January 15th, 2003
from WebMD Scientific American® Medicine
J. William Lindsey, MD, Assistant Professor of Neurology, Department of Neurology, University of Texas Health Science Center at Houston; Jerry S. Wolinsky, MD, The Bartels Family Professor of Neurology, University of Texas Health Science Center at Houston, and Attending Neurologist, Hermann Hospital
In both the central and the peripheral nervous systems, large-diameter axons are myelinated. Myelin is formed and maintained by oligodendrocytes within the central nervous system and by Schwann cells in the peripheral nervous system. Myelin both insulates the invested axons and organizes surface membrane constituents of the axon--functions that are critical for the rapid transfer of signals necessary for coordinated motor activity, proper integration and interpretation of sensory stimuli, and facile cognition. Diseases that affect the integrity of the oligodendrocyte and its ability to produce and maintain myelin or diseases that directly damage the myelin sheath disturb conduction in myelinated white matter pathways and produce a broad array of motor, sensory, and cognitive dysfunctions [see Figure 1].
Figure 1. Structure of Neuron and Mechanism of Demyelination. A single oligodendrocyte may support myelin internodes for 60 or more neighboring axons. A major consequence of myelination is organization of the microenvironment of the larger-diameter axons. Sodium channels are clustered at segments of the axon between myelin segments (the nodes of Ranvier), and potassium channels are diffusely distributed under the myelin-invested segments of the axons. This arrangement allows myelinated axons to rapidly propagate action potentials from the axonal cell body distally to its synapse by saltatory con-duction. Depolarization of the nodes of Ranvier in sequential fashion results in rapid propagation of the neural impulses in the largest-diameter nerve fibers at rates in excess of 100 m/sec.
The upper part of the figure depicts a neuron with a myelinated axon. At the right corner, the neuron is magnified and cut in cross section, demonstrating the concentric lamellar structure of myelin. The middle of the figure shows a neuron with a myelinated axon forming a synapse with another neuron. Two oligodendrocytes are shown; each cell myelinates multiple segments of more than one axon. The bottom neuron has been partially demyelinated, and it is surrounded by T cells, which secrete inflammatory cytokines (interleukin-2 [IL-2], interferon gamma [IFN-and tumor necrosis factor- [TNF-]), and by macrophages, which are stripping myelin from the axon. The macrophages contain myelin debris in phagocytic vacuoles. Conduction in the demyelinated axon is blocked. A blood vessel in cross section shows T cells adhering to the lumen and crossing from the vessel into the brain.
Demyelinating diseases disturb the integrity of myelin, but the axons are relatively spared [see Table 1]. These diseases primarily affect oligodendroglial survival (e.g., progressive multifocal leukoencephalopathy), oligodendroglial metabolism (e.g., vitamin B12 deficiency), and the myelin sheath, with secondary effects on the oligodendrocytes (e.g., multiple sclerosis [MS]).
Table 1. Demyelinating Diseases of the Central Nervous System
Acute disseminated encephalomyelitis
|Metabolic||Vitamin B12 deficiency
Central pontine myelinolysis
|Infectious||Progressive multifocal leukoencephalopathy
Subacute sclerosing panencephalitis
Immune-mediated demyelinating diseases include recurrent or chronically progressive demyelinating diseases (MS and its variants) and monophasic demyelinating diseases (optic neuritis, acute disseminated encephalomyelitis, and transverse myelitis). Monophasic demyelination may be the first clinical sign of MS.
MS is characterized clinically by recurrent or chronically progressive neurologic dysfunction caused by lesions in the CNS. Pathologically, the lesions are multiple areas of demyelination that affect the brain, optic nerves, and spinal cord.
Approximately 250,000 to 350,000 people in the United States have MS; the prevalence is about 100 cases per 100,000 population. MS is more common in women than men, with a ratio of 2:1. MS occurs in all major racial groups but is most common in whites, less common in blacks, and rare in Asians. The onset of disease usually occurs in people between 20 and 50 years of age, with a peak occurring in people 30 years of age. The prevalence of MS varies widely with location; the highest prevalence is found at higher latitudes in northern Europe and northern North America. The geographic variation suggests that MS may in part be caused by the action of some environmental factor that is more common at high latitudes. To some extent, this idea is supported by studies of migrants. Moving from a high-risk to a low-risk area early in life tends to lower the risk of MS, whereas moving from a low-risk to a high-risk area tends to increase the risk. Much of the state-by-state variation in MS risk in the United States, however, correlates with Scandinavian ancestry, which suggests that geographic variation may be a reflection of the geographic distribution of susceptible ethnic groups.
The etiology of MS is unknown. However, the importance of genetic factors has been firmly established by the studies of familial MS, and the contribution of nongenetic factors is demonstrated by the lack of concordance for disease in most identical twins and by the effect of migration on risk of disease.
The underlying disease process is unknown, but most authorities accept that MS is at least partly an autoimmune or immune-mediated disease. The evidence for this conclusion includes pathologic findings (i.e., plaques in the myelinated fibers), an increase in the synthesis of IgG in the cerebrospinal fluid, and a variety of in vitro abnormalities of leukocyte function. The autoimmune response could be either the primary cause of disease or an epiphenomenon of another disease process. The popular molecular mimicry model postulates that the autoimmune attack on myelin is precipitated by an infectious organism that contains a protein similar to a myelin protein. The infection elicits a vigorous immune response from lymphocytes that recognize the cross-reactive protein; in the process of eliminating the organism, the activated lymphocytes damage myelin. The plausibility of this theory has been demonstrated in elegant transgenic experiments in mice, but the relevance of this model in MS remains unproved. MS may be caused by other processes or mechanisms, such as a persistent CNS infection or a biochemical defect in myelin.
The suspicion that susceptibility to MS is at least partly familial has been confirmed in extensive studies. The risk of MS occurring in a monozygotic twin of an MS patient was found to be 31%, whereas the risk of MS occurring in a dizygotic twin was determined to be about 5%. The risk for a sibling or parent of an affected person was 3% to 4%, compared with a risk in the general population of only 0.1%. Further studies in adopted siblings and half-siblings demonstrated that this increased familial risk was entirely attributable to genetic rather than environmental factors.[6,7] These findings imply that several interacting genes influence susceptibility to MS.
The genetic factors that confer susceptibility to MS are only partly known. The only locus reproducibly shown to be associated with MS is human leukocyte antigen (HLA) class II; the DRB1*1501 extended haplotype is associated with MS in white patients. In an attempt to identify additional loci that contribute to MS, independent research groups conducted genome-wide screens on large groups of families with multiplex MS.[10,11] There were no genome regions with particularly strong linkage to MS, but there were several regions with relatively weak evidence of linkage that require further investigation.
Plaques, which consist of varying amounts of perivenular mononuclear cell inflammation, demyelination with relative axonal sparing, loss of oligodendrocytes, and astrocyte proliferation with resultant gliosis, are the hallmark of MS. Within the CNS, plaques can appear wherever there are myelinated fibers. The majority of plaques congregate along periventricular draining veins, but plaques also commonly occur within the spinal cord, optic nerves, brain stem, and white matter of the cerebral hemispheres and cerebellum. Plaques can also occur in the connecting pathways of subcortical white matter. Intracortical plaques can arise because the axons of nerve cell bodies are myelinated along their entire course from near the axon hillock.
The histopathologic appearance of plaques varies over time. Acute, newly formed lesions are dominated by perivenular cellular infiltrates of T cells and macrophages. Blood-brain barrier function is regionally disrupted and is associated with vasogenic edema. There is immunocytochemical and cytochemical evidence of local endothelial cell activation by cytokines, activation of T cells, and activation of macrophages. Longer-standing lesions are characterized by a total loss of myelin and oligodendrocytes, an intense astrogliosis, variable degrees of axonal loss, and a scant residual infiltrate of mononuclear cells, some of which are immunoglobulin-secreting B cells. Axonal transection is common in many MS lesions, particularly those that appear as areas of persistent low signal intensity on T1-weighted MR images, and axonal transection may be the cause of fixed neurologic deficits.[15-17] Careful pathologic studies of autopsy and biopsy material have defined different types of MS lesions; lesion types differ with regard to the pattern of demyelination, the occurrence of apoptosis in oligodendrocytes, and the activation of complement. This suggests that the underlying pathogenesis of MS may be heterogeneous.
The diagnosis of MS is made on the basis of the clinical signs and symptoms;
MRI and other laboratory tests play a supporting role. The diagnosis of
MS requires evidence of the dissemination of lesions in time and space
and the careful exclusion of other causes. The patient should have had
more than one episode of neurologic dysfunction and should have evidence
of white matter lesions in more than one part of the CNS. Because there
is no pathognomonic sign or symptom or definitive laboratory test result,
diagnosis requires careful clinical judgment and should be made only by
an experienced neurologist.
Table 2. Diagnostic Criteria for Multiple Sclerosis*
|Clinically definite MS||Two attacks and clinical evidence of two
Two attacks, clinical evidence of one lesion,
paraclinical evidence of a second lesion
|Oligoclonal bands or increased IgG synthesis
in the CSF
Two attacks and clinical or paraclinical
evidence of one lesion
One attack and clinical evidence of two lesions
One attack, clinical evidence of one lesion,
paraclinical evidence of a second lesion
|Clinically probable MS||Two attacks and clinical evidence of one lesion
One attack and clinical evidence of two lesions
One attack, clinical evidence of one lesion,
paraclinical evidence of a second lesion
Several sets of established diagnostic criteria for MS are available. Those of Poser and coworkers[see Table 2] are widely accepted and include laboratory results as well as clinical data. The clinically definite category requires the presence of two clinical episodes and two lesions; less certain cases are classified as probable or possible. All categories require the exclusion of other diagnoses. These criteria were originally designed for use by investigators in selecting patients for participation in clinical trials. Therefore, these criteria are particularly stringent, and not all patients with MS may meet these criteria. The criteria are nevertheless useful in general clinical practice because they do help identify patients with possible or probable MS who should be reexamined periodically. They cannot be easily applied to patients with a progressive course from disease onset, but new criteria have been proposed for these patients. Revised criteria that better incorporate MRI into the diagnostic algorithm and that can be used for all disease phenotypes are under review by an international panel of experts and should soon be available.
Clinical Features. Almost any neurologic deficit can occur in MS, but there are several signs and symptoms that are characteristic. Although no findings are pathognomonic for MS, the presence of certain signs and symptoms should suggest MS as a possible diagnosis, particularly in young adults.
The typical findings include optic neuritis, internuclear ophthalmoplegia, heat sensitivity, and Lhermitte symptom. Optic neuritis is the initial symptom in about 20% of patients with MS and ultimately develops in more than half of all MS patients. In patients with optic neuritis, vision disturbances are restricted to one eye. These disturbances characteristically occur with central scotoma. There is usually retro-orbital pain that is accentuated with movement of the globe. Results of funduscopic examination are usually normal, but there may be papillitis or pallor of the disk from previous attacks. Symptoms generally evolve over several days before maximal deficits are reached. A second typical symptom is diplopia caused by an internuclear ophthalmoplegia. On examination, there is failure of adduction on lateral gaze but preservation of adduction with convergence. Internuclear ophthalmoplegia is caused by a lesion in the medial longitudinal fasciculus and is suggestive of MS.
Sensitivity to heat is a characteristic complaint in MS. Exercise, fever, a hot bath, or other activities that raise body temperature may cause the appearance of new symptoms or the recurrence of old symptoms. These events occur as a result of temperature-induced conduction block across partially demyelinated fibers. The symptoms resolve when body temperature returns to normal. Lhermitte symptom is also characteristic of MS, with patients experiencing paresthesias that radiate down the spine and into the extremities on neck flexion. This symptom may be reproduced on clinical examination and indicates the presence of a lesion in the cervical spine.
Table 3. Appropriate Distribution of Neurologic Deficits at Onset
of MS and after 5 to 10 Years of Disease[82,83]
|Deficits||At Onset (%)||5 to 10 Years after Onset (%)|
Bowel or bladder
There are a number of other symptoms that are extremely common in MS but also occur in many other disease processes. These symptoms include weakness, sensory loss, ataxia, and bowel and bladder symptoms. All these symptoms develop in the majority of patients during the course of MS [see Table 3]. The weakness associated with MS is of the upper motor neuron type and is accompanied by spasticity and increased reflexes. Weakness may occur in any pattern, including paraparesis, hemiparesis, and monoparesis. In established disease, the lower extremities are usually more affected than the upper extremities. Sensory symptoms are also frequent and can occur in different patterns. Patients may note either paresthesias or loss of sensation. Again, the lower extremities tend to be more severely affected. The loss of vibration sense is often most prominent. Ataxia is uncommon at the onset of MS, but it occurs to some degree in most patients. Difficulties with bladder control are frequent and can be extremely distressing. Most commonly, patients have urinary urgency, frequency, and urge incontinence consistent with a spastic bladder, but hesitancy, retention, overflow incontinence, and dyssynergia also occur. Constipation is the most common bowel complaint.
Although almost any deficit can occur in MS, some are extremely rare. These include seizures, aphasia, movement disorders, and muscle atrophy, which reflect primary involvement of gray matter or peripheral nerves. Although these symptoms can occur in MS, their presence is unusual and should prompt reevaluation of the diagnosis.
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 superb anatomic resolution of MRI permits the exclusion of many diseases that mimic MS. MS lesions are hyperintense on T2-weighted 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.
Figure 2. MRI Changes in Multiple Sclerosis. 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 T1-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, so MRI findings should never be used as the sole basis for the diagnosis. Several sets of criteria have been proposed for increasing the specificity of MRI findings, but all increases in specificity are accompanied by decreases in sensitivity. Useful features for increasing the predictive value of MRI for diagnosis of MS include the presence of three or more white matter lesions, lesions that abut the body of the lateral ventricles, infratentorial 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. In studies involving relapsing-remitting patients 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.[24,25 ]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. 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. Cerebral atrophy is often present on MRI images. Quantitative computed analysis has demonstrated that the amount of atrophy increases over time and correlates well with clinical disability and disease duration.
The use of serial MRI to study MS has led to fundamental changes in our 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 five to 10 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.[30 ]Newer sequences, such as magnetization transfer imaging, fluid-attenuated inversion recovery (FLAIR), and combinations of the two are being developed to show more subtle changes and greater pathology [see Figure 2]. Similarly, magnetic resonance spectroscopic imaging (MRSI) [see Figure 3] provides additional information on the extent of axonal loss within lesions[32,33] and more directly measures lipid release during active demyelination and in the cortex. 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.[36,37]
Figure 3. MRSI in Asymptomatic Woman with Relapsing Multiple Sclerosis. 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.
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 mildly elevated 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 electrophoresis of serum and concentrated CSF, which shows oligoclonal immunoglobulin bands specific to CSF. 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.
Evoked response. Slowing of conduction over demyelinated 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.
Clinical Course. The clinical course of MS varies greatly among patients. Typically, the disease has a relapsing-remitting pattern, with acute exacerbations followed by partial or complete resolution. New neurologic deficits develop over the course of several hours or days, remain stable for a period of a few days to a few weeks, and then gradually improve. Early in the course of the disease, the symptoms may resolve with minimal residua. With repeated exacerbations, permanent neurologic deficits tend to develop. Patients usually have symptom-free intervals of months or years between attacks.
Symptoms may also occur in a progressive manner, with steady accumulation of neurologic deficits in the absence of clearly defined exacerbations. Patients who initially have relapsing-remitting disease and who then enter a progressive phase are said to have secondary progressive disease, whereas those whose symptoms are progressive from onset are said to have primary progressive disease. About 15% of patients have primary progressive disease; of those who initially have relapsing-remitting disease, 30% to 50% will experience progressive symptoms in the first 10 years. Radiologic and pathologic studies suggest that the primary progressive group may be distinct from the relapsing-remitting and secondary progressive group.
A number of clinical or pathologic variants of MS have been identified. Neuromyelitis optica, or Devic disease, is characterized by the simultaneous or sequential involvement of the optic nerves and spinal cord; it often has a malignant course. 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. Baló disease is a pathologic variant in which concentric areas of demyelination occur in the cerebrum.
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. 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 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 corticosteroid 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 attacks.[42,43] A short, tapering course of oral corticosteroids may be given afterward. Equivalent doses of oral corticosteroids may have a similar effect, but treatment with lower doses (e.g., 1 mg/kg/day) is controversial. The early benefits may be similar, but low-dose steroids may shorten the interval between attacks.[45,46] The important roles of reduced physical activity during an exacerbation and early institution of rehabilitation therapy should not be ignored. Relative contraindications to corticosteroids include type 1 (insulin-dependent) 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 unknown.
Prevention of Relapse. In the past few years, three different medications that affect the long-term clinical course of MS have been approved: interferon beta-1b, interferon beta-1a, and glatiramer acetate (previously known as copolymer-1). 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. 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 progression of disability, but they have limited effect on the progression of disability in secondary-progressive MS. 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.
In 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 in an extended controlled study.[24 ]The frequency of contrast-enhanced lesions was markedly reduced, and 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 38% of treated patients.
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. 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. Of those who tolerate treatment, benefit may be lost for some that develop neutralizing antibody. Nevertheless, patients who avoid these pitfalls of treatment stand to benefit substantially, independent of disability status at initiation of therapy.[48,49]
Interferon beta-1a produces similar benefits. In patients with slight to mild disability who experience relapse, a dose of 30 mg (6 million IU) of interferon beta-1a, given once a week intramuscularly, 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 prolonged. This recent finding supports the early initiation of immunomodulatory treatment in relapsing forms of multiple sclerosis to limit attacks and accumulation of disability. Thus far, however, none of the data have convincingly shown that the proportion of patients with remitting disease who continue to the progressive phase of the disease is reduced.
In one study, when interferon beta-1a was given subcutaneously at a higher dosage (44 mg three times a week) to patients with mild to moderate disability, the relapse rate decreased by 33% and the progression of disability slowed. 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 addition, patients receiving interferon beta-1a develop antibodies that neutralize biologic activity. In the United States, interferon beta-1a is currently available only in the low-dose, once-weekly formulation. The higher-dose preparations will likely become available in the next several years. In studies of both interferon beta-1a and interferon beta-1b, the beneficial effects were greater with higher doses.[25,50]
Glatiramer is a synthetic random polymer of four amino acids. 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.[51,52] Glatiramer reduces the frequency of relapses in MS, may reduce progression 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. The progression of disability is also slowed, and benefits may be maintained over 6 or more years. The number of contrast-enhanced lesions is reduced by 35%, which correlates well with the effect on relapse rate. 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.
In summary, prophylactic treatment with either a beta interferon or glatiramer is appropriate for patients with relapsing disease and mild to moderate disability. The choice of which agent to use depends on the particular patient. Patients who are maintained on these therapies can expect an 18% to 50% reduction in attack frequency. Unfortunately, the two interferons available in the United States are marketed in single-dose formulations. Despite the substantial evidence that higher doses produce greater clinical benefit, dosage adjustment is difficult. Best responses with any of the available drugs appear to result from initiation of treatment relatively early in the disease course. Combination therapy with glatiramer and an interferon is attractive but has not produced additional benefit in animal studies. A carefully monitored trial of the combination of interferon and glatiramer in MS is now in progress. Other immunomodulatory drugs, as well as several antigen- or disease-specific interventions, are currently under active study, and additional therapeutic alternatives may be available in the near future.
Progressive MS. Treatment of progressive MS is not as well established as it is for relapsing disease. As discussed (see above), disease that is progressive from onset is called primary progressive, whereas disease that is initially characterized by relapses and remissions and then enters a progressive phase is called secondary progressive. Results of interferon-beta treatment in secondary progressive MS have been mixed and disappointing. In one trial of interferon beta-1b, disease progressed in 50% of the patients who received placebo, whereas disease progressed in 39% of patients treated with interferon beta-1b. However, subsequent studies of interferon beta-1a and beta-1b have not shown an effect on the progression of disability. Relapse rates and MRI measures of disease activity were decreased in all of these studies. These results suggest that the pathophysiologic processes causing progressive symptoms may be different from those causing acute exacerbations and CNS inflammation detected by MRI.
Experience with glatiramer acetate in progressive disease is limited. Glatiramer had limited or no benefit in a small study of patients with progressive disease that probably included patients with both primary and secondary progressive disease. A study of the use of glatiramer in primary progressive disease is now in progress.
In addition to interferon and glatiramer, various aggressive immunosuppressive therapies have been tried.[59,60] Most are used only rarely because of lack of efficacy, excessive side effects, or both. Cyclophosphamide, cladribine, methotrexate, azathioprine, and monthly high-dose corticosteroid therapy all have been advocated, but the risks of therapy need to be carefully balanced against the demonstrated benefits. A number of controlled and uncontrolled trials of mitoxantrone suggest that on the basis of favorable clinical and MRI end points, this intercalating agent may have a role in a highly selected group of MS patients. The drug is nearing regulatory approval for the indication of rapidly advancing MS that is refractory to immunomodulatory treatments. However, potential cardiotoxicity limits total drug exposure and restricts its general use in the treatment of this chronic disease.
Symptomatic Therapy. Several of the common symptoms of MS respond to pharmacologic treatment [see Table 4]. Prominent among the most frequent symptoms of MS are depression and fatigue.
Table 4. Symptomatic Therapy for MS*
|100 mg b.i.d. or t.i.d.
37.5 to 112.5 mg q.d.
10 mg b.i.d. to 20 mg t.i.d.
100 mg b.i.d.
5 mg b.i.d. to q.i.d.
2 mg b.i.d.
25 to 75 mg q.h.s.
0.125 mg b.i.d. to 0.25 mg q.i.d.
7.5 mg t.i.d. to 15 mg q.i.d.
10mg b.i.d. to 20 mg t.i.d.
0.1 mg b.i.d. to 0.2 mg t.i.d.
1 to 5 mg q.d.
Four or more times daily
10 mg t.i.d. to 50 mg q.i.d.
Clonidine (adjunctive to baclofen)
|5 mg t.i.d. to 20 mg q.i.d.
2 mg t.i.d. to 10 mg q.i.d.
4 mg q.d. to 12 mg q.i.d.
0.5 mg t.i.d. to 5 mg q.i.d.
0.1. mg b.i.d. to 0.2 mg t.i.d.
25 mg q.d. to 100 mg q.i.d.
0.5 mg t.i.d. to 5 mg q.i.d.
100 to 600 mg t.i.d.
Misoprostol (trigeminal neuralgia)
100 to 300 mg t.i.d.
300 to 400 mg q.d.
100 to 200 µg q.i.d.
50 to 150 mg q.h.s.
300 to 400 mg q.d.
100 to 600 mg t.i.d.
250 to 1,000 mg t.i.d.
*Usual adult dose for medications commonly used to treat MS syndromes. See appropriate reference for complete prescribing information, including contraindications, warnings, side effects, and initiation and termination of treatment.
Depression and fatigue. Depression occurs in about 20% of MS patients, probably more frequently than anticipated for other chronic illnesses. Treatment of depression in MS patients does not differ from that in others. Fatigue is present in at least half of all MS patients; often, it is not proportional to the extent of neurologic compromise. It commonly occurs during relapses and can also be present between attacks. Fatigue in MS is differentiated from normal fatigue by its severity and by the fact that it is frequently unrelated to activity. About 50% of patients with MS obtain at least partial relief by treatment with amantadine, but dosing late in the day, which may induce insomnia, should be avoided. When amantadine fails to relieve fatigue, other agents that may be useful are pemoline, methylphenidate hydrochloride, or selective serotonin reuptake inhibitors. Preliminary studies suggest that modafinil, recently approved for the treatment of narcolepsy, may decrease fatigue in MS patients.
Spasticity. Spasticity is another common symptom that is amenable to treatment. The increased extensor tone in the lower extremities can to some extent compensate for associated weakness, but excessive spasticity inhibits a fluid gait and may result in painful spasms or joint contracture. Centrally active g-aminobutyric acid (GABA) agonists, such as baclofen, often reduce spasticity but preserve functional gait or lower limb strength, which is needed for weight transfer. Effective doses of baclofen vary from as little as 5 mg to 240 mg daily in divided doses. Treatment should be initiated at a low dose and titrated upward to the level that provides maximum benefit. Other drugs that may be helpful include diazepam, clonazepam, and the alpha-adrenergic agonist tizanidine. Although not specifically investigated as an antispasmolytic agent, gabapentin may be useful in reducing spasticity. Some patients benefit from dantrolene. Selected patients with severe spasticity that is unresponsive to oral treatment may benefit from intrathecal baclofen or selective botulinum toxin injections.
Bladder dysfunction. Bladder dysfunction is common in MS. The pathophysiology is complex; the symptoms of detrusor-sphincter dyssynergia, hyperactive detrusor function, and flaccid bladder may occur individually or in various combinations and often fluctuate over time. Formal urodynamic studies are essential to delineate these various patterns and to determine rational approaches to treatment. Most patients will present with symptoms of urgency and frequency, which may be alleviated with smooth muscle relaxants and anticholinergic agents. Periodic determination of postvoided residual urine volumes is used to identify patients who will benefit from self-catheterization programs.
It is important to recognize that bladder infections are common in women with MS. Because of the frequent loss of perineal sensation, acute bladder infections may not cause dysuria but instead may become evident as a global deterioration of neurologic function, which may be mistaken for an acute relapse. The evaluation of patients in relapse should include a search for pyuria. Asymptomatic bacilluria may demand concomitant treatment of acute relapses with a combination of methylprednisolone and an appropriate antibiotic. Significant urinary retention with overflow incontinence may be accompanied by reflex exaggeration of lower limb spasticity. Institution of a self-catheterization program for affected patients often reduces spasticity more effectively than pharmacotherapy.
Pain. Pain is not uncommon in MS. Often, it is secondary to unusual mechanical stress resulting from asymmetrical weakness or spasticity. Appropriate orthotics, antispasmolytics, and self-performed exercise routines, supplemented by simple analgesics, are helpful. Paroxysmal pain syndromes, typified by trigeminal neuralgia, usually respond to low doses of carbamazepine or other antiepileptic drugs, particularly gabapentin. Distal dysesthetic sensations may also respond to these drugs. Low doses of tricyclic antidepressants may prove useful. Ataxia and intention tremor are particularly difficult to manage. Use of counterweights on limbs may aid some patients. Pharmacologic interventions are generally disappointing, but clonazepam or gabapentin at maximally tolerated doses sometimes provides symptomatic relief for patients with disabling upper extremity ataxia.
Although the course of MS varies from patient to patient, the effect of the disease in large cohorts of MS patients has been determined. The median time from onset of disease to disability severe enough for the patient to require aids for ambulation is 15 years. MS has minimal effect on life span. For perhaps 10% to 15% of patients, MS may have a relatively benign course, with patients experiencing minimal or no disability 20 years after onset of symptoms. For patients with relapsing-remitting disease, the mean relapse frequency is about once every 2 years. There are no known factors that are predictive of the clinical course in an individual patient, but female sex, younger age at onset, and optic neuritis or sensory symptoms as the presenting symptoms tend to be associated with a more favorable prognosis.
Optic neuritis is an acute inflammatory optic neuropathy. The cardinal symptoms are unilateral vision loss and retrobulbar pain with eye movement. Differential diagnosis includes anterior ischemic optic neuropathy, which is usually painless and found in patients older than 50 years; hereditary diseases, such as Leber hereditary optic neuropathy; and toxic or nutritional optic neuropathies. Treatment with intravenous methylprednisolone at a dosage of 1 g/day for 3 days followed by oral prednisone for 11 days hastens recovery of vision but has little residual benefit at 1 year. One study showed that prednisone at 1 mg/kg/day for 14 days had no benefit and was associated with an excess of recurrences. Even without treatment, almost all patients begin to recover vision within 4 weeks.
The relation of optic neuritis to MS is controversial. Some regard optic neuritis as a distinct entity, but others consider it part of the clinical continuum of MS. More than half of all patients with MS have optic neuritis at some time during the disease. Of patients who present with optic neuritis and who have no other neurologic deficit, almost 40% have one or more ovoid or periventricular lesions, as revealed on brain MRI; clinically definite MS eventually develops in 60%.[46,63] Patients with completely normal results on MRI and comprehensive CSF evaluation seldom progress to MS.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is a monophasic syndrome that is usually preceded by a viral exanthem, an upper respiratory infection, or vaccination. The most commonly associated viruses are measles, paramyxovirus, varicella, rubella, and Epstein-Barr virus. Onset is often rapid and is characterized by meningeal signs, headache, seizures, and altered mental status. The associated neurologic deficits are variable and may include hemiplegia, paraplegia, sensory loss, vision loss, and transverse myelitis. ADEM can be fatal, but most patients begin to recover within 2 to 4 weeks. Acute hemorrhagic encephalomyelitis is probably a fulminant variant of ADEM. The main pathologic features of ADEM are multiple areas of perivascular inflammation and demyelination, without evidence of active viral infection. ADEM may be caused by an autoimmune response against myelin antigens elicited by cross-reactive viral proteins. Usually, multiple white matter lesions are present on MRI, and the majority of the lesions can be enhanced with contrast. Corticosteroid treatment is often used, although the efficacy of this approach has not been proved in clinical trials. Plasmapheresis may also be useful. Prognosis varies with the inciting virus, but mortality may be as high as 30%, and survivors may be left with residual symptoms.
Acute transverse myelitis is a syndrome of spinal cord dysfunction; it has a rapid onset. Like ADEM, it may occur after infection or vaccination or it may occur with no discernible precipitant. It may also be the initial presentation of MS. Symptoms include paraparesis, which is initially flaccid and then spastic; loss of sensation with a sensory level on the trunk; and bowel and bladder dysfunction. Back pain precedes the neurologic symptoms, and the sensory symptoms may begin distally and ascend. The thoracic cord is most often affected. The differential diagnosis includes other causes of acute myelopathy, such as compression of the cord by an extradural structural lesion, spinal cord neoplasms, ischemia, and systemic lupus erythematosus. MRI is extremely useful for excluding structural lesions and for confirming the presence of an intramedullary lesion at the level in the spinal cord commensurate with the symptoms. The lesions of acute transverse myelitis are typically hyperintense on T2-weighted imaging; they involve the majority of the cross-sectional area of the cord over several segments and may be enhanced with contrast. The lesions may cause swelling of the spinal cord.[68,69] No treatment has proved beneficial, but corticosteroids are often used. Prognosis is variable: one third of patients have a good outcome, one third have a fair outcome, and one third do not recover. Spinal shock, back pain, and catastrophic onset are associated with poor outcome.
Inherited Demyelinating Diseases
Adrenoleukodystrophy is an inherited disorder that is associated with progressive demyelination and dysfunction of the adrenal cortex. The inheritance pattern may be either autosomal recessive or X-linked recessive. The X-linked form is caused by the mutation of a gene encoding an integral membrane protein found in the peroxisome. Defects in this gene lead to accumulation of very long chain fatty acids (VLCFAs). The phenotypes may vary considerably, even within the same family. In the childhood form, the patient presents with cognitive deficits; rapid neurologic deterioration then occurs, with death occurring in 2 to 5 years. The adult form, called adrenomyeloneuropathy, presents at a mean age of 28 years as progressive spinal cord dysfunction with spastic paraparesis, sensory loss, and bowel and bladder symptoms. Cerebral involvement may be minimal. Only half of patients with adult-onset disease have brain abnormalities on MRI; these are most often found in the corticospinal tracts. Most patients have diffuse atrophy of the spinal cord. Diagnosis is made on the basis of the combination of neurologic and adrenal involvement, family history, and elevated levels of serum VLCFAs. Dietary treatment with unsaturated fatty acids lowers the level of VLCFAs but does not significantly affect the progression of symptoms. Bone marrow transplantation may be effective if performed before severe symptoms develop. Prognosis is poor for patients with the childhood form of disease. Patients with adult-onset disease usually require assistance with ambulation within 10 to 15 years, and rapidly progressive cerebral lesions develop in a large percentage of patients 5 to 10 years after the onset of spinal cord symptoms.
Metachromatic leukodystrophy is an autosomal recessive disorder that results in demyelination of axons in the central and peripheral nervous systems. It is caused by mutations in the gene for arylsulfatase A that lead to accumulation of metachromatically staining sulfatides. Onset usually occurs in infancy or childhood; adult onset is rare. The symptoms of adult-onset disease are progressive behavioral abnormalities, dementia, ataxia, and neuropathy. MRI or CT of the brain demonstrates atrophy and diffuse white matter abnormalities, particularly in the frontal lobes. Diagnosis is confirmed by measurement of arylsulfatase A activity in peripheral blood leukocytes, urine, or skin fibroblasts. True arylsulfatase deficiency must be distinguished from a common pseudodeficiency state that is caused by an allele with low enzymatic activity. The symptoms of metachromatic leukodystrophy are relentlessly progressive, and earlier onset is associated with more rapid progression. The mean survival for adult-onset disease is about 12 years. No effective treatment is available, but allogeneic bone marrow transplantation and gene therapy are under investigation.
Metabolic Demyelinating Diseases
Central pontine myelinolysis (CPM) is a syndrome in which neurologic deficits occur after rapid correction of hyponatremia. CPM usually occurs in young to middle-aged adults and is often associated with alcohol abuse or malnutrition. Signs and symptoms usually begin 3 days after the start of sodium replacement and consist of changes in mental status, dysarthria and other signs of corticobulbar dysfunction, and spastic quadriplegia. Improvement usually begins about 2 weeks after the onset of symptoms, but the degree of recovery is variable. The most striking finding on pathologic examination is the presence of symmetrical demyelinated lesions in the central pons. Demyelinated lesions may also occur in a relatively symmetrical pattern in the basal ganglia, thalamus, internal capsule, subcortical white matter, and cerebellum. T2-weighted MRI usually demonstrates the presence of hyperintense lesions. These lesions usually cannot be enhanced with contrast. CPM may also occur after liver transplantation. There is no specific treatment once symptoms have developed. Long duration and rapid correction of hyponatremia increase the risk of CPM; the recommended rate for correction of hyponatremia is no faster than 10 to 12 mEq in 24 hours.
Vitamin B12 deficiency results in demyelination of axons in the central and peripheral nervous systems. The dorsal and lateral white matter tracts of the spinal cord are most affected--a characteristic that has given rise to the name subacute combined degeneration of the spinal cord. The most common presenting symptoms are paresthesias, sensory loss that begins in the feet and progresses proximally, and sensory ataxia. Weakness almost always begins after sensory loss. Memory difficulties, irritability, and confusion occur in a minority of patients. On examination, patients usually have decreased vibration and position sense, which is worse in the feet than in the hands, and may have spastic paraparesis. Pathologic examination reveals symmetrical loss of myelin in the posterior and lateral columns of the spinal cord and sometimes patchy demyelination in the cerebral white matter. MRI of the spinal cord often demonstrates white matter lesions, which resolve with treatment. Diagnosis is made on the basis of the clinical findings and a low serum cobalamin level. Macrocytosis or anemia is present in most patients but cannot be used in place of the cobalamin level as a diagnostic measure. For patients who have symptoms and a low-normal cobalamin level, demonstration of elevated levels of serum methylmalonic acid and total homocysteine can confirm the presence of a functionally significant cobalamin deficiency. If cobalamin deficiency is present, the underlying etiology should be investigated. About 80% of patients with cobalamin deficiency have pernicious anemia. Administration of cobalamin prevents progression of symptoms and produces clinical improvement in most patients. Nitrous oxide prevents the metabolism of cobalamin and can cause similar symptoms after prolonged exposure; after a single exposure, it can unmask a subclinical cobalamin deficiency.
Progressive multifocal encephalopathy is a lethal demyelinating disease caused by an opportunistic viral infection of oligodendrocytes in immunocompromised patients. The causative agent is JC virus, a ubiquitous papovavirus that infects the majority of the population before adulthood and establishes a latent infection in the kidney. In immunocompromised hosts, the virus can reactivate and productively infect oligodendrocytes. This previously rare condition is now more common because it occurs in 4% of patients with AIDS. Patients usually present with relentlessly progressive focal neurologic deficits, such as hemiparesis or visual field deficits, or with alterations in mental status. On brain MRI, one or more white matter lesions are present; they are hyperintense on T2-weighted images and hypointense on T1-weighted images. There is no mass effect, and contrast enhancement is rare. Diagnosis can be confirmed by brain biopsy, with demonstration of virus by in situ hybridization or immunocytochemistry. Polymerase chain reaction amplification of JC virus sequences from the CSF can confirm diagnosis without the need for biopsy. Currently, there is no effective therapy. Survival after diagnosis is about 3 to 5 months in AIDS patients [see 11:XVII Slow Viral Central Nervous System Diseases].
Subacute sclerosing panencephalitis (SSPE) is a rare late complication of measles virus infection. It occurs most often in patients who had the initial infection with measles virus before 2 years of age; the mean lag between initial infection and SSPE is 7 years. The use of measles vaccine has greatly reduced the incidence of this complication in developed countries. The earliest symptom is usually progressive cognitive deterioration, which is followed by motor dysfunction and myoclonus associated with distinctive electroencephalographic abnormalities. Pathologic examination reveals active viral infection in the brain, with measles virus protein and RNA detectable in both oligodendrocytes and neurons, and a vigorous inflammatory response. The course is progressive, with occasional temporary remissions. There is no satisfactory treatment [see 11:XVII Slow Viral Central Nervous System Diseases].
Figure 1 Seward Hung.
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