Multiple Sclerosis

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Multiple sclerosis is an inflammatory relapsing or progressive disorder of CNS white matter and a major cause of disability in young adults. Pathologically, it is characterized by multifocal areas of demyelination with relative preservation of axons, loss of oligodendrocytes, and astrogliosis. Although certain clinical features are characteristic of MS, investigative studies are often needed to confirm the clinical suspicion and exclude other possibilities. These tests may be useful in monitoring disease activity in patients with MS. Recently, there have been advances in our understanding of the etiology, mechanisms of myelin injury, and potential for repair. Although ideal treatment does not exist, several new therapies are being investigated and others are or soon will be available for use.

Pathogenesis and Pathophysiology (.Fig 48-2.). The pathogenesis and pathophysiology of MS is at best incompletely understood. There are several proposed mechanisms that may be important in the production of MS plaques: autoimmunity, infection, bystander demyelination, and heredity. Although convincing proof is lacking, dietary factors and toxin exposure have been hypothesized to contribute as well. These mechanisms are not mutually exclusive, and the true pathophysiology is likely to depend on more than one of them.

Autoimmunity. During ontogenesis, autoreactive lymphocytes normally undergo clonal depletion, but some escape and are merely suppressed, becoming tolerant of their antigens. Low levels of autoreactive T and B cells persist even in normal individuals. Autoimmune disorders occur when the tolerance of these cells toward their antigen is broken. The decreased suppressor activity of circulating lymphocytes from patients with MS and other presumed autoimmune diseases may reflect loss of tolerance.'?1 One potential mechanism that may break tolerance is molecular mimicry between self and foreign antigens. Autoreactive T4 lymphocytes may become activated on exposure to structurally similar foreign antigens. Some evidence suggests that molecular mimicry is relevant in MS. Not only do several viral and bacterial peptides share structural similarities with MBP, but it has also been demonstrated that a few of them are able to activate MBP-specific T-cell clones derived from MS patients.'^ Blood-brain barrier leakage alone may break tolerance because it gives CNS-reactive lymphocytes easy access to otherwise inaccessible antigens. Alternatively, a primary event such as an infection or injury may release CNS antigens into the periphery, where they may activate corresponding autoreactive cells. The major support for autoimmunity in the pathogenesis and pathophysiology of MS is by analogy to EAE, the major animal model for MS (see later). EAE is, however, an artificial situation and there is no spontaneous autoimmune animal model of MS.

MBP has been the leading candidate for the autoimmune target in MS because of its ability to induce EAE. Humoral and T-cell immune responses to MBP are found in the blood of both MS patients and healthy controls, although the level may be higher in actively relapsing MS patients. MBP-reactive T-cells activated in vivo have also been identified in peripheral blood of MS patients. 's In the cerebrospinal fluid (CSF), MBP-reactive B and T lymphocytes and anti-MBP IgG are often present in patients with MS and other neurological diseases. '9 The level of these findings seems to correlate with the extent of tissue injury but not necessarily with the etiology. Immune responses toward other CNS antigens have not been investigated as thoroughly but could be important. The findings of MBP-specific T and B cells in CSF and MBP-specific B cells and possibly T cells within CNS lesions leave little doubt as to the existence of an autoimmune response in MS. Because this response may be secondary to the release of sequestered CNS antigens by a primary event, it is uncertain if and to what extent autoimmunity is responsible for the pathology.

Infection. The role of viral infections in the initiation and maintenance of MS has been debated for some time. Several viral infections are known to cause demyelination in animals, including visna virus of goats and sheep, canine distemper virus, and Theiler's murine encephalomyelitis virus (TMEV). Viral infections in humans can also cause demyelination (progressive multifocal leukoencephalopathy 'JC papilloma virus!, subacute sclerosing panencephalitis 'measles virus!, and human T-cell lymphotropic or leukemia

Figure 48-2 Pathology of MS/l, Coronal brain slice showing several focal areas of sclerosfarrowsj. B, Luxol fast blue stain of a coronal brain section showing numerous discrete areas of myelin loc, Hematoxylin and eosin stain of a chronic lesion showing perivascular mononuclear cells and prominent gliosiD, Luxol fast blue/periodic acid-Schiff stain showing perivascular inflammation and loss of myelin.

virus type I 'H^V^-associated myelopathy). The epidemiology of MS suggests that environmental factors may promote the disease state, possibly due to one or more viruses. There are many ways in which a virus may be involved in the pathogenesis of MS:

1. Transient or persistent infection outside the CNS may activate autoreactive T cells by means of molecular mimicry or by other nonspecific means (as superantigens do).

2. Transient CNS infection may initiate a cascade of events that foster autoimmunity (breach the blood-brain barrier, release CNS antigens).

3. Recurrent CNS infections may precipitate repeated inflammation and demyelination.

4. Persistent CNS viral infection could either incite inflammatory reactions detrimental to oligodendrocytes or directly injure them.

Beyond speculation and epidemiology, there is slim evidence for a viral infection in MS. Early serological studies are difficult to interpret because of the nonspecific immune activation and resulting elevation of titers to many different viruses. Many MS patients have elevated CSF titers to such viruses as measles and herpes simplex (HSV), but this also appears nonspecific. Virus has rarely been cultured from CSF of MS patients, but a new strain of HSV (the MS strain) and a new virus (Inoue-Melnick virus) were first isolated from the CSF of MS patients. y , 'n1 Newer molecular techniques to search for a viral genome in CSF and brain have rejected the claim that HTLV-I is associated with MS. In addition, reverse transcriptase activity has not been detected in CSF using a very sensitive assay, thus disputing the involvement of any retrovirus. The finding that human herpesvirus 6, although present in 70 percent of brains from both controls and MS patients, is localized to the oligodendrocyte nuclei near plaques of MS patients and to oligodendrocyte cytoplasm in controls indicates that persistent CNS viral infection is common. y This raises the possibility that MS may depend on an aberrant host response to this normal condition or that a defective virus that lacks the ability to evade immune detection may be to blame.

"Bystander" Demyelination. Immune actions may mediate myelin injury in a nonspecific manner. Many soluble products of the immune response other than immunoglobulins are known or suspected to be toxic to myelin and oligodendrocytes. Activated complement is capable of lysing oligodendrocytes in an antibody-independent fashion. y The proinflammatory cytokine tumor necrosis factor-alpha causes myelin disruption and oligodendrocyte apoptosis in vitro. y Arachidonic acid metabolites may also participate in myelinolysis, and reactive oxygen species released by macrophages cause lipid peroxidation that can damage myelin. Other soluble substances that are potentially

toxic to myelin include nitrous oxide and vasoactive amines.

Heredity. Epidemiological findings support a polygenic hereditary predisposition to MS. A number of candidate genes have been investigated, often with contrary results. The only definitively proven genetic association in MS is with serologically defined human leukocyte antigen (HLA) DR15, DQ6 (one of the DR2 haplotypes and also known as Dw2 in cellular terminology and DRB1*1501, DQA1*0102, DQB1*0602 in molecular nomenclature). However, the risk conferred by this haplotype is small (relative risk of 3 to 4), and it is neither necessary nor sufficient for the development of MS. Linkage to this locus has not been proven, indicating that it plays only a minor role in familial susceptibility. Other susceptibility genes undoubtedly contribute and may include the T-cell receptor (TCR) variable beta region and the IgG heavy-chain variable region, but these have not been confirmed. Twenty percent of MS patients have at least one affected relative. Only about 4 percent of first-degree relatives of patients develop MS, but this represents a 20- to 40-fold increase in risk compared with the general population. Unaffected family members sometimes have abnormal results of head magnetic resonance imaging (MRI), implying that this risk is even higher. One study of MS rates in adopted relatives of MS

patients verified that the familial distribution is due to genetic factors rather than shared environment. y Twin studies lend support to both genetic and environmental influences on MS development. Genetically identical monozygotic twins are more often concordant for MS than dizygotic twins (26 percent and 2.4 percent, respectively), indicating a genetic componenty ; however, even after following monozygotic twins past age 50 or using MRI data, less than 50 percent are concordant, suggesting a role for environmental factors.

Epidemiology and Risk Factors. MS is not a rare disease. It affects millions worldwide and approximately 400,000 in the United States alone. Symptoms usually begin during young adulthood, with the peak onset at age 24. Generally it occurs in persons between the ages of 15 and 50, although the first manifestations occasionally start during childhood or after age 50. Women are affected nearly twice as often as men. MS has a predilection for whites, especially those of northern European heritage. Other races and ethnic populations are resistant to a variable extent. It is virtually unknown among black Africans but occurs in African-Americans at half the rate of whites, possibly due to racial admixture or environmental factors. MS is rare in tropical areas, and the prevalence increases proportional to the distance from the equator, excluding polar regions. Although usually interpreted as the effect of environmental factors, the prevalence gradient is at least partially due to racial susceptibility. [17]

Perhaps the most incriminating evidence for the role of environmental factors in the development of MS are the changing risk with migration and the occurrence of MS clusters and epidemics. Immigrant populations tend to acquire the MS risk inherent to their new place of residence. Furthermore, the age at immigration is important in the subsequent risk of MS. Migration from high to low prevalence before the age of 15 lowers the MS risk, whereas migration after this age does not affect risk. y Migration from low to high prevalence areas increases the risk of MS, but the effect of age is less clear. Many clusters of MS have been reported. One of the more notable ones occurred in Key West in the mid 1980s. y Several others have been disputed; and despite wide speculation, no environmental cause for clustering has been identified. In fact, the majority of community-identified clusters are likely due to statistical chance alone. y The occurrences of MS epidemics in Iceland and the Faroe Islands have been proposed to be the result of exposure to a pathogen brought by British troops during their occupation in World War II.

Epidemiological data support the view that MS is caused or triggered by an environmental factor in persons who are genetically susceptible. The familial frequency and distribution implies that several genes contribute to susceptibility, and this is consistent with the low relative risk conferred by the genetic loci studied so far. Data from clusters, migration studies, and family studies reveal that there is a latent period of some 20 years between exposure to the environmental factor and the development of clinical symptoms and that the age at exposure is around 15, the putative age at acquisition.

The precise environmental events that lead to CNS demyelination are uncertain. Viral infection is the most plausible, but because of the nonspecific elevation of viral titers and long latent period there is little direct evidence. Minor respiratory infections precede 27 percent of relapses in patients with established MS. Measles infection was found to have occurred at a later age in MS patients than controls, although the incidence of MS has not been reduced by immunization against measles. Head injury and trauma have received attention as putative triggering events, but cohort studies have not verified any link. Pregnancy does not alter the risk of developing MS, but it does seem to influence disease activity. The relapse rate drops by about one third during the last two trimesters, but this is offset by an increase in relapse rate in the postpartum period. Most studies have found no long-term effects of pregnancy on the prognosis for progression or disability, although one did report a favorable effect. y A multitude of other environmental factors have been suspected to alter the risk for MS (cold climate, precipitation, amount of peat in the soil, exposure to dogs, and consumption of meat, processed meat, and dairy products), but none has been verified to be an independent risk factor.

Clinical Features and Associated Findings. MS can cause a wide variety of clinical features. Many signs and symptoms are characteristic, and a few are virtually pathognomonic for the disorder. Conversely, some symptoms are atypical and some are so rare as to suggest a different diagnosis ( Tablei48-2 ). The course of the illness is also variable, but it remains a critical consideration in the diagnosis of MS.

Sensory symptoms are the most common presenting manifestation in MS and ultimately develop in nearly all patients. y Loss of sensation (numbness), paresthesias (tingling), dysesthesias (burning), and hyperesthesias are common. These may occur in practically any distribution: one or more limbs, part of a limb, trunk, face, or combinations.

The more distinctive sensory relapses of MS consist of the sensory cord syndrome and the useless hand syndrome.

TABLE 48-2 -- DIAGNOSIS OF MULTIPLE SCLEROSIS

Clinical Features Suggestive of MS

Clinical Features Not Suggestive of MS

Onset between the ages of 15 and 50

Onset before the age of 10 or after 55

Relapsing/remitting course

Continued progression from onset without relapses

Optic neuritis

Lhermitte's sign

Early dementia

Partial transverse myelits

Seizures

Internuclear ophthalmoplegia

Aphasia

Sensory useless hand

Agnosia

Acute urinary retention (especially in young men)

Apraxia

Paroxysmal symptoms

Homonymous or bitemporal hemianopia

Diurnal fatigue pattern

Encephalopathy

Worsening symptoms with heat or exercise

Extrapyramidal symptoms

Uveitis

Peripheral neuropathy

Whereas features listed in the right column may be seen in MS, they are atypical and should prompt consideration of alternate explanations.

Whereas features listed in the right column may be seen in MS, they are atypical and should prompt consideration of alternate explanations.

A common scenario is that of numbness or tingling beginning in one foot, ascending first ipsilaterally and then contralaterally. The sensory symptoms may ascend to the trunk, producing a sensory level, or may involve the upper extremities. Associated symptoms commonly include poor balance, weakness, urinary urgency, constipation, and Lhermitte's sign (see later). Brown-Sequard syndrome may occur with sensory disassociation and hemiparesis. The sensory cord syndrome reflects an evolving demyelinating lesion that begins in the medial posterior column ipsilateral to the first symptoms. A suspended sensory loss on one side of the trunk may also occur, possibly involving the upper extremity. Sensory cord syndromes are common in MS and suggest the diagnosis when they occur in young persons and remit spontaneously or in response to corticosteroids. Patients with the sensory useless hand may note subjective numbness and lose discriminatory and proprioceptive function, resulting in difficulty writing, typing, buttoning clothes, and holding on to objects especially when not looking at their hand. This can occur bilaterally even without lower extremity symptoms. The responsible lesion is in the lemniscal pathways either in the cervical spinal cord or in the brain stem. This syndrome usually remits over several months. The useless hand syndrome is a very specific symptom and is only rarely caused by other disorders.

A large portion of MS patients have persistent sensory loss usually consisting of diminished vibratory and position sensation in distal extremities. Itching may occur in a dermatomal distribution with relapse or in paroxysms. Pain is not a major manifestation of MS, but when it does occur it can be distressing to the patient. The most common complaints of pain are lower extremity dysesthetic pain associated with spinal cord involvement, radicular pain from lesions at the root entry zone, paroxysms (see later), and an uncomfortable sensation of pressure or tightness surrounding a leg or the trunk.

Pyramidal tract dysfunction is common in MS and causes weakness, spasticity, loss of dexterity, and hyperreflexia. Motor deficits can occur acutely or in a chronic progressive fashion and are usually accompanied by other symptoms. Paraparesis, quadriparesis, hemiparesis, weakness of one limb, and facial weakness are common manifestations. Subtle deficits are frequently worsened by exercise or heat. Weakness of trunk muscles resulting from spinal cord lesions may cause abnormal posture and occasionally respiratory muscle weakness occurs from cord or brain stem lesions. Symptoms of spasticity such as leg stiffness that impairs gait and balance or extensor and flexor spasms are other major causes of disability. Muscle atrophy is usually due to disuse, but lesions of the exiting lower motor neuron fibers or of the anterior horn itself can cause a pseudora-diculopathy with segmental weakness, atrophy, and diminished reflexes.

The initial symptom of MS is optic neuritis in 17 percent of patients, and more than 50 percent experience a clinical episode of optic neuritis during their lifetime. The most common manifestation is visual loss in one eye that evolves over a few days. Periocular pain, especially with eye movement, usually accompanies and may precede the visual symptoms. Bilateral simultaneous optic neuritis is uncommon in adults, but formal visual field testing reveals unexpected defects in the clinically normal eye in a substantial number of patients. Children and Asian patients are more likely to have bilateral simultaneous optic neuritis. Examination shows an afferent pupillary defect, diminished visual acuity, subdued color perception, and often a central scotoma. Funduscopic examination is usually normal but occasionally will reveal papillitis (more common in children) or venous sheathing. Most patients begin to recover within 2 weeks, and significant visual recovery is common. There may be persistent visual blurring, altered color perception, or Uhtoff's sign (see later). Progressive worsening of visual acuity sometimes occurs, and MS patients without a clinical history of optic neuritis often have evidence of optic nerve involvement on funduscopic examination or visual evoked potentials.

Cerebellar pathways are frequently involved during the course of MS, but a predominately cerebellar syndrome is uncommon at onset. The manifestations include dysmetria, dysdiadochokinesia, action tremor with terminal accentuation, dysrhythmia, breakdown of complex motor movements, and loss of balance. Symptoms range from mild dyscoordination or gait unsteadiness to violent movement-induced tremor and complete loss of balance. Patients with long-standing MS may develop a "jiggling" gait and an ataxic dysarthria with imprecise articulation, scanning speech, or varying inflection, giving it an explosive character.

Urinary urgency, frequency, and urge incontinence (due to detrusor hyperreflexia or detrusor-sphincter dyssynergia) result from spinal cord lesions and are frequently encountered in MS patients. Symptoms of bladder dysfunction may be transient and occur with an exacerbation but are commonly persistent. Impaired vesicular sensation causes a high capacity bladder and may lead to bladder atonia with thinning and disruption of the detrusor muscle. This is an irreversible condition in which overflow incontinence results in constant dribbling of urine. Interruption of brain stem micturition center input sometimes leads to co-contracture of the urinary sphincter and detrusor muscles or detrusor-sphincter dyssynergia. The resulting high pressure

may lead to hydronephrosis and chronic renal failure if untreated. Constipation is a common problem, especially in patients with limited activity and spinal cord involvement. Fecal incontinence is a socially devastating symptom that is often associated with perineal sensory loss in MS patients.

Sexual dysfunction is a common problem of MS that is seldom mentioned. Nearly two thirds of patients report diminished libido. One third of men have some degree of erectile dysfunction, and a similar percentage of women have deficient vaginal lubrication. Besides direct neurological impairment, sensory loss, physical limitations, depression, and fatigue additionally contribute to sexual difficulties in MS patients. In addition, the partner's attitude and psychological factors dealing with self-image, self-esteem, and fear of rejection may also lead to impotence or loss of libido.

Intense vertigo associated with nausea and emesis is an occasional manifestation of MS relapse. In the absence of a clear diagnosis of MS, these symptoms are often attributed to vestibular neuronitis. Patients may also develop more persistent mild vertigo that is precipitated by movement, or this may be the residua after an acute relapse. Internuclear ophthalmoplegia, caused by a lesion in the medial longitudinal fasciculus, is the most common cause of diplopia in MS patients. When symptomatic, it produces horizontal diplopia on lateral gaze that usually remits. Examination discloses incomplete or slow adduction of the eye ipsilateral to the lesion and nystagmus of the contralateral eye during abduction (see Chapter.9 ). Dissociated nystagmus may be the only finding of an old or subtle internuclear ophthalmoplegia. Bilateral internuclear ophthalmoplegias are strongly suggestive of MS, although they rarely occur with tumor, infarct, mitochondrial cytopathy, Wernicke's encephalitis, and Chiari malformation. Vertical and diagonal diplopia usually result from skew deviation. Nystagmus, slow saccadic movements, broken ocular pursuits, and ocular dysmetria are other eye findings produced by lesions of cerebellar and vestibular pathways (see ChapterJ.2 ). Cranial nerve impairment is an unusual cause of diplopia in MS patients. Abducens paresis occurs on occasion, but oculomotor and trochlear nerve impairment are rare.

Brain stem plaques are seen on MRI more often than the occurrence of acute brain stem relapses. Corticospinal, spinothalamic, lemniscal, vestibular, and cerebellar pathways can all be affected. In addition, cranial nerve impairment may be seen with lesions that affect brain stem nuclei or exiting and entering fibers. Usually this occurs in association with other symptoms. Because of the long spinal tract and nucleus, the trigeminal nerve is frequently involved. Facial nerve paresis does occasionally occur, but MS is an extremely rare cause of Bell's palsy in patients without previous symptoms. Acute unilateral hearing loss is a fairly uncommon manifestation. Dysphagia is often due to impairment of cranial nerves IX, X, and XII and generally appears late in the course of some patients.

Once thought uncommon, cognitive disorders are now known to be present in 40 to 70 percent of MS patients. y Age, duration of MS, and physical disability do not predict the presence of cognitive dysfunction, but the total lesion load seen on MRI does seem to correlate with the degree of cognitive decline. Brain atrophy, enlarged ventricles, and thinning of the corpus callosum also portend symptoms of cognitive dysfunction. Often the problems are subtle and may not be detected on standard mental status evaluation. The pattern of cognitive decline in MS is typified by memory loss, inattention, slow information processing, and difficulty with abstract concepts and complex reasoning. General intelligence is not typically affected. As expected, cortical symptoms such as aphasia, apraxia, and agnosia are distinctly unusual. Homonymous hemianopia, which can be caused by cortical or subcortical lesions, is also uncommon. Despite prominent cerebral white matter involvement, many of the disconnection syndromes such as alexia without agraphia, conduction aphasia, and pure word deafness have not been reported in MS patients.

Affective disorders are more frequent in MS patients than in the general population. These include both anxiety and depression. Neither of these symptoms is related to physical or cognitive disability or the lesion load visualized by MRI. Patients sometimes experience uncontrollable weeping or less commonly laughter noncongruent with their mood. Interruption of inhibitory corticobulbar fibers is responsible for these symptoms (pseudobulbar affect).

Fatigue is a pervasive symptom among MS patients that is not related to disability or depression. Severely affected patients often have a lack of initiative for both physical and mental activity and become easily tired. A diurnal pattern is characteristic and follows the normal circadian pattern of body temperature fluctuations, with the worse symptoms occurring in afternoon hours (peak core body temperature) giving way to improvement in the late evening.

MS symptoms may fluctuate in a predictable fashion. Transient worsening of symptoms frequently follows exercise or elevation of body temperature. One example is Uhtoff's phenomenon, in which visual blurring occurs during strenuous activity or with passive exposure to heat. These episodes resolve when the body temperature cools to normal or after a period of rest. An intercurrent infection with fever can induce worsening of symptoms and may be confused with a relapse. Heat sensitivity is presumably related to conduction block because demyelinated axons are more prone to failed conduction than normal, myelinated fibers.

Paroxysmal symptoms are characteristic of MS. They are believed due to the lateral spread of excitation, or ephaptic transmission, between denuded axons in areas of demyelination. Symptoms are typically brief in duration (seconds to 2 minutes) and occur frequently, occasionally dozens of times per day. They may be precipitated by hyperventilation, certain sensory input, or particular postures. Tonic spasms (paroxysmal dystonia) most often affect the arm and leg on one side, but the face, one limb, or bilateral limbs are sometimes involved. These spasms can result from lesions anywhere along the corticospinal tract. They often begin during the recovery phase after an acute relapse and remit after a few months. Intense pain and ipsilateral or crossed sensory symptoms may accompany them. Paroxysmal weakness occurs, but it is uncommon.

A wide variety of paroxysmal sensory symptoms may occur with MS, including tingling, prickling, burning, or itching; and sharp neuralgic pain is not uncommon. Trigeminal neuralgia may appear in patients with MS. The

occurrence of trigeminal neuralgia in a person younger than 40 is suggestive of MS. Lhermitte's sign (transient sensory symptoms usually precipitated by neck flexion) is usually described as an electrical or tingling sensation that travels down the spine or into the extremities. Although quite common in MS, Lhermitte's sign can also occur with a wide variety of other disorders, such as vitamin B12 deficiency, spondylosis, Chiari malformation, and tumors, and after cisplatin chemotherapy. Several other paroxysmal symptoms are occasionally encountered, including paroxysmal dysarthria and ataxia, paroxysmal dyskinesia/dystonias, paroxysmal diplopia, and combinations of these symptoms. Facial myokymia and hemifacial spasm are additional transient (lasting months) phenomena sometimes due to brain stem demyelination.

Seizures occur in about 10 percent of MS patients. Focal motor seizures, possibly with secondary generalization, are the most frequent. The occurrence of seizures usually follow one of two patterns. On occasion, focal onset seizures begin early in the course of MS and later remit. The start of seizures late in the course of MS

more often poses a chronic problem and are frequently difficult to control.

MS is typified by multifocal CNS involvement and acute relapses, remissions, and/or slow progression of neurological deficits. A single episode of neurological dysfunction can be suggestive of MS if it follows the typical time course of a relapse: progression over less than 2 weeks (usually days), with or without a period of stabilization, and improvement or resolution (often over months). Insidious progression of deficits localized to a single site in the CNS can also be due to MS, but other possible causes must be excluded. The temporal course of MS can be described by one of four categories: relapsing/remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). y

Other terms have been used in the past to designate the course of MS, but because of the nonspecific terminology and overlapping course descriptions they are no longer used. Many previous clinical drug trials were performed in patients with a chronic progressive course. It is difficult to interpret these data because patients with both PP and SP Ms were included and these patients may respond differently to treatment. Many physicians use the term relapsing progressive, which encompassed patients with SP, PR, and even those with RR MS who have stepwise relapse-related worsening disability. This term has recently been abandoned. Other terms that relate to the course of MS but have no consensus regarding their definition are sometimes encountered. Benign MS generally refers to patients who have had MS for a long period of time but yet have little or no disability. Malignant MS is sometimes used to describe patients with frequent relapses and incomplete recovery but is also used in reference to patients with acute fulminant demyelinating syndromes (see later).

The eye is the only organ outside the nervous system that is sometimes involved in MS. Uveitis and retinal periphlebitis each occur in at least 10 percent of MS patients. The uveitis can involve the posterior, intermediate (pars planitis), or rarely anterior portion and resembles that seen in other inflammatory (e.g., sarcoid, Reiter's syndrome, Behcyet's syndrome, inflammatory bowel disease, systemic lupus erythematosus) and infectious (e.g., syphilis, tuberculosis, Lyme disease) conditions. Periphlebitis is seen as venous sheathing on funduscopic examination and is histologically identical to the perivascular inflammation present in brain white matter. It is interesting that inflammation commonly occurs in the retina, which has a peripheral type of myelin produced by Schwann cells.

There are occasional reports of peripheral nerve or nerve root demyelination in MS patients as well as central demyelination in acute inflammatory demyelinating polyradiculoneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy (see Ch§pter,49 ). Some of these cases may be due to the incidental occurrence of two unrelated disease processes. However, because the PNS and CNS share many antigens, including MBP, it is possible that an autoimmune reaction or a viral infection could involve both the CNS and PNS.

Persons with one autoimmune disorder generally have an increased risk of others. Even though there are several reports of systemic and organ-specific autoimmune diseases in MS patients, population-based studies have not confirmed any increase in prevalence of these disorders among Ms patients. y In fact, there appears to be a negative association between MS and rheumatoid arthritis. No increased risk of brain tumors or hematological malignancies have been found despite occasional reported associations.

Differential Diagnosis. There are few diseases that cause neurological deficits, regress spontaneously, and relapse in different areas of the CNS over the course of many years. However, because of the remarkable heterogeneity of MS, many disorders may resemble MS (,Table.,48z3 ), especially in the first years of active disease.

Other primary idiopathic inflammatory demyelinating CNS disorders may be mistaken for MS. Acute disseminated encephalomyelitis (ADEM) usually causes monophasic CNS demyelination. Although it frequently involves multifocal areas of white matter near simultaneously, ADEM cannot always be reliably differentiated from the initial clinical episode of MS. Fulminant brain demyelination in persons without previous symptoms of MS is more likely due to ADEM or other conditions (Schilder's myelinoclastic diffuse sclerosis, Balo's concentric sclerosis, Marburg's variant of MS). Neuromyelitis optica differs from MS primarily in the topography and intensity of the lesions.

Several systemic or organ-specific inflammatory conditions can involve the CNS white matter. Optic neuritis, myelitis, and other syndromes sometimes occur with systemic lupus erythematosus. Whether this autoimmune disease increases the risk of developing MS or causes similar syndromes by a different pathological process is unknown. Sarcoidosis can affect the nervous system in several ways, including multifocal corticosteroid-responsive white matter lesions. Sjogren's syndrome sometimes occurs with MS, but this may only represent a chance association. Behcet's disease has a predilection for the brain stem when it involves the CNS. Occasionally, isolated demyelinating syndromes are associated with inflammatory bowel disease.

A wide variety of vasculitic syndromes (e.g., primary angiitis of the CNS, periarteritis nodosa, Wegener's granulomatous angiitis, vasculitis associated with rheumatoid arthritis, Susac's syndrome, Eales' disease) may mimic MS. However, these syndromes can usually be distinguished by involvement of the cortex, seizures, early dementia,

TABLE 48-3 -- DIFFERENTIAL DIAGNOSIS OF MULTIPLE SCLEROSIS

Other inflammatory demyelinating CNS conditions

Cerebrovascular disorders

Multiple emboli

Hypercoagulable states

Acute disseminated encephalomyelitis

Sneddons syndrome

Neoplasms

Neuromyelitis optica

Metastasis

Systemic or organ-specific inflammatory diseases

Lymphoma

Paraneoplastic syndromes

Systemic lupus erythematosus

Metabolic disorders

Sjogrens syndrome

Vitamin B12 deficiency

Behcets disease

Vitamin E deficiency

Inflammatory bowel disease

Central (or extra) pontine myelinolysis

Vasculitis

Periarteritis nodosa

Leukodystrophies (especially adrenomyeloneuropathy)

Primary CNS angiitis

Susac's syndrome

Leber's hereditary optic neuropathy

Eales' disease

Structural lesions

Granulomatous diseases

Spinal cord compression

Sarcoidosis

Chiari malformation

Wegener's granulomatosis

Syringomyelia/syringobulbia

Infectious disorders

Foramen magnum lesions

Lyme neuroborreliosis

Spinal arteriovenous malformation/dural fistula

Syphilis

HTLV-I associated myelopathy

Degenerative diseases

Hereditary spastic paraparesis

Viral myelitis (HSV, VZV) Spinocerebellar degeneration

Progressive multifocal leukoencephalitis Olivopontocerebellar atrophy

Psychiatric disorders

Subacute sclerosing panencephalitis Conversion reactions

Malingering

HTLV-I, human T-cell lymphotropic virus type I; HSV, herpes simplex virus; VZV, varicella-zoster virus; CNS, central nervous systen .

personality changes, psychosis, infarcts involving large vessel territories on MRI, and lack of improvement. Findings characteristic to the particular vasculitis (uveitis and vitreal hemorrhage in Eales' disease; retinal and cochlear involvement in Susac's syndrome; upper and lower respiratory tract involvement in Wegener's granulomatosis) also aid in the correct diagnosis.

A few infections must also be considered in the differential diagnosis of MS. Both Lyme disease and syphilis may cause multifocal white matter lesions. HTLV-I causes a chronic progressive myelopathy (HTLV-I-associated myelopathy/tropica! spastic paraparesis). Acute or recurrent myelitis can be caused by varicella-zoster virus or HSV. Progressive multifocal leukoencephalopathy and Toxoplasma abscesses should be considered in immunocompromised patients with progressive neurological decline. Bacterial endocarditis with brain abscess formation, subacute sclerosing panencephalitis, or chronic rubella encephalomyelitis may need to be considered in the appropriate circumstances.

Cerebrovascular disease is only rarely mistaken for MS. Occasionally, however, an MS relapse has an abrupt onset that may mimic an infarct, especially in those not previously diagnosed with MS. The usual circumstance is that of a hemisensory or hemimotor deficit imitating a lacunar infarct. Disorders with multiple cerebral infarcts (emboli, hypercoagulable states, Sneddon's syndrome, vasculitis) may produce an MRI appearance and course resembling MS. Vascular malformations may also produce symptoms similar to MS.

Additional neurological illnesses capable of producing multifocal lesions rarely manifest similar to MS. Metastatic tumors and multifocal gliomas have been reported as being suggestive of MS, but this must be considered extraordinarily rare. Lymphoma more commonly masquerades as MS because the lesions may involve the white matter, may be multifocal, and are corticosteroid responsive. In addition, demyelination sometimes presents as one (or a few) mass lesion(s). In this situation, biopsy may be needed for diagnosis. Neoplasms can cause paraneoplastic syndromes that may be confused with MS. A high index of suspicion must be kept for older age at presentation, subacute ataxia, early dementia, and personality changes.

A few metabolic disorders may resemble MS such as vitamin B12 deficiency, vitamin E deficiency (seen in Bassen-Kornzweig syndrome, hypobetalipoproteinemia, and Refsum's disease), and central pontine or extrapontine myelinolysis. Leukodystrophies are usually not difficult to distinguish from MS. Krabbe's disease (galactocerebroside-beta-galactosidase deficiency), metachromatic leukodystrophy (arylsulfatase A deficiency), and the usual adult form of adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) exhibit both central and peripheral dysmyelination. Blood leukocyte or fibroblast culture enzyme activity levels will confirm the diagnosis of Krabbe's disease and MLD, and elevated levels of very long chain fatty acids occur in ALD/AMN. Mitochondrial disorders should also be given consideration because symptoms and MRI appearance may be similar to MS. A relapsing remitting disorder identical to MS is sometimes seen in patients with the mutations responsible for Leber's hereditary optic neuritis. ^ This usually occurs in female patients, and there may not be a family history of visual loss. A number of rare biochemically defined illnesses and other genetic disorders may occasionally merit consideration (including cobalamin and folate dysmetabolism, adult polyglucosan body disease, hereditary spastic paraparesis, spinocerebellar degeneration, and hereditary cerebroretinal vasculopathy). y

Several additional disorders must be excluded before diagnosing primary progressive MS. Spinal cord compression from spondylosis or tumor may produce chronic progressive myelopathy. Chiari malformations, syringomyelia, syringobulbia, other foramen magnum lesions, spinal arteriovenous malformations, and dural fistulas may also need consideration. These structural abnormalities are readily identified by imaging. Degenerative diseases such as olivopontocerebellar atrophy may mimic PP MS. MRI and CSF examination will help distinguish between the two.

When clinical and paraclinical findings are absent among a multitude of complaints or when apparent severe loss of function, without clinical evidence of neurological disease, is faced with a lack of concern, it may be appropriate to consider psychiatric disorders such as somatization, malingering, or conversion reactions.

Evaluation. The diagnosis of MS is based on the demonstration of white matter lesions disseminated in time and space in the absence of another identifiable explanation. MS remains a clinical diagnosis, although MRI, evoked potentials, and CSF examination can help clarify less certain cases. For research purposes, various categories of MS have been defined based on the certainty of the diagnosis. y At least two attacks and evidence of two separate CNS

Figure 48-3 Head MRI of patients with MS/A, Ti-weighted sagittal image showing multiple hypointense periventricular lesioB, Axial T2-weighted image shwoing confluent periventricular high-intensity lesions most prominent at the frontal and occipital horns. A focal lesion is also present in the posterior limb of the left internal capsuC and D, Periventricular lesions suggestive of MSE, A single large right cerebellar hemisphere lesion seen on T2-weighted MR Peripherally gadolinium-enhanced large right occipital white matter lesion. Enhancement can also be seen along the temporal horn of the lateral ventricles.

lesions (clinical or paraclinical) are required for the designation of clinically definite MS (CD MS). Two attacks and evidence for one or one attack and evidence of two CNS lesions (clinical or paraclinical) is considered clinically probable MS. Cases that fulfill the criteria for clinically probable MS and have supportive CSF findings are labeled as laboratory-supported definite MS. Patients with a clear history of at least two attacks and supportive CSF but a normal neurological examination and no paraclinical evidence of CNS lesions are categorized as having laboratory-supported probable MS. Suspected cases that do not fit any of these criteria may be regarded as possible MS. Paraclinical evidence generally refers to abnormalities on evoked potential studies or imaging procedures, but urological studies and hot bath tests can also be used. To exclude the simultaneous development of lesions, as in ADEM, when using paraclinical evidence in patients with only one attack it must be known that the studies were normal at the time of that attack or, in the case of MRI, that new lesions have developed. The presence of both enhancing and nonenhancing white matter lesions on a single MR image must not be used as evidence of dissemination in time as well as space, because these can also be seen in ADEM. The presence of oligoclonal bands (OCBs) and an elevated IgG index or synthesis rate provide supportive CSF findings.

Ancillary tests are frequently required to confirm the diagnosis of MS and to exclude other possibilities. Laboratory tests on peripheral blood can help to exclude many of the infectious and other inflammatory disorders. A chest radiograph is generally needed to assess for sarcoid or paraneoplastic disorders if these are under consideration. An ophthalmological examination may be needed to search for alternate causes of visual loss. Imaging studies, CSF examination, and evoked potentials are often helpful because characteristic abnormalities are frequently present.

MRI of the head is the most sensitive study for MS and

is far more useful than computed tomography (CT). Eighty-five to 95 percent of CD MS patients have abnormalities on head MRI ( m Fig 48-3 ). Focal areas of increased T2-weighted and decreased T1-weighted signal reflect the increased water content associated with demyelinated plaques. The MRI appearance of MS lesions, however, is not specific and similar abnormalities may be seen in normal aging, small penetrating vessel infarcts, Lyme disease, tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM), sarcoid, systemic lupus erythematosus, Sjogren's syndrome, mitochondrial cytopathies, vasculitis, and ADEM. The specificity for MS can be increased by consideration of lesion number, size, location, and shape. y This is especially important in persons older than 50. MRI characteristics that are strongly suggestive of MS include multiple lesions (more than three), size larger than 6 mm, oval shape (often with the long axis directed perpendicular to lateral ventricles), and locations in the periventricular area, corpus callosum, and posterior fossa.

Longitudinal MRI studies have shown the evolution of MS lesions. y Gadolinium enhancement, indicating blood-brain barrier disruption, sometimes precedes the development of T2-weighted lesions and lasts for 2 to 4 weeks. The new T2-weighted lesion has a fuzzy border and enlarges over a few weeks. After a period of stabilization, the T2-weighted lesion regresses and becomes more sharply delineated from the surrounding white matter as edema resolves. Most of the time, a residual abnormality with increased T2 weighting and decreased T1-weighted signal remains, reflecting demyelination and gliosis. The MRI activity of disease, defined as either the number of new, recurrent, and enlarging lesions or the number of gadolinium-enhancing lesions, is much higher than the clinical activity. This may be either because of the involvement of asymptomatic areas of the CNS or because of a pathophysiological difference between symptomatic and nonsymptomatic lesions based on the presence or absence of axonal dysfunction.

There is only a poor correlation between disability and lesion load (volume of white matter abnormalities) determined by head MRI. Sometimes individuals have severe impairment and few abnormalities, and the converse may occur. This disparity is partially explained by variable spinal cord involvement, but a pathophysiological difference may account for some of the discrepancy.

MRI has become an important component of recent clinical trials. Because of the high sensitivity of MRI for disease activity, it is reasoned that periodic MRI can determine treatment efficacy much more quickly than monitoring relapse rate or disability level. Many studies have used MRI as a secondary outcome, and a few have used it as a primary outcome, a true surrogate marker of the main parameter of interest.

Additional MRI techniques have also proven useful in the diagnosis of MS. MRI of the spinal cord shows discrete lesions in about 80 percent of CD MS patients. Fluid attenuated inversion recovery eliminates the CSF signal from T2-weighted images and increases the contrast of lesions and sensitivity of both head and spine MRI. Short time-inversion recovery suppresses fat signal and is useful in detecting optic nerve lesions. Magnetization transfer imaging takes advantage of the macromolecular environment of protons and can discern early edematous lesions, which are frequently reversible, from chronic demyelinated and gliotic lesions that are nonreversible. MR spectroscopy is used to determine the biochemical changes that occur in lesional and nonlesional white matter of MS patients.

CSF evaluation remains a valuable diagnostic tool for MS. A lymphocytic pleocytosis occurs during acute exacerbations in about one third of patients, but this seldom

exceeds 50 cells. Total protein is often mildly elevated, and the proportion of gamma-globulin is high owing to the synthesis of immunoglobulins within the blood-brain barrier. The majority of CSF immunoglobulin is IgG, although IgM and IgA may also be elevated. Measures of intrathecal IgG production have been devised that are more useful than simple gamma-globulin levels. The IgG index and synthesis rate are elevated in 70 to 90 percent of CD Ms patients and occasionally in other disorders (see later). Agarose gel electrophoresis, or the more sensitive isoelectric focusing of CSF proteins, often reveals discrete bands of immunoglobulin, each a monoclonal antibody. It is pertinent to compare serum and CSF banding patterns because peripheral monoclonal gammopathies may produce CSF bands. To reduce false-positive results, only unique CSF OCBs should be reported. Between 85 and 95 percent of CD MS patients have OCBs; however, early in the course they are not as prevalent. Once present, OCBs persist and the pattern does not vary, although new bands occasionally appear. Unlike subacute sclerosing panencephalitis, in which the majority of OCBs are antibodies specific for measles virus, the specificity of OCBs in MS is unknown.

The presence of OCBs does not necessarily imply MS, because up to 8 percent of non-MS CSF samples contain them. y Other inflammatory or infectious illnesses are usually responsible for OCBs in non-MS patients, and in these instances they often do not persist. The presence of myelin components, antimyelin antibodies, and kappa light chains in CSF has also been used in the diagnosis of MS. However, the sensitivity and specificity of these products is less than that of OCBs.

Evoked potentials are summed cortical electrical responses to peripheral sensory stimulation that can be used to localize sites of pathology and measure conduction velocity along sensory pathways. Visual evoked potentials (VEP) and somatosensory evoked potentials (SSEP) may detect subclinical sites of demyelination, thus providing evidence of multifocality. Brain stem auditory evoked potentials (BAEP) are occasionally informative. More than 90 percent of persons with a history of optic neuritis have an abnormal VEP, and 85 percent of CD MS patients have abnormalities on VEPs even when the history of optic neuritis is absent. Slowed conduction is present on SSEP in nearly three fourths of patients with CD MS. BAEPs are the least sensitive, with abnormalities in approximately 50 percent. MRI has largely supplanted the use of evoked potentials in MS because of the greater sensitivity in the diagnosis and the detailed anatomical information it provides.

Management. There is no available prevention or cure for MS. Yet a number of therapies may hasten recovery from exacerbations, provide symptomatic relief of symptoms, maximize physical abilities, and prevent certain complications. In addition, treatments that alter the natural course of MS have become available and others are being developed. Methods of enhancing recovery are also being explored.

Acute Exacerbations. Corticosteroids are the most commonly used treatment for MS, although there have been few studies to address their efficacy. Adrenocorticotropic hormone (ACTH) was shown to speed recovery from an exacerbation but had no effect on the ultimate degree of recovery. Because of the unpredictable cortisone response to ACTH, oral prednisone and later intravenous methylprednisolone became the preferred treatments. The Optic Neuritis Treatment Trial verified that intravenous methylprednisolone but not prednisone increased the recovery rate and unexpectedly increased the time to the next relapse, thus delaying the diagnosis of CD MS. y Moreover, the prednisone-treated group had twice as many recurrences. The reason for this unconfirmed finding and its relevance to those with definite MS are unknown. Nonetheless, it has affected the practice of treating acute MS exacerbations. The current recommendation is to treat disabling attacks with 500 to 1000 mg of intravenous methylprednisolone per day for 3 to 5 days with or without a short tapering dose of oral corticosteroids.

Because up to one third of patients do not have adequate recovery after a relapse despite the use of corticosteroids, other therapies are needed. Unfortunately, the only additional controlled clinical study to address this evaluated the combination of simultaneous ACTH and cyclophosphamide with true or sham plasma exchange.y Although the group treated with plasma exchange was thought to recover faster, the benefit was marginal at best and this treatment program has found no clinical utility. Plasma exchange alone was found beneficial in some patients with severe inflammatory demyelinating episodes who had failed to improve with intravenous therapy with methylprednisolone,y and a double-blind crossover study is in progress to confirm this finding.

Alteration of the Natural Course. The primary goal of drug treatment is to alter the natural course of the disease. In MS clinical trials, this means reduction in the frequency and severity of relapses, preventing the chronic progressive phase, and slowing the progression of disability. The activity of disease seen on MRI is often used as a secondary outcome. Many different immunosuppressive and immunomodulating therapies have been evaluated, and several other studies are in progress.

Cyclophosphamide is an alkylating agent that has indiscriminant cytotoxic effects on rapidly dividing cells, including lymphocytes, making it a potent immunosuppressant. Several studies have claimed a beneficial effect in both relapsing and progressive patients. Because one of the major studies included ACTH, intravenous methylprednisolone is sometimes given with the cyclophosphamide. Other trials have not found a favorable effect. Because of the inconsistent results, high potential for serious side effects, and adverse reactions, including hemorrhagic cystitis and malignancy, cyclophosphamide is not widely used. Some centers, however, use cyclophosphamide in patients with aggressive disease in whom more conventional treatments have failed.

Numerous studies have shown azathioprine, a purine analog antimetabolite, to have marginal efficacy in the treatment of MS. A meta-analysis of all blind, placebo-controlled studies confirmed a slight benefit of slowed progression and less frequent relapses. y The toxicity of azathioprine and its slow onset of action have prevented its widespread use. Besides the liver toxicity and hematological effects, the induction of malignancies has been a concern. One retrospective study did not find an increased incidence

of cancer in MS patients treated with azathioprine, but this remains a potential risk.

Methotrexate is a folate antagonist that is effective in rheumatoid arthritis. Weekly low-dose oral methotrexate was found to delay upper extremity dysfunction in SP MS patients, although it had no effect on the more traditional measures of disability, including the Expanded Disability Status Scale (EDSS). y

The use of cyclosporine in the treatment of MS has been evaluated in three clinical trials, none of which have demonstrated a convincing benefit. In addition, side effects such as hypertension and elevation of creatinine were fairly common. Cladrabine is a nucleoside derivative that was found to decrease relapse rate and slow the progression in patients with SP MS in an initial investigation. y Although cladrabine was administered intravenously through a surgically implanted central venous line in that study, a large clinical trial is being done to determine whether the drug is effective when administered subcutaneously. The drug is better tolerated than other parenteral immunosuppressants, although bone marrow suppression is a risk.

Interferons are a class of peptides that have antiviral and immunoregulatory functions. A pilot study of interferon-gamma in MS was aborted after an increased exacerbation rate was noted. In retrospect, this was not surprising because it is now known to be a proinflammatory, TH1-related cytokine that acts in part by increasing HLA type II expression. Interferon-alfa and interferon-beta have similar physiological actions and are part of the anti-inflammatory TH2 response. Interferon-beta 1b (Betaseron) was the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of MS. A large clinical study in RR MS patients demonstrated a reduction in the frequency of relapses by about one third with subcutaneous injection every other day. '3s1 The severity of relapses was also lessened. Perhaps the most striking observation was its effect on MRI. The placebo-controlled group continued to accumulate white matter lesions, whereas patients in the high dose arm (8 million IU) had stabilization of their MRI and did not accumulate higher lesional volumes. No difference was found in the disability levels, however. Patients on a low dose of interferon-beta 1b actually did worse than placebo-treated patients on clinical measures, although there was a favorable effect on MRI behavior. This observation remains unexplained. Interferon-beta 1b is being further investigated in SP MS patients. Side effects include injection site reactions, flulike symptoms (low-grade fever, myalgias, headache; these lessen in frequency after treatment for a few months), mild liver enzyme elevation, and lymphopenia. Depression and attempted suicide were more common in the treated groups. One particularly disturbing result was the production of neutralizing autoantibodies in 38 percent of patients after 3 years of treatment. Not only do patients with these antibodies thereafter fail to respond to this drug, but there is also a concern that neutralizing antibodies may cross react with natural interferon-beta and interfere with its function. The long-term effects of these antibodies are unknown.

Another formulation of interferon-beta has been approved by the FDA. Interferon-beta 1a (Avonex) has the same amino acid sequence as natural interferon-beta and differs from interferon-beta 1b by one amino acid as well as by the presence of carbohydrate moieties. Once-weekly intramuscular interferon-beta 1a has been found to have effects similar to that of interferon-beta 1b in reducing the frequency of MS relapses. y In addition, a favorable effect on disability was also demonstrated and side effects were less common. Neutralizing antibodies occurred half as often as with interferon-beta 1b. MRIs showed less enhancing lesions in the treated group but no difference in the change of lesional volume after 2 years. Duration of follow-up was, however, much less in the interferon-beta 1a study than in the interferon-beta 1b trial.

Copolymer 1 is a synthetic mixture of polypeptides produced by the random combinations of four amino acids that are frequent in MBP. After a preliminary study suggested efficacy, a randomized, double-blind, placebo-controlled, multicenter trial showed a 29 percent reduction in relapse rate and a mild positive effect on disability in RR MS patients. y No MRI data have been presented.

Numerous additional therapies have been tested, and many others are undergoing evaluation. The antiherpesvirus drug acyclovir has been shown to reduce relapse frequency in a small prospective trial. Total lymphoid irradiation was found to slow the chronic progression of MS; but because this approach precludes the later initiation of immunosuppressant drugs and may be associated with a higher mortality rate, it is not widely used. Results of the initial small study of the immunosuppressant drug mitoxantrone seemed promising, but subsequent studies have found only modest effects. Monthly treatment with intravenous immunoglobulin in RR MS patients resulted in fewer and less severe relapses in addition to slowing the accumulation of disability in one small study. A unique mechanism of action is being explored with the use of oral myelin in a large phase III clinical trial. This trial tests the hypothesis that the oral administration of antigen may induce tolerance through either active suppression or anergy/ deletion. Vaccination with CD52, CD4, irradiated MBP-specific CD4 cells, TCR variable beta 6, and variable beta 5.2 are under investigation in MS patients. Additional ongoing studies are investigating the potential role of sulfa-salazine and tacrolimus.

Symptomatic Treatment. Spasticity is common even in patients with only minimal weakness. It is usually prudent to begin treatment of mild spasticity with a stretching program. The addition of an evening dose of benzodiazepine may help relieve extensor spasms and clonus that may interfere with sleep. As spasticity worsens it becomes necessary to use baclofen. Doses should be escalated slowly to prevent the occurrence of overt side effects, and up to 120 mg/day may be required. Although baclofen is well tolerated in most patients, limiting side effects such as sedation and increased muscle weakness occur, and rarely a paradoxical increase in spasticity is noted. Liver enzyme elevation and nonconvulsive status epilepticus presenting as encephalopathy have also been reported in association with baclofen. Abrupt withdrawal of baclofen may result in hallucinations or seizures, making it necessary to taper doses. Despite symptomatic improvement, antispasticity measures may not increase function or independence. In paraplegic patients with severe spasticity and intolerance

to the required oral dose, intrathecal baclofen delivered by a subcutaneously implanted pump allows a much smaller dose and is often effective in alleviating intractable spasticity and may lessen urinary urgency. Tizanidine seems to be as effective as baclofen. Dantrolene has been used for spasticity, although the therapeutic window is small.

The treatment of fatigue is far from optimal, and medications are only partially effective. Amantadine at 100 mg twice per day is the standard initial treatment, although pemoline 37.5 mg daily is also superior to placebo. The stimulating effects of the selective serotonin reuptake inhibitors may also be somewhat effective in combating MS-related fatigue. Often, however, patients need to limit activities and schedule rest periods. Similarly, emotional incontinence may be amenable to a low dose of a tricyclic antidepressant.

Paroxysmal symptoms are highly responsive to medical treatment. A small dose of carbamazepine is often very effective. If not tolerated, several alterna

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