Multiple Sclerosis

Diagnosis

Indications for Testing

  • Course of neurologic symptoms (sensory or motor) that do not fit other known neurologic diseases (see Clinical Presentation in the Clinical Background tab)

Laboratory Testing

  • Initial testing – screen for more common diseases
    • CBC, metabolic panel, sedimentation rate, vitamin B12, antinuclear antibody, rheumatoid factor, thyroid stimulating hormone, HIV
    • Other tests based on clinical situation
  • Diagnosis for multiple sclerosis (MS) may include a lumbar tap with cerebrospinal fluid (CSF) analysis or MRI and evoked potential testing
    • CSF examination
      • Preferred tests are oligoclonal bands (OCBs) and IgG index
        • OCBs present in 90-95% of patients
          • OCBs have modest specificity for MS – may also occur in central nervous system (CNS) disease involving other autoimmune disorders, infection, or trauma
            • Isoelectric focusing and immunofixation is considered the gold standard test for detection of OCBs in CSF
            • Criteria for positive test requires presence of ≥2 bands in CSF that are not also present in serum
        • IgG index – >0.66 is indicative of MS (elevated in ~75% of patients)
      • Myelin basic protein – not recommended for workup of suspected MS due to low diagnostic specificity
      • Other tests
        • Cell count – rule out presence of infectious agent (meningitis)
          • Lymphocyte pleocytosis common
          • If cell count >50 cells/mm, seek other diagnosis
        • Glucose, protein, lactate
          • Typically normal
          • If protein >110 mg/dL, seek other diagnosis
  • Aquaporin-4 receptor antibody – consider this test for differentiation of MS from NMO in difficult-to-diagnose cases with clinical symptoms that share characteristics with NMO

Imaging Studies

  • MRI – presence of gadolinium-enhancing white matter lesions; 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
    • Abnormally delayed potentials indicate positive result

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

Monitoring

  • Interferon beta neutralizing antibodies – 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 (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

Clinical Background

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

Epidemiology

  • Incidence
    • 10-20/100,000
    • Highest prevalence in Northern Europe (30/100,000)
  • 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
    • Relapsing/remitting
    • Progressive
      • Primary – gradual progression of disability
      • Secondary – relapsing-remitting course, becomes progressive

Clinical Presentation

  • Early
    • Sensory disturbances
    • Unilateral optic neuritis – may be initial presentation; pain with vision loss
    • Diplopia (internuclear ophthalmoplegia)
    • Lhermitte sign (trunk and limb paresthesias evoked by neck flexion)
    • Limb weakness
    • Clumsiness
    • Ataxia, gait problems
    • Transverse myelitis
    • Trigeminal neuralgia in a young patient suggests MS
    • 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
  • Late
    • Cortical signs – aphasia, apraxia, seizures
    • Extrapyramidal signs – chorea, rigidity
    • Cognitive impairment
    • Vertigo
    • Progressive quadriparesis and sensory loss
    • Spasticity

Treatment

  • Corticosteroids – high doses used most often in acute relapses
  • Interferons – beta 1-a, beta 1-b
  • Glatiramer acetate
  • Mitoxantrone
  • Natalizumab therapy (Tysabri)
  • Possible adjunct therapies include methotrexate, plasma exchange, intravenous immune globulin

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

Rule out presence of infectious agent (meningitis)

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

Differentiate multiple sclerosis from neuromyelitis optica

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

Aids 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

Aids 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

Assist in the clinical assessment of suspected MS

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

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

Myelin Basic Protein 0080515
Method: Chemiluminescent Immunoassay

Not recommended for the workup of suspected multiple sclerosis

Preferred test is oligoclonal band profile

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Normal value in MS

Glucose, CSF 0020515
Method: Enzymatic

Normal value in MS

Lactic Acid, CSF 0020516
Method: Enzymatic

Normal value in MS

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

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 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: Clotting/Semi-Quantitative Enzyme-Linked Immunosorbent Assay