Multiple Sclerosis

Indications for Testing

Course of neurologic symptoms (sensory and/or motor) that do not fit other known neurologic diseases

Laboratory Testing

Cerebrospinal fluid (CSF) examination
- Oligoclonal bands present in 90-95% of patients
  - Not specific for MS – may occur in CNS disease involving autoimmune disorders, infection or trauma
- Cell count – rule out presence of infectious agent (meningitis)
  - Lymphocyte pleocytosis (probably not MS if cell count >50 cells/mm)
- Glucose, protein, lactate – normal in MS
- Myelin basic protein – increased in about 80% of patients during active attack and remains elevated for 5-6 weeks
- IgG index – >0.7 is indicative of MS

Imaging Studies

MRI – presence of gadolinium-enhancing white matter lesions; revised McDonald diagnostic criteria may be helpful
Diagnosis for MS generally includes a lumbar tap with CSF analysis, MRI, and evoked potential testing plus an appropriate clinical setting
- Definitive diagnosis per McDonald criteria requires ≥2 clinical attacks and ≥2 lesions on an MRI

Other Testing

Evoked potential testing (visual) positive
- Abnormally delayed potentials indicates positive result

Prognosis

Largely unpredictable from individual to individual
- 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
- Migraine
- Antiphospholipid syndrome
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
Infectious disorders
- Human herpesvirus 6
- HIV myelopathy
- HTLV-1 myelopathy
- Borrelia burgdorferi
- Meningovascular Treponema pallidum
- Herpes simplex virus
- Varicella-zoster virus
- Progressive multifocal leukoencephalopathy
Vasculitis
- Primary angiitis
- Polyarteritis nodosa
- Wegener granulomatosis
Genetic disorders
- Wilson disease
- Porphyrias
- Hereditary spastic paraparesis
Structural disorders
- Spondylosis
- Syringomyelia

Interferon beta neutralizing antibody – test for antibodies if patient
- Is experiencing decreased efficacy of interferon-related therapy (experiencing relapse)
- Has been receiving interferon >24 months
- Is receiving interferon therapy at 12 months with previous negative test

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
- 31% concordance rate among monozygotic twins
- Presence of HLA-DRB2 increases risk of MS
Residence in Northern latitude

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
  - Secondary (relapsing/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

Tests generally appear in the order most useful for common clinical situations

Test name: Oligoclonal Band Profile

ARUP #: 0080440

Methodology: Qualitative Isoelectric Focusing/Immunofixation/Nephelometry

Use:

Assist in the clinical assessment of suspected MS

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

Limitations: Isoelectric focusing and immunofixation is considered to be the gold standard test for the detection of oligoclonal bands in CSF

Test name: Cell Count, CSF

ARUP #: 0095018

Methodology: Cell Count/Differential

Use:

Rule out presence of infectious agent (meningitis)

Test name: Interferon Beta Neutralizing Antibody with Reflex to Titer

ARUP #: 2003390

Methodology: Cell Culture/Chemiluminescent Immunoassay

Use:

Detect antibodies in patients who are failing interferon therapy

Additional Tests Available

Test name: Immunoglobulin G, CSF Index

ARUP #: 0050676

Methodology: Quantitative Nephelometry

Comments:

Assist in the clinical assessment of suspected MS

Test name: Oligoclonal Bands in CSF and Serum

ARUP #: 0081135

Methodology: Qualitative Isoelectric Focusing/Immunofixation

Comments:

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

Test name: Myelin Basic Protein

ARUP #: 0080515

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Assist in the clinical assessment of demyelination activity for MS

Order in conjunction with oligoclonal bands testing

MBP will increase in patients with head trauma or anoxic brain damage

Test name: Protein, Total, CSF

ARUP #: 0020514

Methodology: Reflectance Spectrophotometry

Comments:

Normal value in MS

Test name: Glucose, CSF

ARUP #: 0020515

Methodology: Enzymatic

Comments:

Normal value in MS

Test name: Lactic Acid, CSF

ARUP #: 0020516

Methodology: Enzymatic

Comments:

Normal value in MS

Test name: Aquaporin-4 Receptor Antibody

ARUP #: 2003036

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Differentiate multiple sclerosis from neuromyelitis optica

Test name: Natalizumab Antibodies

ARUP #: 2005593

Methodology: Qualitative Bridging Enzyme-Linked Immunosorbent Assay

Comments:

Antibodies to natalizumab may develop in some patients with may prevent or diminish therapeutic effects of drug

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Brettschneider J, Jaskowski TD, Tumani H, Abdul S, Husebye D, Seraj H, Hill HR, Fire E, Spector L, Yarden J, Dotan N, Rose JW. 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

Grenache, David G., PhD. Medical Director, Special Chemistry at ARUP Laboratories; Associate Professor of Pathology (Clinical), University of Utah

Comprehensive Review: March 2011
Last Update: March 2011

Neuromyelitis Optica

Neuropathic Disease

Paraneoplastic Neurological Syndromes

Sarcoidosis