Neuromyelitis Optica Spectrum Disorders (NMOSD)

Historical Background & Definition

Pathophysiology

• AQP4-IgG (an IgG1 autoantibody) binds to AQP4 on astrocytic endfeet at capillaries, the pia, and Virchow-Robin spaces, and around the central canal of the spinal cord.
• This triggers complement activation (C5b-9 membrane attack complex), producing a "rim and rosette" pattern of immune complexes.
• The result is primary inflammatory astrocytopathy with secondary demyelination - distinct from MS which is primarily oligodendrocyte/myelin-targeted.
• Inflammatory infiltrate includes T cells, B cells, macrophages, and uniquely for NMOSD: neutrophils and eosinophils.
• Areas of damage show necrosis, vascular immunoglobulin and complement deposition, and loss of AQP4 expression.

Epidemiology

• Bradley and Daroff's Neurology in Clinical Practice; Grainger & Allison's Diagnostic Radiology

Core Clinical Characteristics (Wingerchuk 2015 Criteria)

1. Optic Neuritis (ON) - typically severe, often bilateral, involving long segments of the optic nerve and frequently the posterior optic pathway (chiasm, optic tracts). Recovery may be incomplete.
2. Acute Myelitis - characteristically a longitudinally extensive transverse myelitis (LETM): contiguous spinal cord lesion spanning ≥3 vertebral segments, often extending from cervical to thoracic cord. Affects motor, sensory, and bowel/bladder function.
3. Area Postrema Syndrome - intractable nausea, vomiting, or hiccups due to dorsal medulla involvement; presenting symptom in up to 10% of patients.
4. Acute Brainstem Syndrome - double vision, dysphagia, ataxia, oculomotor dysfunction, respiratory compromise.
5. Symptomatic Narcolepsy or Acute Diencephalic Syndrome - with typical NMOSD diencephalic MRI lesions (hypothalamic involvement causes anorexia, hypothermia, hypersomnia, inappropriate diuresis).
6. Symptomatic Cerebral Syndrome - with typical NMOSD brain lesions (corticospinal tract, periventricular).

• Grainger & Allison's Diagnostic Radiology (Table 58.4); Bradley and Daroff's Neurology in Clinical Practice (Table 80.5)

Diagnostic Criteria (Wingerchuk et al., Neurology, 2015)

AQP4-IgG Seropositive NMOSD

1. At least 1 core clinical characteristic
2. Positive AQP4-IgG (cell-based assay strongly recommended; sensitivity 76.7%, specificity 99.8%)
3. Exclusion of alternative diagnoses

AQP4-IgG Seronegative NMOSD (or unknown status)

1. At least 2 core clinical characteristics from ≥1 attack, with:
   • At least one must be ON, LETM myelitis, or area postrema syndrome
   • Dissemination in space (two or more different core characteristics)
   • Fulfillment of additional MRI requirements
2. Negative AQP4-IgG or unavailable
3. Exclusion of alternative diagnoses

Investigations

CSF

• Pleocytosis >50 leukocytes/mm³ (often with neutrophils and eosinophils) is common
• Oligoclonal bands (OCBs): present in only 10-20% (vs. 80-90% in MS) - Bradley and Daroff's

AQP4-IgG

• Cell-based assay: sensitivity ~76-80%, specificity ~94-100%

MOG-IgG (anti-MOG)

• Found in a subset of AQP4-seronegative patients
• Also seen with ADEM, isolated ON, LETM
• Associated with younger age of onset, equal sex ratio, more often monophasic course, better prognosis

MRI Findings

Spinal Cord

Sagittal T2 MRI: confluent hyperintense LETM spanning the entire cervicothoracic cord - the hallmark of NMOSD (Adams and Victor's Principles of Neurology)

Three patterns of NMOSD spinal cord involvement: (A) LETM with intense peripheral enhancement, (B) pseudo-syringomyelia (T1 hypointense), (C) bright spotty sign - highly specific for NMOSD (Grainger & Allison's Diagnostic Radiology)

• LETM (≥3 contiguous vertebral segments) - most specific finding
• Central location (gray matter predominance) on axial
• Bright spotty sign (T2 hyperintense foci) - differentiates from MS
• T1 hypointensity ("pseudo-syrinx") indicates necrosis
• Peripheral/rim contrast enhancement in acute phase
• Progression to atrophy and syrinx formation

Optic Nerve

Optic chiasm involvement in NMOSD: T2 hyperintense enhancing lesion (arrows) causing bilateral visual loss (Grainger & Allison's Diagnostic Radiology)

• Bilateral and longitudinally extensive, typically >1/2 optic nerve length
• Predominantly posterior optic pathway: intracranial optic nerves, chiasm, optic tracts
• Acute: T2 hyperintensity + gadolinium enhancement; chronic: atrophy

Brain

Brain MRI in NMOSD: T2-FLAIR lesions involving (A) corpus callosum, (B) hypothalamus (arrow), (C) dorsal pons, and (D) large corticospinal tract lesion (Grainger & Allison's Diagnostic Radiology)

• Hypothalamus, periependymal areas, corpus callosum (long "pencil-thin" lesions, unlike MS's short ovoid ones)
• Dorsal brainstem adjacent to 4th ventricle (area postrema)
• Periventricular/periaqueductal white matter
• Large hemispheric white matter lesions (atypical for MS)

NMOSD vs. MS: Key Differentiators

MOG Antibody-Associated Disease (MOGAD) - Key Distinctions

• Demographics: More common in children/young adults; nearly equal sex ratio (vs. female predominance in AQP4+)
• Course: Often monophasic or episodic; persistent high titers predict relapsing course
• ON: Disc edema prominent; long optic nerve involvement; often bilateral
• Myelitis: Lower in spinal cord, can be short-segment or LETM; area postrema syndrome less common
• Prognosis: Better than AQP4+ NMOSD; less severe neurological deficits; but bowel/bladder/erectile dysfunction can be permanent
• Pathology: Demyelination targets oligodendrocytes (not astrocytes); no complement deposition

Clinical Course & Prognosis

• ~85% relapsing course with severe, stepwise disability accumulation
• Unlike MS, progressive course without relapses is rare
• Individual attacks tend to be more severe: complete blindness or paralysis from single attacks is common
• Respiratory failure from high cervical myelitis is a major cause of death
• AQP4-seropositive patients: more severe attacks, higher relapse rate, worse outcomes vs. seronegative
• Untreated: ~50% of patients become blind in one eye or need walking support within 5 years

Treatment

Acute Attack Management

1. High-dose IV methylprednisolone - 1 g/day for 5-10 days, followed by oral prednisone taper
2. Plasma Exchange (PLEX) - 5-7 exchanges at 1.5 plasma volumes - used for:
   • Severe attacks not responding to steroids
   • Attacks with serious neurological deficit (early use improves outcomes)
   • May be used as first-line in severe attacks
3. IVIG - alternative for incomplete steroid recovery

Relapse Prevention (Long-term Immunotherapy)

• Rituximab (anti-CD20 B-cell depletion)
• Mycophenolate mofetil
• Azathioprine
• Mitoxantrone, cyclophosphamide (limited use)

• Eculizumab/ravulizumab: Meningococcal vaccination mandatory; monitor for meningococcal infection (boxed warning)
• Inebilizumab: Monitor serum IgG and CBC (neutropenia risk)
• Satralizumab: Screen for HBV, TB; monitor LFTs and CBC; weight gain in ~30%

Recent Evidence

Differential Diagnosis Summary

• Multiple sclerosis - OCBs, periventricular lesions, no AQP4-IgG, short cord lesions
• ADEM - typically monophasic, post-infectious, pediatric, MOG-IgG common
• Systemic autoimmune disease (SLE, Sjögren's) - may coexist or mimic; always test AQP4-IgG in these patients presenting with myelitis/ON
• Spinal cord infarction - DWI positive, vascular risk factors
• Paraneoplastic myelopathy - search for occult malignancy if atypical
• Sarcoidosis - leptomeningeal enhancement, systemic features