Neuromyelitis Optica - NMO

Diagnosis

Indications for Testing

• Optic neuritis, acute myelitis, suspected multiple sclerosis with central nervous system symptoms

Criteria for Diagnosis (Wingerchuk, 2006 revised)

• Major criteria – presence of optic neuritis, acute myelitis and at least 2 of the following minor criteria
• Minor criteria
  • Contiguous spinal cord lesions on MRI extending >3 vertebral segments
  • Brain MRI findings not consistent with MS
  • NMO-IgG seropositive status (anti-AQP4 positive)
    • 70% sensitivity in patients with NMO

Laboratory Testing

• Nonspecific testing to rule out infection or vasculitis
  • CBC and differential
  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)
  • Anti-nuclear antibody (ANA)
  • Antineutrophil cytoplasmic antibodies (ANCA)
• Testing to rule out mimicking dieseases
  • Syphilis serology – rule out syphilis 
  • Angiotensin converting enzyme (ACE) serum – rule out neurosarcoidosis 
  • B₁₂ serum – rule out B₁₂ deficiency
• Testing to differentiate NMO from infection or MS
  • Cerebral spinal fluid (CSF)
    • Typically demonstrates pleocytosis ≥50 cells/mm³ (MS usually <50 cells/mm³) or ≥5 neutrophils/mm³ (MS usually presents with lymphocytosis); CSF eosinophils also common
    • Elevated protein level
    • Oligoclonal bands – may be present, but usually in ≤30% of cases (compared to ≥90% of patients with MS)
      • Bands typically disappear with time (as opposed to bands in MS)
      • IgG and IgG index – IgG typically elevated, index elevated in 10-30% of cases (MS elevated in>90%)
    • S-100 protein and glial fibrillary acidic protein (GFAP) – frequently elevated in acute phase
    • Matrix metalloproteinase 9 concentrations may be elevated (but are usually much more elevated in MS)
• Serologic marker
  • Aquaporin-4 (AQP4) receptor antibody – specific for NMO
    • Presence of antibody in patient with autoimmune disease suggests NMO and not a neurologic variant
    • Absence of marker does not rule out NMO (~25% seronegative)
    • Antibody detected in up to 60% of opticospinal MS cases
    • Detected by direct immunofluorescence, fluorescence immunoprecipitation, ELISA, and Western blot
    • Sensitivity 75%, specificity 90% in non-limited forms; drops to around 30-50% with isolated recurrent optic neuritis

Imaging Studies

• MRI is study of choice
  • Demonstrates enhancement of the optic nerve and spinal cord – typically large spinal cord lesions
  • White matter changes are rare (MS white matter lesions define the disease)
    • Usually located in AQP4-rich regions – hypothalamus, periaqueductal brain stem, cerebellum

Other Testing

• Evoked potentials (visual, auditory, somatosensory) – may be necessary in seronegative cases

Differential Diagnosis

• MS
  • Classic
  • Opticospinal MS
• Acute transverse myelitis
• Infectious
  • T. pallidum (neurosyphilis)
  • M. tuberculosis (optochiasmatic and spinal arachnoiditis)
  • HIV (neuro-AIDS)
  • West Nile virus 
  • Varicella-zoster virus 
  • Dengue fever 
• Vasculitis
  • SLE 
  • Antiphospholipid antibody disease 
  • Behçet disease
  • Sjögren syndrome 
• Adrenomyeloneuropathy
• Sarcoidosis
• Genetic
  • Neurofibromatosis
  • Arteriovenous malformations (with recurrent myelopathy)
• Drugs
  • Clioquinol toxicity
• Nutritional
  • B₁₂ deficiency
• Autoimmune
  • Myasthenia gravis (optic neuritis)

Monitoring

Clinical Background

The spectrum of transverse myelitis (TM) disorders includes neuromyelitis optica (NMO), multiple sclerosis (MS), longitudinally extensive spinal cord lesions/transverse myelitis (LESCL/LETM), optic spinal MS (OSMS), acute disseminated encephalomyelitis (ADEM), acute complete TM (ACTM), and acute partial TM (APTM).

NMO (also known as Devic disease, Devic syndrome, or Devic neuromyelitis optica) is an acquired demyelinating disease of the central nervous system that may mimic MS.

Epidemiology

• Incidence – rare; 1-4/100,000
• Sex – M<F, 1:3-9
• Age – 39 years (median for MS is 29 years)
• Ethnicity – more common in non-Caucasians (particularly African Americans, Asians, Pacific Islanders)

Pathophysiology

• Inflammatory disorder of the spinal cord and optic nerves
  • Involves white and gray matter
• Neuroanatomical lesions in spinal cord, optic nerve, brainstem, hypothalamus, and corpus callosum
  • Usually linear; Dawson finger configuration is absent
  • Lesions display edema, perivascular and parenchymal inflammatory infiltrates (neutrophils, eosinophils and macrophages), necrosis, and perivascular immunoglobulin deposition in rim or rosette pattern
• Aquaporin-4 (AQP4) 
  • Type III transmembrane protein
  • Regulates water entry into and out of specific brain cells and interfaces with blood vessels
  • Brain contains aquaporin 1, 4 and 9 (4 in highest concentration)
  • Overwhelming evidence indicates AQP4 antibody has a pathogenic role in development of NMO

Clinical Presentation

• NMO follows two general courses
  • Monophasic
    • Rapid, sequential episodes with moderate recovery
  • Relapsing
    • Extended intervals (can be months or years) between episodes followed by severe relapses
• Ophthalmic – visual disturbance, ocular pain, unilateral or bilateral optic neuritis
• Neurologic – symmetrical paraparesis or quadriparesis, bladder and bowel dysfunction, severe sensory loss below the level of myelitis
• Neurologic and ophthalmic symptoms can occur simultaneously or in discrete attacks separated by weeks to years
• Coexisting autoimmune inflammatory disorders
  • Systemic lupus erythematosus (SLE)
  • Sjögren syndrome
  • Celiac disease

Treatment

• Intravenous methylprednisone – typically used to treat cases acutely
  • Some patients may develop steroid refractory disease 
  • In these cases, consider plasma exchange or intravenous immunoglobulins

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory