Neuromyelitis Optica - Devic Syndrome

Diagnosis

Indications for Testing

  • Optic neuritis
  • Acute myelitis
  • Suspected multiple sclerosis (MS) in combination with central nervous system symptoms

Criteria for Diagnosis (Wingerchuk, 2006 revised)

  • Major criteria
    • Optic neuritis
    • Acute myelitis
  • At least 2 of the following supportive criteria
    • Contiguous spinal cord lesions on MRI extending >3 vertebral segments
    • Brain MRI inconsistent with MS
    • Neuromyelitis optica (NMO)-IgG seropositive status (anti-AQP4 positive)

Laboratory Testing

  • Rule out other diseases that may mimic NMO in presentation
  • Nonspecific testing to rule out infection or vasculitis
    • CBC with differential
    • Erythrocyte sedimentation rate (ESR)
    • C-reactive protein (CRP)
    • Antinuclear antibody (ANA)
    • Antineutrophil cytoplasmic antibodies (ANCA)
  • Specific testing to rule out diseases with similar presentation
    • VDRL or RPR 
    • Angiotensin converting enzyme (ACE)
    • Vitamin B12
    • Testing to differentiate NMO from MS
      • Typical CSF presentations

        Typical CSF Presentations

        MS

        NMO

        Pleocytosis (≥50 cells/mm3)

        No

        Yes

        Cell type

        Lymphocytosis

        ≥5 neutrophils/mm3

        Protein level

        Normal

        Elevated

        Oligoclonal bands

        ≥90% of patients

        May be present; usually in ≤30% of cases

        Oligoclonal bands disappear with time

        No

        Yes

        IgG

        Not elevated

        Typically elevated

        IgG index

        Elevated in >90% of cases

        Elevated in 10-30% of cases

        S-100 protein

        Not elevated

        Frequently elevated in acute phase

        Glial fibrillary acidic protein (GFAP)

        Not elevated

        Frequently elevated in acute phase

        Matrix metalloproteinase 9 concentrations

        May be elevated (usually much higher level than NMO)

        May be elevated

        NMO autoantibody (AQ4P)*

        Usually not present

        May be present

        *NMO autoantibody testing using CSF concurrently with AQ4P serum tests increases sensitivity for NMO

  • Serologic marker
    • Aquaporin 4 (AQP4) receptor antibody – relatively high specificity for NMO
      • Detected by direct immunofluorescence, fluorescence immunoprecipitation, ELISA, and Western blot
      • Sensitivity/specificity of test
        • Presence in patient with autoimmune disease suggests NMO and not a neurologic variant (70% sensitivity)
        • Absence does not rule out NMO (~25% seronegative)
        • Detected in up to 60% of opticospinal MS cases
        • Sensitivity 75%, specificity 90% in nonlimited forms
        • ~30-50% with isolated recurrent optic neuritis

Imaging Studies

  • MRI
    • Study of choice
      • Enhancement of the optic nerve and spinal cord – typically large spinal cord lesions
      • White matter changes are rare
        • Usually located in AQP4-rich regions – hypothalamus, periaqueductal brain stem, cerebellum
        • Different from MS, which is defined by white matter lesions

Other Testing

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

Differential Diagnosis

Monitoring

  • AQP4 antibody – levels should 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 – 35-45 years (older than patients with MS)
  • Ethnicity – more common in non-Caucasians (particularly African Americans, Asians, Pacific Islanders)

Pathophysiology

  • Inflammatory disorder of the spinal cord and optic nerves
    • Involves white matter 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 aquaporins 1, 4 and 9 (aquaporin 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
    • Sequential and longitudinally extensive transverse myelitis
  • 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 not uncommon

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
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    
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