Demyelinating Disorders of the
Central Nervous System

History

Role of myeline

Multiple sclerosis

Neuromyelitis optica

Isolated inflammatory demyelinating disorders

Experimental allergic encephalomyelitis

Acute disseminated encephalomyelitis

HISTORY

Multiple sclerosis (MS) is now known to be a common malady even though it was first recognized as a distinct clinicopathological entity less than 150 years ago. The lack of reports before the early 1800s is sometimes interpreted as evidence that MS is a relatively new disease. However, it is more likely that the evolution of medicine as a science, which began at approximately the same time, led to more precise observation and description of human diseases. This view is strengthened by the observation of what may be the earliest clinical description of MS: the case of St. Lidwina of Schiedam (1380-1433), who developed a relapsing neurological disorder at the age of 18. аOllivier was the first to report a clinical case in the medical literature in 1824. Shortly thereafter, Carswell illustrated a case of what is now clearly recognizable as MS in his atlas of anatomical pathology. Cruveilhier published gross pathological descriptions of MS together with clinical case descriptions. Although others certainly contributed (including Frerichs, Valentiner, Turck, Rokitansky, and Rindfleisch), Vulpian first suggested the rubric of "sclerose en plaque" in 1866. Charcot was primarily responsible for establishing MS as a unique and recognizable syndrome. He also described the clinical spectrum and the histological appearance. Pierre Marie was the first to suggest an infectious cause of MS in 1884, a hypothesis that is still debated. Toxins were also considered to be responsible in the early 1900s. A major advance toward the understanding of demyelinating diseases was the discovery of experimental allergic encephalomyelitis (EAE) by Rivers in 1935. A variety of different demyelinating diseases have subsequently been described ( Table 48-1 ).

ROLE OF MYELIN

Myelin provides insulation for axons and is necessary for saltatory conduction. It is composed of tightly wrapped lipid bilayers with specialized protein constituents. Peripheral nervous system (PNS) myelin is formed by the extension of Schwann cells, and central nervous system (CNS) myelin is produced by oligodendrocytes. As the cell processes wrap around the axon, cytoplasm is extruded, leaving the inner (cytoplasmic) and outer (extracellular) plasma membrane leaflets in close apposition. Electron microscopy reveals several dozen spirals containing dense lines. The darker, major dense line is formed by the apposition of the inner leaflets, and the lighter, intraperiod line is formed by the close approximation of outer leaflets (Fig. 48-1 (Figure Not Available) ). The myelin coating is interrupted at regular intervals (nodes of Ranvier) where the axon membrane with its concentration of voltage-gated sodium channels is exposed to the extracellular environment.

CNS and PNS myelin differ in a number of important ways. Schwann cells myelinate only one internodal segment from a single PNS axon, whereas oligodendrocytes myelinate multiple CNS axons. The proteins also differ. Proteolipid protein (PLP) accounts for approximately 50 percent of the CNS myelin proteins. PLP is an integral membrane protein responsible for holding the outer

 

leaflets together at the intraperiod line. Mutations in this highly conserved protein cause Pelizaeus-Merzbacher disease. Protein zero (P0) is the major PNS myelin protein and performs a function similar to PLP in compacting the intraperiod line. Myelin basic protein (MBP) makes up 30 percent of CNS and 10 percent of PNS myelin proteins. MBP is not an integral protein but binds to the cytoplasmic surface and is responsible for compaction at the major dense line. Myelin associate glycoprotein (MAG) accounts for about 1 percent of both peripheral and central myelin. Myelin oligodendrocyte glycoprotein (MOG) and cyclic nucleotide phosphodiesterase (CNP) are minor constituents of CNS myelin and are not found in the PNS. Peripheral myelin protein 22 (PMP22) is a minor component of PNS myelin.

MULTIPLE SCLEROSIS

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. 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. 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. 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. 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 leukoencephalopathyа JC papilloma virus , subacute sclerosing panencephalitisа measles virus , and human T-cell lymphotropic or leukemia virus type Iа HTLV-I -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 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. 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.^а аThe proinflammatory cytokine tumor necrosis factor-alpha causes myelin disruption and oligodendrocyte apoptosis in vitro.^а аArachidonic 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.^а аTwin 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 component^а а; 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.^а а

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.^а аMigration 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.^а аSeveral 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 aloneThe 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.^а аA 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 ( Table 48-2 ). 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. 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.

 

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. 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. 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.^а аAge, 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).^а а

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. 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. 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), 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,

 

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/tropical 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).

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. At least two attacks and evidence of two separate CNS

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. 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. 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. 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.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.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.^а аAlthough 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, 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. 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)

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. 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. 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. 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. 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 alternative medications may be tried, including phenytoin, acetazolamide, baclofen, and gabapentin. In addition, misoprostol has been claimed to be effective in MS-related trigeminal neuralgia. After about 1 month of treatment, periodic attempts at tapering off these medications is a reasonable approach because these symptoms usually remit. Seizures are treated no differently than in non-MS conditions. Heat sensitivity may require avoidance of precipitating activities, but this depends on the nature of symptoms and the situation in which they occur. If the precipitating activity cannot be avoided, a cooling jacket may be an option. A potassium channel blocker, 4-aminopyridine improves temperature sensitivity in some patients but occasionally causes seizures or disturbing paresthesias. Action tremor is a common disabling symptom. Unfortunately, it is often only marginally amenable to medical therapy. Clonazepam may afford some relief, but tolerance frequently develops, necessitating increasing doses. Isoniazid and carbamazepine have also been found marginally beneficial. One clinical trial showed ondansetron to reduce tremor-related disability. Anecdotal reports suggest that gabapentin may be partially effective. Improvements in stereotactic neurosurgery have made thalamotomy a legitimate option in those whose disability is mainly due to tremor and not ataxia.

Dysesthetic pains are difficult to control but sometimes respond to tricyclic antidepressants, carbamazepine, or baclofen. Gabapentin and tramadone may also be effective. Standard analgesics are not often useful in MS-associated pain, and narcotics should be avoided in the treatment of chronic pain.

Symptoms of a hyperreflexic bladder (urgency, frequency, and urge incontinence) are often manageable with anticholinergics such as oxybutynin, propantheline, or imipramine. A flaccid bladder can sometimes be aided by bethanechol, although intermittent catheterization is more often needed. Symptoms that suggest urinary retention (a feeling of incomplete emptying, frequency, hesitancy, or a need to apply pressure to the lower abdomen to urinate) should prompt evaluation with urinalysis and a post-void residual urine measurement. Residuals in excess of 15 ml are abnormal; and if they are above 50 ml, consideration should be given to urological consultation for more thorough investigation and to blood chemistries to determine urea and creatinine levels. Detrusor-sphincter dyssynergia, diagnosed by cystometrography, is treated with anticholinergics, sometimes with the addition of an alpha-1 blocking agent (terazosinа Hytrin ) or intermittent catheterization. It is important to reassess bladder function periodically, and residuals should be monitored if there are any persistent changes in function or symptoms. Intermittent catheterization should be considered when post-void residuals reach 100 ml. A chronic indwelling urinary catheter should be avoided if reasonably possible. It is usually not necessary to use antibiotics prophylactically in the prevention of urinary tract infections. Urinary calculi may be prevented by acidification of the urine with cranberry juice. Constipation can usually be managed with bulk laxatives and stool softeners. More severe cases may require osmotic agents, bowel stimulants, anal stimulation, suppositories, or enemas. Bedridden patients may develop fecal impaction unresponsive to these measures and require manual disimpaction. Fecal incontinence can be minimized by adherence to a schedule for bowel movements.

It is pertinent to determine the precise nature of any sexual dysfunction in patients with MS. Physical difficulty from spasticity may be alleviated by premedication with baclofen, and a fast-acting anticholinergic such as oxybutynin may calm urinary urgency. Sexual dysfunction should not be automatically attributed to MS. It may be necessary to investigate hormonal levels and to obtain urological or gynecological consultation. Manual lubrication with gel is a ready solution to vaginal dryness. Erectile dysfunction may be treated by vacuum devices, intracavernous injections of papaverine (or combinations of papaverine, prostaglandins, and epinephrine; triple agent), or penile implant.

It is advisable for MS patients to attain good health habits, including proper diet and fitness. Smoking, excess alcohol, and obesity should be avoided. Exercise can help maximize function by increasing and maintaining joint mobility, strength, and stamina. This may in addition promote fitful sleep and possibly reduce the impact of fatigue. Physical and occupational therapy can play an important role in regaining independence. Canes, walkers, and wheelchairs or scooters may be needed to maintain safe mobility. Hand controls can be installed in automobiles for patients with lower extremity dysfunction. In debilitated, immobilized patients, periodic shifts in posture to change weight-bearing regions and air or water mattresses prevent bed sores. Passive range of motion exercises prevent contractures.

Enhancement of Recovery. The exact reason for persistent neurological deficits in MS is unknown. Primary demyelination, axonal dysfunction, extensive gliosis, or axonal loss may all contribute. In the past it was thought that the CNS had no potential for remyelination. Pathological studies have suggested that limited remyelination does occur but is arrested for unknown reasons. Immunization with spinal cord homogenate was found to markedly enhanced central remyelination in an EAE model. Using the TMEV model (confirmed in EAE), Rodriguez identified two monoclonal autoantibodies that promote CNS remyelination. A preliminary study based on these studies found that intravenous immunoglobulin (IVIG) improved vision and VEP latencies in some MS patients with presumably permanent visual impairment. Currently phase II trials are being done to determine if IVIG treatment can lead to functional improvement in patients with apparently irreversible weakness or optic nerve dysfunction.

Pregnancy. Before initiation of any drug in a woman of reproductive age, the potential for teratogenicity must be discussed. The treatment of acute exacerbations is unchanged during pregnancy, although one might have a higher threshold for treatment. Both corticosteroids and plasma exchange are relatively safe to use during pregnancy. None of the drugs used to alter the disease course, however, should be used during pregnancy, and they should be stopped if pregnancy occurs. The cytotoxic immunosuppressants have teratogenic effects, and interferon-beta induces spontaneous abortion in animals. The effects of many of the other drugs are unknown. It is best if these drugs are stopped several months before a planned pregnancy.

Prognosis and Future Perspectives. Because most information on the prognosis of MS is reported in terms of the EDSS, it is important to have some understanding of this scale. The EDSS is a 10-point scale with each increase representing worsening symptoms or function. The score is derived from severity scores in each of six systems as well as ambulation and work ability. A score of 0 means no signs or symptoms; 1 to 3 represent mild disability with no or minimal impairment of ambulation; 3.5 to 5.5 refer to moderate disability and impairment of gait; the need for a cane to walk one-half block (100 m) marks a score of 6; an EDSS of 8 refers to the need for a wheelchair and effective upper extremity function; an EDSS of 10 refers to death related to MS.

MS has a highly variable outcome, ranging from asymptomatic to fulminant with death ensuing in a matter of months. Autopsy series have estimated that unsuspected MS may occur in as many as 0.2 percent of the population. Even when symptomatic, MS may cause only nuisance symptoms. Benign MS, when defined as unrestricted ambulation or EDSS of 3 or less 10 years after onset, accounts for about one third of cases. However, many of these patients acquire more disability at a later time. When considering all patients with MS, Weinshenker found that 15 years after onset, 80 percent had EDSS worse than 3, 50 percent had reached EDSS of 6 or more, 10 percent were at EDSS 8, and 2 percent had died. The percentage of patients with initially RR MS who develop SP MS increases steadily with disease duration. At 10 years, 40 to 50 percent have continual deterioration; and after 25 years, approximately 80 percent have slow progression.

Natural history studies have identified several prognostic indicators that predict outcome to a limited extent. Factors associated with a better prognosis (slower accumulation of disability, longer time before chronic progression) include young age at onset, female gender, RR course (as opposed to PP MS), initial symptoms of sensory impairment or optic neuritis, first manifestations affecting only one CNS region, high degree of recovery from initial bout, longer interval between first and second relapse, low number of relapses in the first 2 years, and less disability at 5 years after onset (both EDSS and number of systems affected--sensory, motor, sphincter, brain stem, vision, cerebral). Despite the indolent nature, a PP course is the worst prognostic factor, with the median time to reach EDSS 6 of only 6 years, compared with approximately 20 years in RR patients. Men and patients with an older age at onset are more likely to have PP MS.

The survival of MS patients is only slightly below expected. Seventy-six percent of patients are alive 25 years after onset, which is 85 percent of that seen in age- and sex-matched controls.^а аMS is rarely the direct cause of death, although respiratory failure from cervical myelopathy or extensive cerebral and brain stem demyelination and death occasionally occurs with acute or subacute exacerbations. Complications of MS such as pneumonia, pulmonary emboli, aspiration, urosepsis, and decubiti are responsible for 50 percent of deaths. Most of the other deaths are from heart disease, cancer, cerebrovascular disease, and trauma. Suicide is the only cause of death that is overrepresented among these cases. The suicide rate among MS patients may be as high as two to seven times that of non-MS persons.

The next decade may bring further delineation of susceptibility genes and possibly the mechanism by which they exert their actions. The virology of MS, including the possible role of human herpesvirus 6, will likely be further clarified. Persistence of additional viruses within the CNS may be discovered, adding complexity to this situation.

It seems clear that global immunosuppression is only marginally effective. Current studies concentrate on immune modulation by inhibiting or augmenting certain aspects of the immune response. The strategies employed include the following: induction of tolerance to MBP and other myelin components; reduction of T-cell subsets by the use of monoclonal antibodies, vaccination, or drugs; administration of anti-inflammatory (TH2) cytokines; inhibition of proinflammatory (TH1) cytokines; and blocking the trafficking of activated lymphocytes into the CNS.

NEUROMYELITIS OPTICA

Neuromyelitis optica (NMO) is an uncommon neurological illness characterized by the occurrence of optic neuropathy and myelopathy in close temporal relationship. The separation from MS has become questioned, owing to the frequent dissemination of lesions outside the optic nerves and spinal cord. Part of the difficulty lies with the broad, imprecise, and inconsistent definition. The names Devic's syndrome, Devic's disease, and NMO are often used interchangeably, although the first name encompasses all patients who fit the above definition and the second and third should only be used to refer to those patients presumed to have a distinct disorder. The term opticospinal MS is often used in the Far East to denote patients with exclusive or predominant involvement of optic nerves and spinal cord, encompassing most patients with Devic's syndrome.

Pathogenesis and Pathophysiology. Devic's syndrome may occur with ADEM, autoimmune disorders, MS, and possibly viral infections. Not surprisingly, the pathological descriptions are quite varied because these patients are invariably a heterogeneous group. Classically, acute spinal cord lesions demonstrate diffuse swelling and softening that extend over several levels or involve nearly the entire cord in a continuous or patchy distribution. Acutely, there is destruction with dense macrophage infiltration involving white and gray matter, loss of myelin and axons, and lymphocytic cuffing of vessels. In chronic lesions, the cord is atrophic and necrotic, with cystic degeneration and gliosis. In the absence of perivascular cuffing, these extensive lesions resemble infarctions. The prominent spinal cord swelling in the confines of the restrictive pia presumably may raise intramedullary pressure, leading to the collapse of small parenchymal vessels, further propagating tissue injury. Proliferation of vessels with thickened and hyalinized walls similar to that seen after infarction or other extensive injury may occur.^а аLess fulminant lesions commonly coexist and are much more typical of inflammatory demyelination. The optic nerves, chiasm, and occasionally cerebral hemispheres are involved in a similar fashion with either demyelinating lesions, necrotizing lesions, or both.

Epidemiology and Risk Factors. Devic's syndrome occurs in patients of varied ages (range, 1 to 73). The mean age at onset of monophasic Devic's syndrome is 27, whereas relapsing NMO (see later) tends to occur in an older age group (mean age at onset of 43). Monophasic Devic's syndrome affects males and females equally, whereas relapsing NMO affects females predominantly (F:M, 3.8:1). One third of patients have a preceding infection within a few weeks of neurological symptom onset. Most commonly this is a nonspecific upper respiratory tract infection, flu, or gastroenteritis. The most common specific infections preceding the development of Devic's syndrome are chickenpox and pulmonary tuberculosis. Devic's syndrome has also followed vaccination for swine flu and mumps. Only a few instances of the familial occurrence of Devic's syndrome have been reported, and in one of these families a unique mitochondrial mutation was found. Devic's syndrome is said to be more common in Japan and East Asia, although even there it is uncommon (less than 5 per 100,000).

Clinical Features and Associated Findings. Symptoms of optic neuritis and myelitis develop over hours to days and are often preceded or accompanied by headache, nausea, somnolence, fever, or myalgias. Continued progression of symptoms over weeks or months occasionally occurs. Most patients (greater than 80 percent) develop bilateral optic neuritis. Bitemporal or junctional field deficits, indicating chiasm involvement, are sometimes present early in the course of the optic neuritis. Visual loss is often accompanied by periocular pain, and myelitis onset is sometimes heralded by localized back or radicular pain. Lhermitte's sign is common. Severe degrees of neurological deficits are usual, and the degree of recovery is variable.

Patients who present with Devic's syndrome can follow one of several possible courses. Approximately 35 percent have a monophasic illness, 55 percent develop relapses nearly limited to the optic nerves and spinal cord (relapsing NMO or opticospinal MS), and rarely patients have a fulminantly progressive course without relapses or a course typical of MS.^а аRelapsing NMO is often associated with autoimmune disorders, most commonly systemic lupus erythematosus. These patients also frequently have an elevated erythrocyte sedimentation rate and nonspecific elevation of autoantibodies, including antinuclear antibodies, anti-dsDNA, and antiphospholipid antibodies. Tonic spasms and neuropathic lower extremity pain are common sequelae to the spinal cord damage. Symptoms referable to brain stem lesions (nystagmus, ophthalmoparesis, vertigo) can occur in these patients as well.

Differential Diagnosis. The differential diagnoses for Devic's syndrome includes MS, ADEM, pulmonary tuberculosis, and viral infection (especially in the immunocompromised patient). In patients with an apparent affected family member, consideration should be given to mitochondrial disease. Relapsing NMO should raise the suspicion for associated autoimmune disorders. Because Devic's syndrome can occur in persons older than the age of 60, when an unrelated ischemic optic neuropathy could occur, and because isolated or recurrent myelopathy may precede the optic neuritis, additional consideration must be given to spinal cord compression, spinal cord tumor, and spinal arteriovascular malformation or dural fistula.

Evaluation. Imaging is needed to exclude structural lesions and provide information on the pathological process. Optic nerve or chiasm enlargement, T2-weighted signal changes, and enhancement may be seen on head MRI during the acute phase. Increased T2-weighted signal in the medulla is not uncommon and usually represents extension of high cervical lesions. Cerebral white matter lesions can be seen on head MRI in about 25 percent of cases. Spine MRI characteristically shows cord swelling, signal changes, and enhancement extending over several levels. This appearance may resemble a spinal cord tumor, prompting consideration for biopsy. An occasional patient may need prone and supine myelography to exclude a spinal dural-based AVM. Laboratory investigations reveal an elevated erythrocyte sedimentation rate in one third, positive antinuclear antibodies in nearly one half, and occasionally other autoantibodies.^а аIt is reasonable to exclude syphilis, Lyme disease, and human immunodeficiency virus by laboratory testing. A chest radiograph helps to exclude pulmonary tuberculosis and sarcoidosis. CSF examination is an essential part of the evaluation for Devic's syndrome, and repeated studies are sometimes necessary to ensure that there is no infection in that the CSF findings are sometimes atypical for inflammatory demyelination. In contrast to MS, a minority of patients with Devic's syndrome (17 percent) have a normocellular CSF during the acute phase. A marked pleocytosis is often present, sometimes exceeding 100 cells. Moreover, neutrophils are commonly seen in CSF and may predominate, a situation virtually unknown in MS.^а а, ^аааThe protein concentration is often very high and in 41 percent exceeds 100 mg/dl. Despite the intense inflammatory response, OCBs are conspicuously absent in the majority, being present in fewer than 20 percent of patients. CSF serology for the herpesvirus family (HSV types 1 and 2, varicella-zoster virus, Epstein-Barr virus, and cytomegaloviruses) is important, and polymerase chain reaction testing should be done in cases suggestive of viral infection (immunocompromised patients).

Management. Patients with acute or subacute Devic's syndrome often respond to corticosteroids (e.g., intravenous methylprednisolone). Limited experience suggest that they may respond to plasma exchange even when intravenous methylprednisolone does not produce significant improvement. Attempts at preventing relapses and the subsequent disability are often disappointing even with the use of immunosuppressive agents (e.g., azathioprine, cyclophosphamide).

Supportive care is a mainstay of management. Patients with Devic's syndrome are prone to many complications and require measures to prevent deep venous thrombosis and pulmonary embolism, urinary tract infection, decubiti, and contractures. Mechanical ventilation may be needed either temporarily or permanently. Patients with monophasic Devic's syndrome generally have simultaneous or rapid onset of the optic neuritis and myelitis (interval usually less than 1 month). Although some have significant residual disability, many recover remarkably and have little or no permanent deficits. A history of previous vague neurological symptoms or definite demyelinating events is predictive of future relapses, either typical of MS or relapsing NMO. Those patients destined for recurrent myelitis and optic neuritis have a longer interval between the onsets of myelitis and optic neuritis. The vast majority of patients with relapsing NMO have very aggressive disease with frequent and severe exacerbations and a poor prognosis.

ISOLATED INFLAMMATORY DEMYELINATING CNS SYNDROMES

Region-restricted episodes of CNS inflammatory demyelination in persons without prior symptoms often represent the initial manifestation of MS, although some may be a forme fruste of ADEM (see later). The probability of recurrent demyelinating episodes has been the subject of several important investigations, and several clinical features and test results are of predictive value. Optic nerve, spinal cord, and brain stem are the most common sites of these recurrent monosymptomatic events, and the time profile follows that of MS relapses. The pathogenesis, pathophysiology, epidemiology, clinical features, associated disorders, differential diagnosis, evaluation, and management are the same as in MS and are discussed previously.

In these cases, the prognosis for visual recovery after each episode of optic neuritis is good and most patients regain normal visual acuity. Profound visual loss, recurrent optic neuritis, and age older than 35 are associated with a higher risk for poor recovery. Investigators have concluded that recurrent multifocal demyelinating episodes, fulfilling the diagnostic requirements of CD MS, develop in 50 percent or more of patients after isolated optic neuritis when follow-up is extended beyond 20 years.^а аMost of this risk is incurred within the first few years, although significant risk may continue into the fourth decade after the event. Children much more often develop simultaneous bilateral optic neuritis and have a lower risk for subsequent MS than adults. Factors that are associated with an increased risk of developing MS as a disseminated illness are the presence of venous sheathing, recurrent optic neuritis, family history of MS, white race, previous vague or nonspecific neurological symptoms, and the presence of OCBs, elevated IgG index, or IgG synthesis rate in CSF. Head MRI gives the most strongly predictive information. The relative risk of one or more cerebral white matter lesions, found in approximately 50 percent of optic neuritis patients, is 3 to 14. Of the 44 patients with monosymptomatic optic neuritis in one study, 82 percent of those with abnormal MRI fulfilled the diagnosis of MS within 5 years whereas only 6 percent of those with normal or nonspecific findings on MRI developed MS.^а аThe Optic Neuritis Treatment Trial also found an increased risk of MS in those with cerebral white matter lesions on MRI (27.7 percent of those with an abnormal head MRI vs. 9.3 percent of those with a normal head MRI after 3 years of follow-up).^а аBoth of these studies found that a higher number of lesions correlated with an even greater risk of MS.

The severity of acute transverse myelitis is inversely related to the risk of acquiring further symptomatic demyelinating lesions. Complete transverse myelitis with profound loss of motor, sensory, and sphincter function imparts a relatively low risk of 3 to 14 for the later diagnosis of MS. Partial transverse myelitis with preservation of significant motor function at peak is associated with a much higher incidence of MS. Head MRI further delineates the risk. In a study by Ford and associates, 11 of 12 patients with partial transverse myelopathy and cerebral white matter lesions on MRI developed MS within 3 years of follow-up whereas only 1 of the 3 patients with normal MRI progressed to MS.^а аExcluding the 2 patients with complete transverse myelopathy in Morrissey's study, 59 percent of the patients with an isolated spinal cord syndrome and abnormal head MRI met the criteria for MS during a 5-year follow-up and 11 percent of patients with normal MRI had recurrences of multifocal demyelination.^а а

Although monosymptomatic brain stem demyelination is not as common as either optic neuritis or acute transverse myelitis, similar conclusions have been reached. In the only study available, two thirds of these patients with cerebral white matter lesions detected on MRI developed MS within 5 years, compared with none of 5 patients with normal head MRI.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

As mentioned earlier, there is no spontaneous animal model that closely resembles MS. EAE is the most widely studied animal model of this disease. EAE is an antigen-specific, T-cell-mediated autoimmune disease that can be induced in many species, although rat and mice models predominate in the literature. Acute EAE is a monophasic illness that more closely resembles ADEM. Chronic-relapsing EAE closely mimics the clinical course of MS with repeated clinical relapses from which the animal makes an incomplete recovery; some animals develop a slow progressive course after several relapses. Although there is considerable variability in the various EAE models, several closely parallel the pathological picture of MS with perivascular inflammation and primary demyelination initially and subsequent gliosis and axonal loss.

Studies in EAE have advanced our understanding of the various stages of disease initiation that may underlie the MS disease process, including the initial immune activation of T cells by encephalitogenic antigens and factors that influence T cell recognition; TCR restriction; the genetic influences on disease resistance, susceptibility, and recovery; T cell/macrophage interactions; the various roles of soluble mediators of inflammation (including TH1 and TH2 cytokines); factors regulating blood-brain barrier permeability; T cell/adhesion molecule interactions; factors influencing oligodendrocyte function and survival; and possible ways to reduce astrocytic proliferation and induce remyelination.

For decades, investigators have used EAE to screen for potentially effective therapies. Recent work has focused on the chronic-relapsing EAE model, extending the multitude of previous studies of immunosuppressive drug therapies. Current work includes strategies to enhance TH2 cytokine production and block TH1 cytokine function; therapies that target T-cell subsets, class II molecules of the major histocompatibility complex, and TCRs used for the recognition of encephalitogenic antigens (using monoclonal antibodies, altered peptide analogues, and T-cell vaccination studies that target TCR variable regions). EAE has been used to enhance understanding of the many possible mechanisms whereby interferons may influence immunemediated CNS injury and to explore the possibility that antigen-specific immunotherapy may ultimately be applicable to patients through either oral tolerance ("bystander suppression," anergy or clonal deletion) or with peptide analogues to encephalitogenic antigens.

Another widely studied animal model is Theiler's murine encephalomyelitis virus model. Intracranial inoculation with Theiler's virus leads to chronic infection and chronic inflammatory demyelination. Studies have shown that immune suppression ameliorates the pathological damage in this model, verifying that it is the immune response and not the viral infection that is responsible for the chronic demyelination. TMEV has been particularly useful in exploring a number of possible mechanisms of inducing remyelination in the setting of chronic demyelination. As outlined earlier, both polyclonal antispinal cord immunoglobulins and monoclonal antibodies directed against several protein antigens and chemical haptens have been shown to promote extensive CNS remyelination in TMEV. This work has led to two phase II clinical trials of human immunoglobulin in patients with optic neuritis and multiple sclerosis.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Acute disseminated encephalomyelitis is a monophasic inflammatory demyelinating disorder that characteristically begins within 6 weeks of an antigenic challenge such as infection or immunization. It occurs more often in the young and causes the rapid development of multifocal or focal neurological deficits. Perivenous inflammation, edema, and demyelination are the pathological hallmarks of ADEM, although these lesions commonly enlarge and coalesce, forming lesions pathologically indistinguishable from MS. Moreover, perivascular changes typical of ADEM are common in patients with MS. There is considerable overlap in the epidemiological, clinical, CSF, imaging, and pathological features between ADEM and MS, often making it difficult to distinguish between the two with reasonable confidence when encountering patients with a single demyelinating event.

Pathogenesis and Pathophysiology. ADEM closely resembles EAE both clinically and pathologically and is most likely due to a transient autoimmune response toward myelin. The occurrence of ADEM after vaccination with the rabbit spinal cord preparation of rabies virus led to the discovery of EAE. Infections and non-CNS-containing vaccinations may induce ADEM by molecular mimicry or by activating autoreactive T-cell clones in a nonspecific manner. Lymphocyte reactivity toward MBP has been identified in blood and CSF from patients with ADEM, but its absence in others indicates a role for other antigens.

Epidemiology and Risk Factors. ADEM can occur at any age but, perhaps because of the higher frequency of immunization and exposure to new antigens, it is most common during childhood. Unlike MS, both sexes are affected with equal frequency. No association has been noted with pregnancy.

ADEM has been reported to follow a number of different immunizations, usually within 6 weeks, including those for pertussis, diphtheria, measles, mumps, rubella, and influenza (postvaccination ADEM). However, the only epidemiologically and pathologically proven association is with rabies vaccination, which also causes demyelinating peripheral neuropathies. The original Pasteur rabies vaccine, prepared in rabbit spinal cord, was associated with an incidence of ADEM of approximately 1 per 3,000 to 35,000 vaccinations and is no longer in use. A later vaccine, made in duck embryo, which contains little neural tissue, carries a risk for ADEM of 1 per 25,000 vaccines. The use of human diploid cell lines, which contain no nervous system tissue, for the production of rabies vaccine has virtually eliminated the risk of ADEM. The association of bee stings with ADEM has also been reported.

Parainfectious ADEM usually follows onset of the infectious illness, often during the recovery phase, but because of the latency between pathogen exposure and illness it may precede clinical symptoms of infection or the two may occur simultaneously. The most commonly reported associated illness is a nonspecific upper respiratory tract infection. There have been a vast number of specific infections associated with ADEM, such as virus infections (including rubella, mumps, herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus, influenza, and coxsackievirus) and infection with Mycoplasma, Borrelia burgdorferi, and Leptospira. Measles carries the highest risk for ADEM of any infection, occurring in 1 per 400 to 1,000 cases. Although ADEM has been reported in association with measles immunization, the risk is far lower than the risk of acquiring measles and its neurological complications.

Clinical Features and Associated Disorders. A prodrome of headache, low-grade fever, myalgias, and malaise often precedes the onset of ADEM by a few days. Neurological symptoms develop rapidly and are commonly associated with encephalopathy, stupor, coma, meningismus, and seizures. A variety of neurological manifestations may occur, reflecting the focal or multifocal involvement of brain, brain stem, cerebellum, optic nerves, and spinal cord. The mortality rate is generally 10 to 25 percent. Peak severity occurs within several days, and recovery may begin soon afterward. More than 50 percent of survivors have a marked recovery with no or minimal functional impairment. Occasionally, ADEM may evolve over a few months and there may be a second clinical deterioration or subacute progression for a time. In these unusual cases, the distinction from MS is difficult.

Differential Diagnosis. One of the primary concerns after a single demyelinating episode is whether other bouts can be expected (e.g., MS). Several features may tip the balance toward one or the other, but the proper diagnosis becomes apparent only with time. Classically, ADEM is characterized by the multifocal involvement at onset whereas MS often presents with monosymptomatic deficits such as optic neuritis. However, ADEM may cause unifocal symptoms and MS may present with multifocal CNS involvement, especially in children. The monosymptomatic deficits caused by ADEM are more commonly severe, such as bilateral optic neuritis and complete transverse myelitis. Although OCBs occur transiently in about one third of ADEM cases, their persistence implies a diagnosis of MS. The subsequent disappearance of OCBs, when performed by consistent techniques, is evidence against MS. The MRI appearance of these two disorders is often identical, аbut the presence of basal ganglia or cortical lesions, or large globular white matter lesions, is more frequent in ADEM.

The fulminant development of ADEM is distinctive but not pathognomonic, because a rare form of MS known as Marburg's MS is also rapid in onset and often deadly. The appearance of brain stem, periventricular, and multiple, large cerebral white matter lesions and the presence of OCBs may distinguish Marburg's variant from ADEM.

On rare occasions, inflammatory demyelinating lesions may reach a large size and resemble tumors (especially lymphoma) on MRI, necessitating biopsy for clarification. There is usually one dominant lesion, but smaller separate lesions may be identifiable. These have been referred to as both ADEM and MS in the literature. The prognosis for recovery is often quite good, although approximately one third suffer subsequent attacks. Some develop typical MS, whereas others have recurring tumor-like lesions. The term multiphasic ADEM has been used when patients have large recurrences in the same location, and relapsing ADEM refers to recurrences at different sites. The relationship of these entities with MS is unclear.

Balo's concentric sclerosis refers to the pathological finding of alternating bands of demyelination and remyelination. These patients typically have large lesions and subacute deficits similar to those described earlier. Typical demyelinating lesions commonly coexist, and rarely CD MS patients are noted to have similar-appearing lesions. The reason for this peculiar alternating pattern is unknown.

Schilder's myelinoclastic diffuse sclerosis is another rare condition that may be confused with ADEM or other demyelinating conditions. This is a progressive demyelinating disorder that usually begins in childhood. The features are often atypical and include dementia, aphasia, homonymous hemianopia, seizures, psychosis, elevated intracranial pressure, and the absence of OCBs. The most characteristic finding is the presence of two large, roughly symmetrical lesions on MRI, one in each hemisphere. The diagnosis is made by excluding the known inherited leukodystophies, especially adrenoleukodystrophy.

Management. Treatment with intravenous methylprednisolone seems to halt progression and allow recovery to begin sooner, just as with MS. Plasma exchange can be tried in those with severe deficits and little response to corticosteroids.