eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases
Multiple Sclerosis: Differential Diagnoses & Workup
Updated: Sep 11, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Other Problems to Be Considered
Neuromyelitis optica (Devic disease)
Diffuse cerebral sclerosis of Schilder (encephalitis periaxialis diffusa)
Concentric sclerosis of Balo
Workup
Laboratory Studies
- Cerebrospinal fluid examination
- Oligoclonal bands are distinct electrophoretic patterns that reflect substantial elevation of IgG produced by a restricted set of plasma cells and are demonstrated in CSF samples of approximately 85% of patients with multiple sclerosis.
- Glucose level is usually normal. Protein level can be normal or slightly elevated. WBC count can be slightly to moderately elevated (6-40 x 109/L) but is usually <5 (predominantly mononuclear cells).
- IgG index is usually elevated. This index is derived from the following formula: IgG Index= [IgGCSF/albuminCSF]/[IgGserum/albuminserum]
Although the sensitivity of measurements may vary among laboratories, a typically normal CSF IgG is <4.7 mg/dL (less than 12% of serum protein), and the normal IgG index is <0.77. Most patients with MS have a clearly elevated IgG index (>1.7). - Myelin basic protein (MBP) is a major component of myelin and levels may be elevated in the CSF of patients with MS. However, its clinical utility as a marker of disease activity or progression is limited (not recommended).
- Blood tests
- Patients with MS and atypical features should initially be tested for B-12 and folate levels or antinuclear antibody (ANA) titers. For instance, rapid cognitive deterioration or evidence of subacute combined degeneration of the spinal cord by clinical examination should prompt testing for folate and B-12 levels.
- Other patients with atypical features suggesting disorders other than MS must be recognized. Investigation for the antiphospholipid antibody syndrome must be undertaken in patients with evidence of blood dyscrasia and in women with unexplained miscarriages or history of deep venous thrombosis. This syndrome is typically assessed with blood tests for the following: anticardiolipin, anti-beta2 glycoprotein I, and antiprothrombin antibodies. Patients with optic neuritis and longitudinally extensive spinal cord lesions by MRI should be tested for neuromyelitis optica (NMO), searching for the presence of aquaporin 4 antibodies in the serum.
- An elevated erythrocyte sedimentation rate (ESR) and positive titers of rheumatoid factor (RF) should help identify the presence of a vasculitic disorder that may be mimicking MS.
- If patients come from an endemic region for Lyme disease or have been exposed to tick bites, the physician should check Lyme titers. Evaluation by a rheumatologist should be sought if positive Lyme or ANA titer, elevated ESR, or evidence of vasculitis is uncovered.
- If clinical suspicion for a peripheral neuropathy arises, electrophysiological studies and blood tests for metabolic or toxic neuropathies should be performed.
Imaging Studies
MRI of head or spine, with and without gadolinium, should be performed according to clinical suspicion for lesion localization.
- Typical multiple sclerosis lesions appear as T2 hyperintensities in the periventricular regions; they have an ovoid appearance with their largest axis oriented perpendicular to the ventricular surface; they typically involve only the white matter, and several arise from the corpus callosum (see Media files 2-3). This characteristic configuration has been demonstrated in pathologic specimens and sometimes is referred to as "Dawson fingers" on the basis of neuropathologic work done in 1916 at the University of Edinburgh by James Dawson, who identified the perivascular distribution of inflammatory cells and the resulting fingerlike appearance of affected veins and venules in MS brain tissues.
MRI of the head of a 35-year-old man with relapsing remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
MRI of the head of a 35-year-old man with relapsing remitting multiple sclerosis. This MRI, performed 3 months after the one shown in Media file 2, shows a dramatic decrease in the size of lesions.
- The most common infratentorial locations for plaque formation are the surface of the pons, the cerebellar peduncles, and white matter regions adjacent to the fourth ventricle.
- Lesions that enhance with gadolinium are thought to reflect active disease, as enhancement may correspond to breakdown of the blood-brain barrier from an ongoing subacute inflammatory process (few days to a few weeks). Usually a combination of enhancing and nonenhancing lesions is seen, reflecting the chronicity of the demyelinating process.
- In a patient with a first clinical attack who presents with numerous (ie, >10) lesions by MRI, the presence of gadolinium enhancement in most or all the lesions should prompt a differential diagnosis of ADEM versus an aggressive first presentation of MS. A history of recent exposure to a vaccine or viral illness may be helpful in supporting the diagnosis of ADEM. However, note that exceptions occur and some patients with MS present with a fulminant and active demyelinative disease form from the onset.
- Chronic hypointensity of lesions in T1 images (T1 holes) may reflect some degree of axonal damage or more chronic tissue damage resulting in gliosis. The clinician should attempt to correlate lesions with high T2 signal intensity with their corresponding T1 images to assess chronicity.
- Although a lesion may appear old (low T1), it may exhibit a ringlike enhancement around the hypointense region after gadolinium, suggesting that even seemingly old lesions may have a component of active inflammation, especially at the advancing edge of lesion formation.
- Additionally, a new lesion may present with T1 hypointensity, reflecting marked edema. Lesions range from a few millimeters to more than a centimeter in diameter with occasional large, rounded, tumorlike lesions. The latter are seen as areas of pronounced gliosis and demyelination on pathologic inspection.
- The application of modern MRI techniques to detection and characterization of early lesions is changing rapidly. Recent MRI techniques such as FLAIR have increased the ability to detect demyelinating lesions due to MS. A disadvantage of FLAIR remains the less-than-optimal visualization of the posterior fossa.
Other recent techniques, such as fast FLAIR and fast spin-echo, may increase the sensitivity of prediction for diagnostic and prognostic purposes. Short inversion imaging recovery (STIR) images of the spinal cord can enhance sensitivity in detecting lesions. Magnetization transfer ratio (MTR) abnormalities may precede the appearance of T2-weighted and proton-density high-intensity lesions. Finally, MRS, which can identify neutral fat, helps identify the appearance of myelin breakdown products that result from the active inflammatory response. Neuronal or axonal loss or dysfunction is identified on MRS by the detection of reduced levels of N -acetylaspartate (NAA), a marker of neuronalintegrity/metabolism. - Patients with normal-appearing white matter (NAWM) on conventional MRI may be found to harbor abnormalities by MRS.7
- Recent MRI studies have begun to establish significant involvement of cortical (gray matter) tissues by inflammation or neurodegeneration in MS. In some cases, cortical atrophy can be more pronounced, relative to white matter tissue loss, and its association with cognitive and physical decline is beginning to emerge.8
- In a prospective study, Lebrun et al performed clinical and MRI follow-up on patients with demyelinating lesions fulfilling the Barkof/Tintore criteria. Patients (n=70) who had their first brain MRI for a variety of medical symptoms not suggestive of MS were observed over a mean of 5.2 years. Additional diagnostic studies of the blood, cerebrospinal fluid, and visual evoked potential were conducted. Clinical conversion to MS was observed in 23 patients (33%). The mean time between the first brain MRI and the first clinically isolated syndrome was 2.3 years (range, 0.8-5 y). This prospective study describes the first clinically isolated syndrome cohort with preclinical follow-up.9
- Many of these imaging techniques are investigational and cannot be used by most centers to clinically monitor individuals with MS. The exact correlation of MRI to clinical outcomes in patients with MS remains unknown.
Other Tests
- Evoked potential testing (visual, auditory, or somatosensory) is especially helpful in 1) detecting clinically silent lesions, and 2) documenting an organic basis for vague complaints. The most sensitive are the visual evoked potentials (50-80% sensitivity), followed by the somatosensory potentials (50-70% sensitivity).
Procedures
- Lumbar puncture (see Lab Studies)
Histologic Findings
Histopathologic examination reveals that multiple sclerosis lesions are caused by perivenular infiltration of lymphocytes (most of which are CD4+ T cells) and macrophages (see Media file 4).
Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.
Some lesions may have more infiltration by B cells. In fact, recent immunostaining reports by Lucchinetti et al show that MS lesions have considerable heterogeneity of microscopic appearance, with some lesions exhibiting oligodendrocyte apoptosis and others marked complement and antibody presence.10 Luxol fast blue stains (which stain myelin with an intense blue) reveal demyelinated areas as pale and confluent patches, with variable degrees of associated inflammation (see Media file 5).
Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.
Transected axons may be found in chronic and sometimes in acute MS lesions, as demonstrated in recent studies by Trapp and collaborators11 ; these recent studies have helped refocus neurologists' attention to the issue of axonal loss in MS.
Expression of HLA, interferon gamma, IL-12, and B7 molecules is increased, especially in early MS lesions; this reflects the inflammatory nature of plaque formation. Matrix metalloproteinases (MMPs) and molecules involved in oxidative stress pathways, such as inducible nitric oxide synthase (iNOS), are also elevated in MS plaques.12,13
More on Multiple Sclerosis |
| Overview: Multiple Sclerosis |
 Differential Diagnoses & Workup: Multiple Sclerosis |
| Treatment & Medication: Multiple Sclerosis |
| Follow-up: Multiple Sclerosis |
| Multimedia: Multiple Sclerosis |
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References
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Further Reading
Keywords
multiple sclerosis, MS, multiple sclerosis treatment, multiple sclerosis symptoms, MS symptoms, MS treatment, multiple sclerosis diagnosis, myelin, inflammatory disease of central nervous system, demyelinating disease, sclerosis in plaques, CNS disease, disseminated sclerosis, focal sclerosis, insular sclerosis, elevated immunoglobulin G, interleukin-12, IL-12, B7-1, relapsing remitting MS, RRMS
secondary progressive MS, SPMS, primary progressive MS, PPMS, relapsing progressive MS, RPMS, brain atrophy, spinal cord atrophy, short-term memory problems, difficulty executing sequential tasks, visuospatial disturbances, benign MS, cognitive dysfunction, mental slowing, cognitive slowing, lack of sleep, optic nerve dysfunction, Uhthoff phenomenon, Marburg variant of MS
necrotizing myelopathy, neuromyelitis optica, Devic disease, acute disseminated encephalomyelitis, ADEM, Schilder disease, Baló concentric sclerosis, ataxia, hemiparesis, paraparesis, depression, bipolar disorder, dementia, optic neuritis, orbital pain, patchy loss of vision, cecocentral scotoma, afferent pupillary defect
facial palsies, trigeminal neuralgia, facial myokymia, nystagmus, internuclear ophthalmoplegia, painful limb syndromes, central vertigo, diplopia, dysarthria, pseudobulbar affect, social disinhibition, chronic inflammatory demyelinating polyradiculopathy, CIDP, conversion reactions, la belle indifference, urinary retention
urinary incontinence, sexual dysfunction, Kurtzke Expanded Disability Status Scale, immune dysfunction, HLA-DR2 allele, pro-demyelinative tumor necrosis factor alpha molecule, pro-inflammatory interferon gamma, proinflammatory interferon gamma
