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 diseases
  • 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)
      • NMO autoantibody testing in conjunction with serum tests increases sensitivity
  • 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

Monitoring

  • AQP4 antibody – expect levels to decrease with effective therapy

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

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Rule out infectious process

   
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification
May be helpful in assessing inflammatory process    
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

May be helpful in assessing inflammatory process

   
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

First-line test for connective tissue disease screening

All ELISA results reported as detected are further tested by IFA

ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

 
Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Differentially diagnose systemic vasculitic syndromes

If screen is positive, titer and MPO/PR-3 antibodies testing will be added to aid in antibody determination

   
Angiotensin Converting Enzyme, Serum 0080001
Method: Quantitative Enzymatic

May be helpful in evaluation for neurosarcoidosis

   
Vitamin B12  0070150
Method: Quantitative Chemiluminescent Immunoassay

Rule out B12 deficiency

   
Rapid Plasma Reagin (RPR) with Reflex to Titer 0050471
Method: Semi-Quantitative Charcoal Agglutination

Rule out syphilis

   
Cell Count, CSF 0095018
Method: Cell Count/Differential

May be helpful in differentiating infectious vs. inflammatory process in the CNS

   
Protein Electrophoresis, CSF 0050590
Method: Quantitative Electrophoresis

Assist in the clinical assessment of suspected MS

   
Oligoclonal Bands in CSF and Serum 0081135
Method: Qualitative Isoelectric Focusing/Electrophoresis

Assist in the clinical assessment of suspected MS

Isoelectric focusing and immunofixation is considered to be the gold standard test for the detection of oligoclonal bands in CSF

MBP will increase in patients with head trauma or anoxic brain damage

 
Aquaporin-4 Receptor Antibody 2003036
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Confirm NMO

Assess disease progression

Presence of AQP4 antibodies should be used in conjunction with diagnostic criteria for NMO; positive AQP4 antibody results should not be used as sole diagnosis of NMO

Absence of marker does not rule out NMO

 
Neuromyelitis Optica (NMO)/Aquaporin-4-IgG (AQP4), CSF 2008593
Method: Qualitative Indirect Fluorescent Antibody
Use in conjunction with serum autoantibody tests in the diagnosis of NMO