Multiple Sclerosis

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

Indications for Testing

  • Neurologic symptoms (sensory or motor) that do not fit other known neurologic diseases
    • See Clinical Presentation (Clinical 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 (2010), diagnosis for multiple sclerosis (MS) may include a lumbar tap with cerebrospinal fluid (CSF) analysis
    • 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 ~90% of patients
        • 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
    • CSF tests cannot rule out MS, but if suspicion is low and results are normal, then patient probably does not have MS
    • 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 therapy, then during 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)
    • Highest prevalence in Northern Europe
  • Age – mean onset is 20s-30s
  • Sex – M<F, 1:2-3
  • Ethnicity – most common in Caucasians

Risk Factors

  • Genetics
    • Most cases of MS are sporadic
      • 1-3% 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

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

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

Cell Count, CSF 0095018
Method: Cell Count/Differential

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

Additional Tests Available

Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

Comments

Aid in evaluation of suspected MS

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

Myelin Basic Protein 0080515
Method: Chemiluminescent Immunoassay

Comments

Not recommended for the evaluation of suspected multiple sclerosis

Preferred test is oligoclonal band profile

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Glucose, CSF 0020515
Method: Enzymatic

Lactic Acid, CSF 0020516
Method: Enzymatic

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

Comments

Rule out infectious process

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Comments

Preferred test to detect inflammatory processes

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Comments

May be helpful in assessing inflammatory process

Comprehensive Metabolic Panel 0020408
Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

Comments

May be helpful in assessing inflammatory process

Vitamin B12 and Folate 0070160
Method: Quantitative Chemiluminescent Immunoassay

Comments

Rule out B12 deficiency

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

Comments

Rule out ANCA-associated vasculitis

Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Borrelia burgdorferi Antibodies, Total by ELISA with Reflex to IgG and IgM by Western Blot (Early Disease) 0050267
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Antiphospholipid Syndrome Reflexive Panel 2003222
Method: Electromagnetic Mechanical Clot Detection/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

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

Krupp L, 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 C, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung H, Hemmer B, Killestein J, McFarland H, Oger J, Pachner A, Petkau J, Reder A, Reingold S, Schellekens H, Sørensen P. 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 E, Buckle G. 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 R, 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

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

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

Pelletier D, Hafler D. 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 M, 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 T, Tumani H, Abdul S, Husebye D, Seraj H, Hill H, Fire E, Spector L, Yarden J, Dotan N, Rose J. 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 D, Schmidt R, Wilson A, Freedman M, Grenache D. 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 T, Rose J, Gardiner G, Kusukawa N, Husebye D, Hill H. 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: January 2016