Multiple Sclerosis


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


  • 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

Clinical Background

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


  • 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


  • 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
Test Name and Number Recommended Use Limitations Follow Up
Oligoclonal Band Profile 0080440
Method: Qualitative Isoelectric Focusing/Electrophoresis/Nephelometry

Preferred CSF test for the workup of suspected multiple sclerosis

Detects oligoclonal bands in CSF and calculates the CSF IgG index

Profile includes

  • IgG, serum
  • IgG, CSF
  • IgG index
  • Albumin, CSF
  • Albumin, serum by nephelometry
  • Albumin index
  • CSF IgG/albumin ratio
  • CSF IgG synthesis rate
  • CSF oligoclonal bands
Cell Count, CSF 0095018
Method: Cell Count/Differential

Evaluate for presence of infection

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

Aid in differentiation of sclerosis from neuromyelitis optica

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

Aid in management of individuals

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

Aid in the management of individuals who are receiving natalizumab therapy and

  • Experience allergic reactions
  • Experience a clinical relapse
  • Show MRI evidence of disease activity
Additional Tests Available
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

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

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

Rule out infectious process

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Preferred test to detect inflammatory processes

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

May be helpful in assessing inflammatory process

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

May be helpful in assessing inflammatory process

Vitamin B12 and Folate 0070160
Method: Quantitative Chemiluminescent Immunoassay

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

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