Multiple Sclerosis

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

Indications for Testing

  • Neurologic symptoms (sensory or motor) that do not fit other known neurologic diseases
    • See Clinical Presentation (Background tab)

Laboratory Testing

  • Use revised McDonald diagnostic criteria
  • Initial testing – screen for most common diseases
    • CBC, metabolic panel, C-reactive protein, vitamin B12, antinuclear antibody, rheumatoid factor, thyroid stimulating hormone, HIV
    • Other tests based on clinical presentation
  • If patient does not meet radiologic criteria for revised McDonald criteria (Polman, 2010), diagnosis for multiple sclerosis (MS) may include a lumbar tap with cerebrospinal fluid (CSF) analysis
  • CSF tests cannot rule out MS, but if suspicion is low and results are normal, then patient probably does not have MS
    • Preferred CSF tests are oligoclonal bands (OCBs) and IgG index
      • Must be performed in parallel with serum sample obtained within 72 hrs of lumbar puncture (Karussis, 2014)
      • Most sensitive/specific method is isoelectric focusing on agarose gels
        • Considered the gold standard for testing
      • OCBs present in ~95% of patients (Fitzner, 2015)
        • OCBs may also occur in central nervous system (CNS) disease involving other autoimmune disorders, infection, or trauma
          • Criteria for positive test requires presence of ≥2 bands in CSF that are not also present in serum in relapsing-remitting MS (Karussis, 2014)
            • PPV 97%, NPV 84%
            • Sensitivity 91%, specificity 94%
      • IgG index >0.66 is indicative of MS – present in ~70-95% of patients (Karussis, 2014)
      • Myelin basic protein – not recommended for evaluation of suspected MS due to low diagnostic specificity​​​
    • Other CSF tests may be useful to rule out other diseases
      • Cell count
        • Lymphocyte pleocytosis common in MS
        • If cell count >50 WBC cells/mm3, seek other diagnosis
      • Glucose, protein, lactate
        • Typically normal in MS
        • If protein >100 mg/dL, seek other diagnosis

Imaging Studies

  • MRI
    • Primary diagnostic/prognostic tool
    • Presence of gadolinium-enhancing white matter lesions – use of revised McDonald diagnostic criteria may help determine likelihood of MS
    • Definitive diagnosis per McDonald criteria requires ≥2 clinical attacks and ≥2 lesions on an MRI

Other Testing

  • Evoked potential testing (visual, somatosensory, or brainstem auditory) – visual most useful and will be delayed in MS in large number of patients

Prognosis

  • Largely unpredictable
    • 10% do well >20 years (so-called benign MS)
    • 70% have secondary progression
  • Relapses are frequent in the first 2 years after disease is identified

Differential Diagnosis

  • Interferon beta neutralizing antibodies (IFNβ) – aid in management of individuals using interferon beta
    • Receiving IFNβ at 12 months and 24 months after initiating therapy
    • Who have never been tested but have been receiving IFNβ for >24 months
    • Experiencing relapse
    • Under consideration for a change in therapy (test prior to changing therapy)
  • Natalizumab
    • Antibodies aid in management of individuals receiving natalizumab therapy and who
      • Experience allergic reactions
      • Experience a clinical relapse
      • Show MRI evidence of disease activity
    • JC virus antibodies
      • Risk stratification for progressive multifocal leukoencephalopathy (PML) – test prior to starting natalizumab therapy, then during therapy (~18 months after starting therapy)
      • Positive antibody at any time points to an increased risk for PML

Multiple sclerosis (MS) is a relapsing and often progressive autoimmune disorder of the white matter (myelin) of the central nervous system (CNS).

Epidemiology

  • Incidence – 10-250/100,000 (Karussis, 2014)
  • Age – mean onset is 20s-30s
  • Sex – M<F, 1:2-3
  • Ethnicity – highest prevalence in Northern Europe

Risk Factors

  • Genetics
    • Most cases of MS are sporadic
      • Small chance of developing MS if parent or sibling had disease
    • 31% concordance rate among monozygotic twins
    • Presence of HLA-DR2 increases risk
  • Residence in northern latitude
  • Infection with Epstein-Barr virus has been linked to MS

Pathophysiology

  • Immune-mediated disorder associated with the synthesis of immunoglobulins by the CNS, reflecting local immune response
  • Pathologic hallmark is demyelinated plaques (lesions)
    • Lesions have a predilection for optic nerves, spinal cord white matter, periventricular white matter, brain stem, and cerebellum
  • Forms (DeAngelis, 2014)
    • Relapsing-remitting – 85-90% of patients initially
      • Discrete attacks followed by some degree of recovery
    • Progressive
      • Primary – steady functional decline from disease onset
      • Secondary – relapsing-remitting disease becomes progressive and deficits are not associated with acute attacks
      • Radiologically isolated syndrome – incidental findings on MRI in the absence of active disease

Clinical Presentation

  • Early
    • Sensory disturbances (predominantly in arms and legs)
    • Unilateral optic neuritis
      • May present with vision loss, visual field cuts, pain, afferent pupillary defect
    • Diplopia (internuclear ophthalmoplegia)
    • Lhermitte sign (trunk and limb paresthesias evoked by neck flexion)
    • Motor weakness described by patient as limb weakness (legs>arms, unilateral>bilateral)
    • Clumsiness
    • Ataxia, gait problems
    • Transverse myelitis
    • Trigeminal neuralgia – if bilateral or in a young patient
    • Uhthoff sign – transience worsening or emergence of neurological symptoms (eg, vision loss) related to a change in body temperature during fever, hot bath, or exertion
    • Urinary symptoms – urgency, frequency
  • Late
    • Cortical signs – aphasia, apraxia, seizures
    • Extrapyramidal signs – chorea, rigidity
    • Cognitive dysfunction
    • Vertigo
    • Progressive quadriparesis and sensory loss
    • Spasticity
    • Fatigue
    • Pain syndromes

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.

Oligoclonal Band Profile 0080440
Method: Qualitative Isoelectric Focusing/Electrophoresis/Nephelometry

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

Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

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

Interferon Beta Neutralizing Antibody with Reflex to Titer 2003390
Method: Cell Culture/Chemiluminescent Immunoassay

Natalizumab Antibodies 2005593
Method: Qualitative Bridging Enzyme-Linked Immunosorbent Assay

Related Tests

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]

Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ M, Sellebjerg F, Tourtellotte WW. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005; 62(6): 865-70. PubMed

Freeman JW, Landis J, VanDemark M. Multiple sclerosis: an essential review. S D Med. 2007; 60(6): 231-3, 235. PubMed

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

Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung H, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekens H, Sørensen PSoelberg. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010; 9(7): 740-50. PubMed

General References

Ali EN, Buckle GJ. Neuroimaging in multiple sclerosis. Neurol Clin. 2009; 27(1): 203-19, ix. PubMed

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

Coles A. Multiple sclerosis. Pract Neurol. 2009; 9(2): 118-26. PubMed

Dale RC, Brilot F, Banwell B. Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol. 2009; 22(3): 233-40. PubMed

De Hu Z, Deng A. Autoantibodies in pre-clinical autoimmune disease. Clin Chim Acta. 2014; 437: 14-8. PubMed

Deangelis TM, Miller A. Diagnosis of multiple sclerosis. Handb Clin Neurol. 2014; 122: 317-42. PubMed

Fitzner B, Hecker M, Zettl UKlaus. Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients Autoimmun Rev. 2015; 14(10): 903-13. PubMed

Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin. 2011; 29(2): 381-8. PubMed

Harrison DM. In the clinic. Multiple sclerosis. Ann Intern Med. 2014; 160(7): ITC4-2-ITC4-18; quiz ITC4-16. PubMed

Karussis D. The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun. 2014; 48-49: 134-42. PubMed

Pelletier D, Hafler DA. Fingolimod for multiple sclerosis. N Engl J Med. 2012; 366(4): 339-47. PubMed

Saguil A, Kane S, Farnell E. Multiple sclerosis: a primary care perspective. Am Fam Physician. 2014; 90(9): 644-52. PubMed

Srivastava R, Murphy MJ, Jeffery J. Cerebrospinal fluid: the role of biochemical analysis. Br J Hosp Med (Lond). 2008; 69(4): 218-21. PubMed

Yeh A, Chitnis T, Krupp L, Ness J, Chabas D, Kuntz N, Waubant E, US Network of Pediatric Multiple Sclerosis Centers of Excellence. Pediatric multiple sclerosis. Nat Rev Neurol. 2009; 5(11): 621-31. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Brettschneider J, Jaskowski TD, Tumani H, Abdul S, Husebye D, Seraj H, Hill HR, Fire E, Spector L, Yarden J, Dotan N, Rose JW. Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases. J Neuroimmunol. 2009; 217(1-2): 95-101. PubMed

Greene DN, Schmidt RL, Wilson AR, Freedman MS, Grenache DG. Cerebrospinal fluid myelin basic protein is frequently ordered but has little value: a test utilization study. Am J Clin Pathol. 2012; 138(2): 262-72. PubMed

Martins TB, Rose JW, Gardiner GL, Kusukawa N, Husebye D, Hill HR. Cell-based reporter gene assay for therapy-induced neutralizing antibodies to interferon-beta in multiple sclerosis. J Interferon Cytokine Res. 2013; 33(2): 52-7. PubMed

Medical Reviewers

Last Update: April 2016