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
    • Borrelia testing for patients in endemic areas
    • Antiphospholipid syndrome testing for patients with history of recurrent miscarriage
    • Neuromyelitis optica (NMO) testing if patient has prominent visual symptoms
• 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 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

• Vision deficits
  • Glaucoma
  • Retinal detachment
  • Central serous retinopathy
  • Vasculitis
  • Neuromyelitis optica
  • Leber hereditary optic neuropathy
• Neurologic deficits
  • Metabolic disorders
    • B₁₂ deficiency
    • Copper deficiency
    • Leukodystrophies
    • Zinc deficiency
  • Autoimmune disorders
    • Sarcoidosis
    • Sjögren syndrome
    • Systemic lupus erythematosus
    • Antiphospholipid syndrome
    • Chronic inflammatory demyelinating polyradiculopathy
    • Behçet disease
  • Migraine
  • Acute demyelinating encephalomyelitis
• Tropical spastic paraparesis
• Other demyelinating disorders
  • Acute disseminated encephalomyelitis
• Vascular disorders
  • Cavernous hemangioma
  • CNS vasculitis
  • AV fistula
  • Susac syndrome
  • Stroke
• Neoplastic disorders
  • Spinal cord tumors
  • Paraneoplastic disorders
  • CNS lymphoma
  • Primary brain tumor
• Infectious disorders
  • Human herpesvirus 6
  • HIV myelopathy
  • HTLV-1 myelopathy
  • Borrelia burgdorferi
  • Meningovascular Treponema pallidum
  • Herpes simplex virus
  • Varicella-zoster virus
  • Progressive multifocal leukoencephalopathy
  • Mycobacterium tuberculosis
• Vasculitis
  • Primary angiitis
  • Polyarteritis nodosa
  • Wegener granulomatosis
• Genetic disorders
  • Wilson disease
  • Porphyrias
  • Hereditary spastic paraparesis
• Structural disorders
  • Spondylosis
  • Syringomyelia

Monitoring

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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: Quantitative Enzyme-Linked Immunosorbent Assay	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 & 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 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 & 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