Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder of the white matter (myelin) of the central nervous system (CNS). MS is disseminated in time (DIT), meaning that the appearance of new CNS lesions occurs over time, and disseminated in space (DIS), meaning that different areas of the brain are affected (Reich, 2018). Common causes for focal neurological disorders should be ruled out prior to a diagnosis of MS. Although MS is by definition a condition that persists over time, a clinically isolated event, which is often in retrospect the presenting episode of MS, should be rigorously evaluated to assist in decision-making about early initiation of treatment. Diagnosis of MS is clinical, with support from magnetic resonance imaging (MRI) findings; however, cerebrospinal fluid (CSF) testing can be useful in equivocal cases.

Diagnosis

Indications for Testing

Focal neurological changes that relapse and remit, and are not accounted for by other diagnoses

Laboratory Testing

  • Use revised McDonald diagnostic criteria
  • CSF analysis
    • Preferred CSF tests are oligoclonal bands (OCBs) and IgG index
      • OCBs present in ~95% of patients (Fitzner, 2015)
      • Most sensitive/specific method is isoelectric focusing on agarose gels – considered the gold standard for testing
      • Tests must be performed in parallel with serum analysis using sample obtained within 72 hours of lumbar puncture (Karussis, 2014)
      • Criteria for positive test requires presence of two or more OCBs in CSF that are not also present in serum in relapsing-remitting MS (Karussis, 2014)
        • Positive predictive value (PPV), 97%; negative predictive value (NPV), 84%
      • OCBs may also occur in CNS disease involving other autoimmune disorders, infection, or trauma
      • International Panel on Diagnosis of MS recommends CSF OCB testing in the following situations (Thompson, 2018)
        • Insufficient clinical and imaging (MRI) evidence
        • Atypical presentation of clinically isolated syndrome (eg, progressive course at onset)
        • Atypical clinical, imaging, or laboratory presentation
        • Individual is from population with lower risk for MS (older age, younger age, nonwhite)
      • 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
      • Lymphocyte pleocytosis common in MS
      • If cell count >50 white blood cells/mm3, seek other diagnosis
    • Glucose, protein, lactate
      • Typically normal in MS
      • If protein >100 mg/dL, seek other diagnosis
  • Testing to screen for other common diseases
    • CBC, metabolic panel, C-reactive protein – nonspecific disease indicators
    • Vitamin B12 – deficiency can cause reversible neurological symptoms
    • Antinuclear antibody – lupus cerebritis
    • Treponemal/nontreponemal testing –  neurosyphilis
    • Thyroid stimulating hormone – hypothyroidism, hyperthyroidism
    • HIV – HIV-associated neuroinflammation
    • Other tests based on clinical presentation
      • Neuromyelitis optica (NMO) testing – if patient has prominent visual symptoms
        • Aquaporin-4 receptor (AQP4) antibody testing
      • Antiphospholipid syndrome testing – for patients with history of recurrent miscarriage
      • Borrelia testing – for patients from endemic areas

Differential Diagnosis

Monitoring

  • Interferon beta (IFNβ) neutralizing antibody testing – aid in management of individuals using IFNβ
    • Test at 12 months and 24 months after initiating therapy
    • In patients who have never been tested but have been receiving IFNβ for >24 months
    • In patients experiencing relapse
    • In patients under consideration for a change in therapy (test before changing therapy)
  • Natalizumab
    • Antibody testing aids in management of individuals receiving natalizumab therapy and who
      • Experience allergic reactions
      • Experience a clinical relapse
      • Show MRI evidence of disease activity
    • JC virus antibody testing
      • Risk stratification for progressive multifocal leukoencephalopathy (PML) – test before starting natalizumab therapy, then during therapy (~18 months after starting therapy)
      • Positive antibody at any time suggests an increased risk for PML

Background

Epidemiology

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

Risk Factors

  • Genetics (Reich, 2018)
    • Most cases of MS are sporadic
      • Slightly increased risk of developing MS if parent or sibling has disease
    • 30-50% concordance rate among monozygotic twins
    • Presence of HLA DRB1*1501 increases risk
  • Residence in northern latitude (Reich, 2018)
  • Tobacco, obesity, mononucleosis associated with increased MS risk (Reich, 2018)

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 (experienced more often in legs than in arms, and more often unilaterally than bilaterally)
    • 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

ARUP Laboratory Tests

Preferred test in the workup of MS

Detect unique IgG OCBs in CSF in conjunction with a matched serum specimen

Calculate CSF IgG index

Profile includes:

  • IgG: serum, CSF, index
  • Albumin: CSF, serum by nephelometry, index
  • CSF: IgG/albumin ratio, IgG synthesis rate, OCBs

Use for assessment of MS

Detect unique IgG OCBs in CSF in conjunction with a matched serum specimen

Preferred test is OCB profile

Index test aids in the workup of suspected MS

Preferred test is OCB profile

Aid in evaluation of NMO and NMO spectrum disorders

Overall agreement between enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody (IFA) detection methods: 96%

ELISA is not suitable for detecting AQP4 antibodies in CSF

Test performance may vary due to differences in methods and/or disease states (new versus established)

Absence of AQP4 receptor antibodies does not rule out NMO

Aid in management of individuals treated with IFNβ

Reflex pattern: if IFNβ neutralizing antibody screen result is positive, then IFNβ neutralizing antibody titer will be added

Aid in the management of individuals who are receiving natalizumab therapy

Related Tests

Not recommended for the workup of suspected MS

Preferred test is OCB profile

Rule out infectious process

May be helpful in assessing inflammatory process

Panel includes sodium, serum/plasma; potassium, serum/plasma; chloride, serum/plasma; carbon dioxide, serum/plasma; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; urea nitrogen, serum/plasma; glucose, serum/plasma; creatinine, serum/plasma; calcium, serum/plasma; protein total, serum/plasma; albumin, serum/plasma; bilirubin total, serum/plasma; anion gap

Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Aid in detection of vitamin B12 and folate deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease

Aid in initial diagnosis of connective tissue disease

A negative ANA by IFA test does not rule out the presence of systemic autoimmune rheumatic disease

Reflex pattern: if ANA are detected by ELISA, then ANA, HEp-2, IgG by IFA will be added

Aid in the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides

Consider ordering this test in conjunction with cyclic citrullinated peptide (CCP) antibody, IgG to increase specificity and sensitivity

Rheumatoid arthritis panel is preferred test

Preferred test for screening and monitoring of thyroid function

Reflex pattern: if HIV-1,2 combo antigen/antibodies screen is repeatedly reactive, then  HIV-1 antibody confirmation by Western Blot will be added

Preferred reflex test to detect Lyme disease in individuals with ≤4 weeks of clinical symptoms or exposure to tick

Reflex pattern: if ELISA result is 1.00 LIV or greater, then IgG and IgM immunoblot will be added

Preferred initial panel for strong suspicion of antiphospholipid syndrome

Panel includes beta-2 glycoprotein 1 antibody, IgG; beta-2 glycoprotein 1 antibody, IgM; cardiolipin antibody, IgG; cardiolipin antibody, IgM; prothrombin time; partial thromboplastin time (PTT); dilute Russell viper venom time (dRVVT); thrombin time; reptilase time; PTT heparin neutralized; PTT 1:1 mix (performed if PTT >48 seconds); platelet neutralization procedure (performed if PTT 1:1 mix >48 seconds); dRVVT 1:1 mix (performed if dRVVT >44 seconds); dRVVT confirmation test (performed if dRVVT 1:1 mix >44 seconds); hexagonal phospholipid neutralization

Reflex pattern: if PTT and dRVVT are normal, then no further testing is performed; if PTT is abnormal, thrombin time is added; if thrombin time is normal, PTT 1:1 mix is added; if thrombin time is abnormal, reptilase time and PTT heparin neutralization are added; if PTT heparin neutralization is abnormal, PTT 1:1 mix is added; if PTT 1:1 mix is abnormal, platelet neutralization procedure is added; if dRVVT is abnormal, dRVVT 1:1 mix is added; if dRVVT 1:1 mix is abnormal, dRVVT confirmation is added; if platelet neutralization procedure and dRVVT confirmation are normal, or if one is normal and the other is not performed, hexagonal phospholipid neutralization is added

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory, ARUP Laboratories
Contributor

Hill

Harry R. Hill, MD
Professor of Clinical Pathology, Pediatrics, and Medicine, University of Utah
Medical Director, Cellular and Innate Immunology, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®