Neuromyelitis Optica - Devic Disease

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Optic neuritis
  • Acute myelitis
  • Spinal cord lesions (suspected multiple sclerosis [MS] in combination with central nervous system symptoms)
  • Autoimmune encephalitis

Criteria for Diagnosis

  • Required for diagnosis of NMO (Wingerchuk, 2007)
    • Major criteria
      • Presence of optic neuritis, acute myelitis, and at least two of the following minor criteria
    • Minor criteria
      • Contiguous spinal cord lesions on MRI extending >3 vertebral segments
      • Brain MRI findings not consistent with MS
      • Neuromyelitis optica (NMO)-IgG seropositive status (anti-aquaporin-4 [AQP4]-positive)
        • 70% sensitivity in individuals with NMO
  • New criteria divide disease into two proposed categories (Wingerchuk, 2015)
    • NMO spectrum disorders (NMOSD) with AQP4-IgG
    • NMOSD without AQP4-IgG
    • Pediatric NMOSD also proposed

Laboratory Testing

  • Rule out other diseases that may mimic NMO in presentation
  • Nonspecific testing to rule out infection or vasculitis
    • CBC with differential
    • Urine analysis with sediment examination
    • C-reactive protein (CRP)
    • Antinuclear antibody (ANA)
    • Antineutrophil cytoplasmic antibodies (ANCA)
  • Specific testing to rule out diseases with similar presentation
    • Venereal disease research laboratory (VDRL) or rapid plasma reagin (RPR)
    • Angiotensin converting enzyme (ACE)
    • Vitamin B12
    • Consider paraneoplastic antibodies (in particular anti-Hu and anti-CV2/CRMP5)
    • Other rare causes based on history
      • Copper deficiency
      • Zinc toxicity
    • Cerebrospinal fluid (CSF) testing to differentiate NMO from MS
  • Antibody testing
    • AQP4 receptor antibody detected in serum – 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
    • AQP4 receptor antibody detected in CSF – positive test increases sensitivity of diagnosis if present

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

  • AQP4 receptor antibody – levels may decline in response to therapy

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 (Trebst, 2014)
  • Sex – M<F, 1:5 for relapsing NMO
  • 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 (myelitis) and optic nerve (optic neuritis)
    • 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
  • Neurologic
    • Sequential and longitudinally extensive transverse myelitis
    • Symmetrical paraparesis or quadriparesis
    • Bladder and bowel dysfunction
    • Variable degree of  sensory loss below the level of myelitis (may be severe)
  • Neurologic and ophthalmic symptoms can occur simultaneously or in discrete attacks separated by weeks to years
  • Other organ involvement
    • Hypothalamic dysfunction
    • Cognitive impairment
    • Encephalopathy
  • Coexisting autoimmune inflammatory disorders not uncommon
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.

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

Limitations 

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

ELISA is not suitable for detecting AQP4 antibodies in CSF; ELISA result must be positive at time of initial evaluation

Test performance may vary due to differences in methods and/or disease states (new versus established)

Aquaporin-4 Receptor Antibody, IgG by IFA with Reflex to Titer, Serum 2013320
Method: Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

Test performance may vary due to differences in methods and/or disease states (new versus established)

Negative result can occur in the setting of immunosuppression

Aquaporin-4 Receptor Antibody by ELISA with Reflex to Aquaporin-4 Receptor Antibody, IgG by IFA 2013327
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/ Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

ELISA is not suitable for detecting AQP4 antibodies in CSF; ELISA result must be positive at time of initial evaluation

Test performance may vary due to differences in methods and/or disease states (new versus established) 

Aquaporin-4 Receptor Antibody, IgG by IFA, CSF with Reflex to Titer 2011699
Method: Semi-Quantitative Indirect Fluorescent Antibody

Limitations 

Negative result can occur in the setting of immunosuppression

Test performance may vary due to differences in methods and/or disease states (new versus established) 

Autoimmune Encephalitis Reflexive Panel 2013601
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Radioimmunoassay

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

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

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

Limitations 

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

In order to confirm local production of oligoclonal IgG in CSF, a matched serum specimen is required

Oligoclonal bands present in CSF, but not in serum, indicate central nervous system production

Oligoclonal band profile will increase in patients with head trauma or anoxic brain damage

ANCA-Associated Vasculitis Profile (ANCA/MPO/PR-3) with Reflex to ANCA Titer 2006480
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Limitations 

Negative antibody testing does not rule out ALD

All interpretation of antibody patterns must be done in conjunction with clinical presentation

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity 

Angiotensin Converting Enzyme, Serum 0080001
Method: Quantitative Enzymatic

Vitamin B12 0070150
Method: Quantitative Chemiluminescent Immunoassay

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

Cell Count, CSF 0095018
Method: Cell Count/Differential

Protein Electrophoresis, CSF 0050590
Method: Quantitative Electrophoresis

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Krupp LB, Banwell B, Tenembaum S, International Pediatric MS Study Group. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007; 68(16 Suppl 2): S7-12. PubMed

Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, Galetta SL, Hutchinson M, Johnson RT, Kappos L, Kira J, Lublin FD, McFarland HF, Montalban X, Panitch H, Richert JR, Reingold SC, Polman CH. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008; 14(9): 1157-74. PubMed

General References

Chang K, Ro L, Lyu R, Chen C. Biomarkers for neuromyelitis optica. Clin Chim Acta. 2015; 440: 64-71. PubMed

Drori T, Chapman J. Diagnosis and classification of neuromyelitis optica (Devic's syndrome). Autoimmun Rev. 2014; 13(4-5): 531-3. PubMed

González C, González-Buitrago JM, Izquierdo G. Aquaporins, anti-aquaporin-4 autoantibodies and neuromyelitis optica. Clin Chim Acta. 2013; 415: 350-60. PubMed

Matà S, Lolli F. Neuromyelitis optica: an update. J Neurol Sci. 2011; 303(1-2): 13-21. PubMed

Nandhagopal R, Al-Asmi A, Gujjar AR. Neuromyelitis optica: an overview. Postgrad Med J. 2010; 86(1013): 153-9. PubMed

Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012; 11(6): 535-44. PubMed

Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, Pasquier RA, Polman CH, Sorensen PS, Hemmer B. EFNS guidelines on diagnosis and management of neuromyelitis optica Eur J Neurol. 2010; 17(8): 1019-32. PubMed

Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, Borisow N, Kleiter I, Aktas O, Kümpfel T, Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS) J Neurol. 2014; 261(1): 1-16. PubMed

Weinshenker B. Neuromyelitis Optica. National Organization for Rare Disorders. Danbury, CT [Accessed: Sep 2015]

Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG, International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Neurology. 2015; 85(2): 177-89. PubMed

Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007; 6(9): 805-15. PubMed

Medical Reviewers

Last Update: August 2016