Laboratory Tests
Magnetic resonance imaging MRI is the single most useful laboratory test in the diagnosis of MS. Most patients with MS have abnormalities that can be seen with MRI, and the superba natomic resolution of MRI permits the exclusion of many diseases that mimic MS. MS lesions are hyperintense on T2-weight-ed or proton-density imaging and are hypointense or isointense on T1-weighted imaging [see Figure 2]. Typical MS lesions are ovoid and periventricular, with their long axis perpendicular to the ventricle, but lesions may appear anywhere in the white matter. Some lesions may be enhanced by the administration of gadolinium chelates; enhancement by gadolinium chelates indicates a breakdown in the blood-brain barrier. Even in early MS, several lesions are usually present, although they may not produce obvious symptoms.
Table 3 Approximate Distribution of Neurologic Deficits at Onset of MS and after 5 to 10 Years of Disease9495
|
Deficits |
At Onset (%) |
5 to 10 Years after Onset (%) |
|
Cognitive deficits |
< 5 |
30 |
|
Visual deficits |
20-30 |
50 |
|
Diplopia |
10-20 |
35 |
|
Weakness |
40 |
80 |
|
Ataxia |
5-20 |
65 |
|
Sensory deficits |
40 |
80 |
|
Bowel or bladder symptoms |
5-10 |
55 |
Figure 2 The composite shows some of the changes captured by serial MRI that are characteristic of the dynamic nature of the underlying pathologic disease activity in multiple sclerosis. The patient was evaluated serially by high-resolution MRI, and the images were quantified automatically. The more conventional appearing images were made using fast spin-echo pulse sequences to produce density-weighted and T2-weighted images and a fast FLAIR (fluid-attenuated inversion recovery) sequence with magnetization contrast pulse to improve identification of the lesions and suppress signals from the cerebrospinal fluid. The gadolinium-enhanced ^-weighted image also incorporates a magnetization transfer contrast pulse to amplify the enhancement effects. All images are from the same region of the brain and are 3 mm thick. The segmented images were computer generated through the use of an algorithm that incorporates information from the multiple images. In the segmented images, gray matter is rendered gray, white matter is pink, cerebrospinal fluid appears blue, and the lesions are shown in yellow. The total lesion load in the entire brain varied from 16.71 to 26.98 ml to 16.98 to 21.52 ml at the intervals shown. The total enhanced tissue volume varied from 0.99 to 2.99 ml to 0.33 to 0.04 ml at the same intervals. The patient had no clinically defined change in his neurologic symptoms or findings during this 7-month interval despite the significant activity demonstrated by MRI.
Although MRI is extremely sensitive in detecting white-matter lesions in patients with MS, it is not very specific. Many other diseases produce multiple white-matter lesions; thus, MRI findings should never be used as the sole basis for the diagnosis. MRI findings supportive of the diagnosis of MS include the presence of three or more white-matter lesions, lesions that abut the body of the lateral ventricles, juxtacortical lesions, infratento-rial lesions, lesions that are greater than 5 mm, and lesions that show gadolinium enhancement.
The changes that occur in MS lesions over time have been investigated with serial MRI. The size and number of T2-weighted hyperintense lesions fluctuate, but new lesions tend to accumulate, and the total lesion burden tends to increase.22 In studies of patients with relapsing-remitting disease who were treated only with short courses of corticosteroids for clinical attacks, the total T2-weighted lesion burden increased at a rate of 6% to 8% a year.23,24 Gadolinium enhancement is a transient phenomenon that usually lasts less than 8 weeks and usually occurs when a new lesion first appears. Gadolinium-enhanced lesions correspond to areas of acute inflammation on pathologic examination, whereas nonenhanced lesions correspond to more chronic disease.25 Stable, hypointense lesions on T1-weighted imaging that are not enhanced by gadolinium appear to reflect extensive tissue disruption, including axonal loss. These lesions are highly correlated with clinical measures of neurologic dysfunction.26 Cerebral atrophy is often present on MRI images. Quantitative computed analysis has demonstrated that the amount of atrophy increases over time27 and correlates well with clinical disability and disease duration.
The use of serial MRI to study MS has led to fundamental changes in neurologists’ concept of the disease process. Disease activity as measured by the appearance of new hyperintense lesions on T2-weighted images or the appearance of contrast-enhanced lesions on T1-weighted images greatly exceeds the severity of disease as evidenced by clinical symptoms. Disease activity as assessed by MRI is still episodic but occurs 10 to 20 times more often than clinical symptoms, which suggests that MS is much more of an ongoing and active process, rather than the intermittent process suggested by clinical activity.
Current clinical studies of new therapies for MS include MRI assessment of disease activity as one of the end points. To facilitate the use of MRI in large trials, several groups have developed automated methods for measuring lesion burden and other parameters of interest.29 Newer sequences, such as magnetization transfer imaging, fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging, and combinations of these, are being developed to show more subtle changes and greater pathology [see Figure 2].30 Similarly, magnetic resonance spectroscopic imaging (MRSI) [see Figure 3] provides additional information on the extent of axonal loss within lesions31,32 and more directly measures lipid release during active demyelination33 and in the cortex.34 MRI may also provide insights into the pathogenesis of the MS lesion. Serial MRI studies demonstrate that a decrease in the magnetization transfer ratio on MRI or the presence of lipid peaks on MRSI in normal-appearing white matter may precede the development of contrast-enhanced lesions, which suggests that the inflammatory response is a secondary factor in the development of a new lesion.35,36
Cerebrospinal fluid Most CSF constituents are minimally affected in MS. A mild mononuclear cell pleocytosis can be found during acute relapses, but total cell counts greater than 50 cells/mm3 are uncommon. The CSF protein level may be mildlyelevated but rarely exceeds 100 mg/dl. During acute attacks, especially those involving the spinal cord and brain stem, the CSF may contain measurable amounts of myelin basic protein. The most characteristic abnormality in MS is intrathecal synthesis of immunoglobulins of restricted heterogeneity. The presence of this abnormality is best determined by comparative elec-trophoresis of serum and concentrated CSF, which shows oligo-clonal immunoglobulin bands specific to CSF. For optimal sensitivity, the paired samples should be analyzed with isoelectric focusing followed by immunofixation. Quantitative measures of immunoglobulin content in CSF, such as the IgG index and the rate of IgG synthesis, are also quite sensitive and useful in clinical practice. Oligoclonal bands or abnormal immunoglobulin synthesis is found in about 90% of patients with clinically definite MS; although not specific to MS, these findings support the diagnosis of MS in equivocal cases. CNS infections or diseases that cause chronic CNS inflammation may also stimulate abnormal immunoglobulin synthesis.
Figure 3 Two-dimensional proton magnetic resonance spectroscopic imaging (MRSI) was used to investigate an asymptomatic woman with relapsing multiple sclerosis. The central figure is a composite of five 3 mm thick spin density-weighted images through the corpus callosum. A number of scattered lesions are seen, and the rectangular region selected for MRSI is highlighted. To the right is a composite of the same region studied by gadolinium-enhanced T1-weighted imaging. Three enhancements are seen. The largest enhanced lesion corresponds to the lesion contained within the yellow box in the central spin density image. The blue box in this image contains an unenhanced lesion, and the green box contains an area of normal-appearing white matter. The MRSI is shown next to the spin density image. Here, the maximal regional intensity of resonances attributed to mobile lipids is depicted in red, which corresponds to the region of the enhanced lesion. Relatively less resonance intensity is shown in colors ranging from yellow to green and, finally, to black, indicating the normal lack of lipid resonances from intact white matter. Spectra from individual MRSI voxels that contain the largest enhanced lesion (yellow spectrum), the unenhanced lesion (blue spectrum), and the area of normal-appearing white matter (green spectrum) are shown for comparative detail. The major metabolites that give rise to well-defined spectral peaks include choline (cho), creatine (cr), and N-acetyl aspartate (naa). Characteristic paired lipid peaks are seen to the right of the naa peak only in the yellow spectrum. These findings are consistent with active myelin breakdown in association with the enhanced lesion.
Evoked response The slowing of conduction over demyeli-nated segments of axons or over incompletely remyelinated pathways provides a useful marker for identifying additional subclinical lesions in sensory pathways. Conduction can be measured along visual, auditory, and somatosensory pathways by use of summated cortical evoked responses. In these tests, a time-locked recording of the electroencephalogram over the afferent cortex of interest is obtained after repeated visual, auditory, or sensory stimulation. If demyelination is significant, conduction over central pathways will be delayed. Evoked responses may be used in MS to reveal evidence of demyelination in a particular sensory pathway when none is clinically evident or to confirm symptomatic pathway involvement in the absence of convincing clinical signs. In general, visual evoked responses provide the most useful information.37
MS variants
A number of clinical or pathologic variants of MS have been identified. Marburg-type MS, or acute MS, is a variant with a fulminant, monophasic course. Schilder disease, or diffuse sclerosis, is a rapidly progressive variant associated with large cerebral demyelinated lesions. Balo disease is a pathologic variant in which concentric areas of demyelination occur in the cerebrum.
Neuromyelitis optica, or Devic disease, is a rare but often severe syndrome that may be distinct from MS. It is characterized by the simultaneous or sequential involvement of the optic nerves and spinal cord with relative sparing of the brain, absence of oligoclonal bands, and longitudinally extensive lesions in the spinal cord on MRI. Demonstration of neuromyelitis optica IgG (NMO-IgG), a serum autoantibody that binds to a component of the cerebral vasculature, may aid in the diagnosis.39 Treatment of neuromyelitis optica differs from that of typical MS: parenteral corticosteroids and, if necessary, rescue plasmapheresis can be used for acute attacks; systemic immunosuppression, usually with azathioprine and oral corticosteroids, may be recommended for relapse prevention; and rituximab may be beneficial.40,41
Differential diagnosis
The differential diagnosis of MS depends on the clinical presentation. For a classic case of relapsing-remitting symptoms in a young adult with typical MRI findings, the differential diagnosis is limited. For an older patient presenting with a progressive myelopathy, the differential diagnosis is extensive.42 There is no standard list of alternative diagnoses that should be considered in every patient suspected of having MS. Instead, the treating physician should carefully consider the clinical and laboratory features of the particular case to generate the relevant list of possible alternative diagnoses. Frequent diagnostic considerations include structural lesions, inherited demyelinating or degenerative diseases, vasculitides, vascular disease, chronic infections (e.g., syphilis, Lyme disease, and human T cell lymphotropic virus type I), vitamin B12 deficiency, and neurosarcoidosis.
Treatment
Treatment of MS can be discussed in terms of the management of acute relapses, the prevention of relapses as modification of the disease process, and the management of symptoms and fixed neurologic deficits.
Acute Relapse
Management of relapses varies with the severity of the presenting signs and symptoms. Mild attacks that do not significantly alter the patient’s ability to function require no more than a supportive physician-patient relationship. High-dose cortico-steroid therapy is indicated for exacerbations that adversely affect the patient’s function. Intravenous methylprednisolone in daily doses of 0.5 to 1.0 g for 3 to 7 days reduces the duration of maximal neurologic signs and symptoms and usually rapidly reverses the fatigue that frequently accompanies acute at-tacks.43,44 A short, tapering course of oral corticosteroids may be given afterward. Equivalent doses of oral corticosteroids may have a similar effect,45 but treatment with lower doses (e.g., 1 mg/kg/day) is controversial. The early benefits may be similar, but the interval between attacks may be shorter with low-dose steroids.46,47 The important roles of reduced physical activity during an exacerbation and early institution of rehabilitation therapy should not be ignored. Relative contraindications to cortico-steroids include type 1 diabetes mellitus, uncontrolled hypertension, and prior steroid-induced depression or psychoses. Although corticosteroids have a short-term beneficial effect when used for acute exacerbations, their long-term effect on the course of MS is less clear.48
Prevention of Relapse
Three different medications that affect the long-term clinical course of MS are available: interferon beta-1b, interferon beta-1a, and glatiramer acetate. In patients with relapsing-remitting MS, these drugs reduce the frequency of attacks, reduce the rate of MS lesion accumulation on MRI, and reduce the accumulation of disability.
The beta interferons reduce major histocompatibility complex (MHC) class II antigen expression, alter the pattern of cytokine secretion, inhibit matrix metalloproteinase activity, and increase antigen-nonspecific suppressor mechanisms in model systems.49 In clinical trials, they reduce the frequency of clinical attacks, decrease the number of contrast-enhanced lesions, and limit fixed-lesion accumulation on MRI. In early relapsing-remitting MS, they may delay the accumulation of disability. Recombinant human interferon beta-1b and interferon beta-1a vary in their routes of administration, side-effect profiles, and apparent magnitude of effects. These differences are only partially explained by the structural properties of the two molecularly engineered molecules and the study designs of their pivotal clinical trials. Both preparations induce antibodies that may limit clinical benefits.23
In an extended controlled study involving patients with relapsing disease of mild to moderate severity, 0.25 mg (8 million IU) of interferon beta-1b, given subcutaneously every other day, reduced the annual exacerbation rate by 30%. This reduction was maintained for 5 years.23 The frequency of contrast-enhanced lesions was markedly reduced; the total burden of disease, as measured by MRI, increased over time in the placebo group but stabilized for those on high-dose treatment. The benefits of treatment with interferon beta-1b were dose dependent, with better results seen at the higher dose. Antibodies that may limit the effect of the drug developed in up to 38% of treated patients.50
The majority of patients experience flulike symptoms of varying severity on initiation of therapy with interferon beta-1b. For most patients, these symptoms can be controlled with prior administration of a nonsteroidal anti-inflammatory drug.51 The symptoms become less severe and may disappear over time. Local injection-site reactions are usually only of cosmetic concern, but frank skin necrosis can occur. About 20% of patients discontinue treatment because of local or systemic side effects or other issues. In some of those patients who tolerate treatment, therapeutic benefit may decrease as a result of the development of neutralizing antibody. Nevertheless, patients who avoid these pitfalls of treatment stand to benefit substantially; moreover, the benefits are independent of the disability status at initiation of therapy.
Interferon beta-1a is currently available in two forms. One is given intramuscularly once weekly at a dose of 30 ^g, and the other is given subcutaneously three times weekly at a dose of 44 ^g for a total weekly dose of 132 ^g. In patients with slight to mild disability who experience relapse, 30 ^g given once a week reduced the relapse rate by 18% and reduced the proportion of patients with sustained progression of neurologic disability. When the same dose of interferon beta-1a was administered within several weeks of symptom onset in patients who had experienced a single attack and were at high risk for having a second, disease-defining attack, the time to the next attack was pro-longed.52 When interferon beta-1a was given subcutaneously at 44 ^g three times a week to patients with mild to moderate disability, the relapse rate decreased by 33% and the accumulation of disability slowed.53 In patients receiving interferon beta-1a, the number of contrast-enhanced lesions decreases and there is an improvement in the MRI burden of disease. In studies of both interferon beta-1a and interferon beta-1b, the beneficial effects were greater with higher doses.54,55
Glatiramer is a synthetic random polymer of four amino acids (hence its original name, copolymer-1). Its mechanism of action is not definitively established, but it promiscuously binds to MHC class II antigen and induces organ-specific T helper type 2 cell responses.56 Glatiramer reduces the frequency of relapses in MS, may reduce accumulation of disability, and does not appear to induce host responses that limit its benefit over time. Glatiramer reduces the annual attack rate by 32%, with the greatest effect seen in those patients with the least neurologic impairment.57 The progression of disability is also slowed, and benefits may be maintained over 6 or more years.58 Over the first 9 months of treatment, the number of contrast-enhanced lesions is reduced by 35%, which correlates well with the effect on relapse rate.59 Side effects are minimal, but a transient systemic reaction occurs in about 15% of patients after one or more injections of the drug. Essentially all patients treated with glatiramer develop antibodies that bind to the drug, but these do not appear to limit the drug’s activity.57
Another drug for the prevention of relapses, with a mechanism of action different from that of glatiramer, was briefly marketed in the United States from November 2004 to February 2005. Natalizumab is a monoclonal antibody against the adhesion molecule a4 integrin. The binding of the antibody to its target inhibits the adhesion of circulating lymphocytes to the blood vessel wall and thus prevents the subsequent migration of those lymphocytes into the CNS. When administered intravenously every 4 weeks for a total of six doses, natalizumab significantly reduced the number of new lesions seen on MRI, as well as the number of clinical relapses.60 In a subsequent, larger study, na-talizumab was given every 4 weeks for a year; this regimen resulted in a reduction of the relapse rate by 68% as compared with placebo. The Food and Drug Administration granted accelerated approval on the basis of these promising results. Soon afterward, however, two cases of progressive multifocal leukoen-cephalopathy, one of them fatal, occurred in patients treated with the combination of natalizumab and interferon. All use of natalizumab is currently suspended, and the future of this drug is uncertain.
In summary, prophylactic treatment with either a beta inter-feron or glatiramer is appropriate for patients with relapsing disease and mild to moderate disability. The choice of agent depends on the particular patient. Patients who are maintained on these therapies can expect an 18% to 50% reduction in attack frequency. With any of the available drugs, best responses appear to result when treatment is initiated relatively early in the disease course.
These agents have only modest effect when used as mono-therapy; consequently, there is intense interest in using these agents in combination to achieve greater benefit. Numerous combinations have been proposed, including glatiramer plus in-terferon, interferon plus one of the many immunosuppressive agents, and glatiramer plus other agents. Some of these combinations are under active investigation, but to date, no adequate, completed clinical trial has demonstrated increased efficacy with combination therapy. For the present, monotherapy with either interferon or glatiramer is recommended for most patients with relapsing-remitting disease. Combinations of drugs, the use of other immunomodulatory drugs, and several antigen-or disease-specific interventions are currently under active study, and additional therapeutic alternatives may be available in the near future.
