiepileptic drugs (gabapentin, pregabalin, carbamazepine), or
• low-dose tricyclic antidepressants (amitriptyline and nortriptyline).
• Painful tonic spasms usually respond to carbamazepine or topiramate
Fampridine:- blocks potassium channels
• Improves ambulation has been safely used in a few patients with
NMOSD and may be similarly beneficial to MS.
Antispamodic medication:- baclofen or tizanidine
J Neurol DOI 10.1007/s00415-017-8445-8

Symptomatic treatment
Bladder dysfunction:-
• Antimuscarinic agents (oxybutynin, tolterodine and solifenacin) and
mirabegron
• Improving urinary frequency and urgency
• Intermittent self-catheterisation
• Injection of botulinum toxin into the bladder wall
• Nocturia, cautious use of desmopressin nasal spray at bedtime will reduce
the volume of urine produced overnight.
J Neurol DOI 10.1007/s00415-017-8445-8

Key points…..
• A single clinical manifestation is not diagnostic when AQP4-IgG is not
detected.
• No single characteristic is exclusionary but some are considered red flags
that signal the possibility of alternative diagnoses
• NMOSD must be considered in the differential diagnosis in patients
presenting with short myelitis lesions.
Neurology® 2015;85:177–189

Key points…..
• AQP4-IgG seronegative patients with clinical and neuroimaging features
of NMOSD should be screened for anti-MOG antibody.
• Current immunotherapeutic strategies are the same for relapsing NMO
and NMOSD, regardless of AQP4-IgG serologic status

Future directions….
• Expanding understanding of pathogenesis and clinical scenario
• Role of established biomarker and invention of new biomarker
• Diagnostic criteria for pediatric and monophasic NMOSD
• Development of new immunosuppressive therapy

References
• Bradely textbook of neurology, 7th edition
• Uptodate.com
• The spectrum of neuromyelitis optica, lancet neurology 2oo7; 6;805
• International consensus diagnostic criteria for neuromyelitis optica
spectrum disorders ,Neurology® 2015;85:177–189
• J Neurol DOI 10.1007/s00415-017-8445-8

References
• EFNS GUIDELINES/CME ARTICLE ,European Journal of
Neurology 2010, 17: 1019–1032
• Jacob A, et al. J Neurol Neurosurg Psychiatry 2013;84:922–930.
• Neuropsychiatric Disease and Treatment 2017:13 2653–2660
• Langille MM, Desai J. Multisystem involvement in neuromyelitis
optica. Ann Indian Acad Neurol 2015;18, Suppl S1:56-8
• Int J Neurosci. 2016 Oct;126(10):863-6. Epub 2015 Nov 19.

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