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2

Clinical and Biological Features

Multiple sclerosis (MS) literally means “many scars,” which refers to the lesions that accumulate in the brain and spinal cord throughout the course of the disease. These scars, or lesions, consist mostly of dead nerve cells, whose axons have been denuded of the myelin sheaths that normally protect them and permit the conduction of nerve impulses. MS is a chronic, degenerative disease that usually begins in young adulthood and most visibly destroys muscular control, although many other brain functions are affected. Most people will live with MS for decades after their diagnosis. MS reduces life expectancy after onset (as measured by current diagnostic criteria) by only about 10-15 years, and about half of the patients survive 30 years or more from onset.110

THE CLINICAL PICTURE: SYMPTOMS, DISEASE COURSE, VARIATION, AND DIAGNOSIS

Disease Activity and Progression

MS, as defined by ongoing central nervous system (CNS) lesion formation and increasing cumulative damage, is now recognized as a disease that is active in most patients most of the time. Disease activity has reversible and irreversible sequelae; irreversible sequelae ultimately lead to progressive impairment and disability in most patients. MS takes a variety of forms, distinguished by the clinical pattern of disease activity (Table 2.1, Figure 2.1). Accumulated deficit can produce sustained worsening in both relapsing and progressive MS. In re-



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Page 29 2 Clinical and Biological Features Multiple sclerosis (MS) literally means “many scars,” which refers to the lesions that accumulate in the brain and spinal cord throughout the course of the disease. These scars, or lesions, consist mostly of dead nerve cells, whose axons have been denuded of the myelin sheaths that normally protect them and permit the conduction of nerve impulses. MS is a chronic, degenerative disease that usually begins in young adulthood and most visibly destroys muscular control, although many other brain functions are affected. Most people will live with MS for decades after their diagnosis. MS reduces life expectancy after onset (as measured by current diagnostic criteria) by only about 10-15 years, and about half of the patients survive 30 years or more from onset.110 THE CLINICAL PICTURE: SYMPTOMS, DISEASE COURSE, VARIATION, AND DIAGNOSIS Disease Activity and Progression MS, as defined by ongoing central nervous system (CNS) lesion formation and increasing cumulative damage, is now recognized as a disease that is active in most patients most of the time. Disease activity has reversible and irreversible sequelae; irreversible sequelae ultimately lead to progressive impairment and disability in most patients. MS takes a variety of forms, distinguished by the clinical pattern of disease activity (Table 2.1, Figure 2.1). Accumulated deficit can produce sustained worsening in both relapsing and progressive MS. In re-

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Page 30 TABLE 2.1 Varieties of MS Asymptomatic MS Autopsy studies indicate there are individuals without any known clinical history who have neuropathologic changes typical of MS. It is difficult to get an accurate estimate of subclinical disease, but one recent review suggested asymptomatic MS might account for up to 25% of all cases. Relapsing-remitting MS This is the major MS subtype. Approximately 85% of patients with a diagnosis of MS start out with relapsing MS. Overall, this subtype accounts for 55% of MS. Relapsing MS patients show a high rate of inflammatory lesion activity (gadolinium-enhancing lesions). Benign relapsing MS This category represents a subset of relapsing patients who have few attacks and make an excellent recovery. They show minimal impairment and disability, even after 20-30 years. The proportion of MS patients with benign disease is controversial. Reasonable studies suggest 10-20% of people with MS fit into this category. Primary progressive MS This subtype accounts for 10% of MS. Patients show gradual worsening from onset, without disease attacks. These patients tend to be older and often present with a spinal cord dysfunction without obvious brain involvement. This subtype is the least likely to show inflammatory lesion activity on MRI (gadolinium-enhancing). Unlike the other subtypes of MS, men are as likely as women to develop primary progressive MS. Progressive relapsing MS This subtype accounts for 5% of MS. Patients show slow worsening from onset, with superimposed attacks. Recent studies suggest these patients are similar to primary progressive patients. Secondary progressive MS This is the major progressive subtype and accounts for approximately 30% of MS. Relapsing MS patients usually transition to secondary progressive disease. They show gradual worsening, with or without superimposed relapses. Natural history studies of untreated relapsing MS indicate 50% of patients will be secondary progressive at 10 years and almost 90% by 25 years. This form of MS shows a lower rate of inflammatory lesion activity than relapsing MS, yet the total burden of disease continues to increase. This most likely reflects ongoing axonal loss. Acute MS Also referred to as Marburg variant MS, this is the most severe form of MS. Significant disability develops much more rapidly than usual, over weeks to months. Pathologic changes are widespread and destructive. These cases are rare and generally occur in young people. Clinically isolated syndromes This refers to patients who present with an isolated CNS syndrome (optic neuritis, incomplete transverse myelitis, brainstem or cerebellar lesion), which is often the first MS attack. Clinical, MRI, and CSF studies indicate that such patients with normal brain MRI and CSF have a low risk of developing MS. In contrast, those with abnormal MRI have a high risk of developing MS. NOTE: CSF = cerebrosinal fluid; MRI = magnetic resonance imaging

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Page 31 ~ enlarge ~ FIGURE 2.1 Spectrum of disease course (refer to Table 2.1 for definitions). SOURCE: Adapted from Lublin and Reingold, 1996.125 lapsing MS, worsening occurs in most patients during acute attacks with incomplete recovery. In progressive MS, the dominant pattern is a gradual accumulation of neurologic deficits, with slow clinical worsening. Disease activity and progression have both clinical and subclinical components. Clinical disease activity and progression are judged by observation and neurologic examination. Subclinical components refer to pathological changes that are not observable in a clinical examination but are observed using a variety of laboratory tests, predominantly neuroimaging parameters. Clinical Activity Relapses. Relapses are variously referred to as acute attacks, exacerbations, or disease flare-ups. They involve the acute, or sudden onset, of focal neurologi-

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Page 32cal disturbances. Examples of typical MS relapses include blurring of vision in one eye (optic neuritis), persistent numbness or tingling of a body part (sensory system relapse), weakness of a body part (motor system relapse), or loss of coordination (cerebellar system relapse). Early in the MS disease process, relapses are likely to involve sensory, motor, cerebellar, or visual system abnormalities ( Figure 2.2, Table 2.2). Later in the disease process, relapses are likely to involve bladder, bowel, cognitive, and sexual function abnormalities. Acute disease attacks are a characteristic feature of the relapsing-remitting MS subtype. Relapses also occur in patients with progressive relapsing disease and in a number of patients with secondary progressive disease. The only clinical disease subtype in which relapses never occur is primary progressive MS. ~ enlarge ~ FIGURE 2.2 Areas of the CNS often affected by MS. Reprinted with permission from University of Delaware. TABLE 2.2 Initial Signs and Symptoms of MS COMMON UNCOMMON Sensory problems (numbness or tingling of a body part) Weakness Difficulty walking Monocular decreased vision Poor coordination Bladder problems Bowel problems Sexual dysfunction Cognitive difficulties Pain

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Page 33 Relapses generally consist of three phases. There is a period of worsening, with onset of new deficits or increasing severity of old deficits. This is followed by a period of stability, with no change in deficits. The final phase is the period of recovery, with variable degrees of improvement in deficits. Most patients recover within six weeks, although for some, improvements can continue over months. Recovery can be complete return to baseline status, partial return, or no improvement. However, some degree of improvement is typical, particularly early in the disease. Relapsing patients then remain clinically stable until the next disease attack. To be considered a relapse, deficits must persist for a minimum of 24 hours. This avoids confusion with deficits lasting only minutes to hours, which are believed to be a consequence of impaired nerve conduction through old lesion areas rather than the formation of a new lesion. Alternatively, new abnormalities that last seconds to minutes, such as Lhermitte's sign (a tingling sensation radiating down the arms, neck, or back on neck flexion), or paroxysmal attacks (stereotypic neurologic deficits occurring multiple times a day that last less than a minute) are also considered relapses if they occur repeatedly over several weeks. Sequential relapses are considered distinct only when they occur at least 30 days apart with a month of clinical stability in between. Although clinical relapses always produce changes in a patient's condition, they are not always associated with changes on neurologic examination. Maximal deficit in an MS relapse typically develops over several days but in some cases can develop much faster, over hours or even minutes, or much more slowly, over a period as long as several weeks. Physiologic factors such as temperature, pH, or electrolyte balance can temporarily disrupt nerve conduction and produce neurologic abnormality. A relapse must be distinguished from a pseudoexacerbation, which is a neurologic deterioration associated with a physiologic change such as infection or fever. This condition can last for days, mimicking a true relapse. Pseudoexacerbation deficits disappear once the precipitating factor has been corrected. They reflect a temporary disruption in nerve conduction, rather than the formation of a new lesion. Approximately 85 percent of MS patients begin with relapsing-remitting disease.222 MS relapses can involve a single neural system, as in optic neuritis, or several anatomically distinct systems at the same time, for example, combined motor and sensory problems. Attacks involving single neural systems are somewhat more common in the first MS relapse. Most patients experience their second attack within two to three years of the first, but 5 percent of patients remain free of relapses for 15 years or more. In most cases, there is substantial recovery from the first relapse; only 4 percent of patients show no improvement. The average relapse rate is one to two attacks a year, but this rate normally declines over time. The longer a person has MS, the less likely it is that relapses will be followed by complete recovery and the more likely it is that relapses will be associated with residual deficits and increasing disability.

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Page 34 TABLE 2.3 Prognostic Relapse Indicators Feature Favorable Prognosis Unfavorable Prognosis Relapse rate in first 2 years <5 relapses ≥5 relapses Relapse rate after 5 years No increase Increasing Duration between relapses Long Short Number of neural systems involved One Multiple Relapse recovery Complete Incomplete Type of systems involved Visual, sensory, brainstem Motor, cerebellar, bowel or bladder Relapse features have prognostic significance (Table 2.3). In the first few years after disease onset, the number and type of relapses, as well as the degree of recovery, help predict future disease course.8 Relapses that involve visual, sensory, or brainstem systems have a better prognosis than those that involve cerebellar, motor, or sphincter systems. In the first two years of disease, a low relapse rate with excellent recovery indicates a better prognosis than a high relapse rate with poor recovery. Relapses restricted to single neural systems are prognostically better than those involving multiple systems. The relapse rate also has prognostic significance in the later stages of MS. With a disease duration of five or more years, an increasing relapse rate, polyregional relapses that involved multiple systems, and incomplete recovery from relapses indicate a worse prognosis.8 Progression. The relapsing form of MS is characterized by acute disease exacerbations. In contrast, progressive MS is characterized by slow deterioration and increasing neurological deficits. There are three forms of progressive MS. Approximately 15 percent of MS patients show slow deterioration from onset. In the second form, 10 percent have either primary progressive MS and never experience acute disease attacks or progressive relapsing MS (5 percent), and have occasional subsequent attacks. The third form, secondary progressive MS, is the major progressive subtype. These are relapsing patients who begin to slowly worsen 5 to 15 years after the first relapse. Once relapsing patients enter a progressive phase, they either stop having relapses or continue to experience exacerbations superimposed on slow worsening. Documentation of a progressive course requires at least six months of observation. Observation over a year or two is often necessary to be confident of progression, since deficits can accumulate at a very gradual rate. The major defining feature of progressive MS is slow deterioration that occurs independently of acute disease relapses and does not reflect residual deficits from acute disease attacks. An analysis of the disease course among 1,844 patients indicated that the presence or absence of relapses during the progressive phase does not significantly affect the progression of irreversible disability45 (4 percent of

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Page 35patients in this study had been treated for up to one year with beta-interferon, but this did not affect the study results). Progressive MS patients can be clinically stable for up to several years at a time and can even show slight improvement for a period of time. Ultimately, however, all progressive MS patients develop disability with limited ability to walk. Progressive MS is a more severe form than benign or relapsing-remitting MS and has a worse prognosis. Subclinical Disease Activity and Progression Clinical parameters such as relapses and progression underestimate the actual damage to tissue that occurs in MS. When macroscopically normal-appearing brain tissue is looked at under the microscope, one can detect inflammation, gliosis (scarring), and myelin damage. Chemical studies of normal-appearing brain tissue often reveal changes in organelles such as lysosomes, in enzymes, and in myelin constituents. In addition, a number of the new research neuro-imaging techniques can detect changes in brain and spinal cord areas that appear free of lesions on conventional magnetic resonance imaging (MRI). Some of these abnormalities are detectable several months to years before they can be seen with conventional MRI. Changes in normal-appearing brain tissue are generally pronounced in MS patients with severe impairment. As a group, secondary progressive MS patients show more abnormalities in normal white matter and brain tissue than relapsing patients. (White matter corresponds to brain regions where axons are ensheathed in myelin; gray matter corresponds to brain regions that are rich in cell bodies.) Primary progressive patients often show subtle but diffuse changes in normal-appearing brain areas. Even conventional MRI indicates that most new lesion formation is clinically silent, meaning that clinical exam does not reveal any corresponding symptoms. Approximately 80 to 90 percent of new brain lesions do not produce identifiable relapses. They might, however, be associated with subtle cognitive changes or other neuropsychological changes that are not detected in clinical examination. The total lesion burden increases in MS patients, on average, 5 to 10 percent per year, reflecting in large part the development of clinically silent lesions. (This does not apply to patients on the disease-modifying therapies discussed later in this section.) Atrophy of both brain and spinal cord can be detected even in patients with minimal symptoms. Atrophy can progress without obvious lesion formation, most likely reflecting loss of axons. MS patients show an accelerated rate of age-related brain and spinal cord atrophy that is three- to tenfold higher than the rate in control populations.76 Spinal cord lesions are generally similar to those in the brain except for the absence of “black holes” (see discussion in Box 2.1 of T1-weighted lesions).69 Spinal MS lesions rarely cover more than half of the cross-sectional area of the cord or exceed two vertebral segments in length. They are found more often in the cervical spinal cord (neck region) than thoracic region (midback) and are most

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Page 36 BOX 2.1 Basic Technical Principles of MRI MRI involves application of a magnetic field to the body that causes nuclei with odd numbers of protons, such as hydrogen nuclei, to behave like tiny magnets. These protons align themselves either parallel or antiparallel to the applied external magnetic field. The net magnetization induces an electric current that forms the basic MR signal. An MR image is formed by determining the spatial distribution of the signal and reconstructing the data into detailed images. The signals are picked up by a very sensitive antenna and forwarded to a computer for processing. Two time constants, T1 and T2 relaxation times, are important in determining the appearance of MR images. T1, or the longitudinal relaxation time, is the time constant when 63 percent of the original longitudinal magnetization is regained as the nuclei return to alignment with the external magnetic field. T2 or the transverse relaxation time, is the time constant when the transverse magnetization decreases to 37 percent of its original value as the nuclei lose alignment with each other following the initial application of an external magnetic field (a radio-frequency pulse). By altering the imaging parameters and pulse sequences used, differences between tissues with intrinsically different proton densities and T1 and T2 relaxation times can be highlighted or obscured. Image contrast can be either T1 weighted or T2 weighted in order to emphasize the differences between normal and pathological tissues. For example, cerebrospinal fluid (CSF) is dark on T1-weighted images and bright on T2-weighted images. White matter is bright on T1-weighted images, whereas a matter is dark but not as dark as CSF. common in the midcervical region. Disease activity is much less frequent in the spine than in the brain. In summary, the clinical manifestations of MS possibly represent only the “tip of the iceberg,” with most of the CNS damage occurring much earlier and being detectable only when the accumulated damage overwhelms the ability of the CNS to compensate. The mechanisms through which CNS tissue is damaged or destroyed are discussed in greater detail later in the chapter. Disease Markers At the present time, neuroimaging provides the best assessment of disease activity in MS (Box 2.1, Figure 2.3). Neuroimaging Abnormalities A number of neuroimaging techniques can measure distinct pathologic changes and thereby provide markers for different aspects of the MS disease

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Page 37 ~ enlarge ~ FIGURE 2.3 MRI scans of the brain of a 25-year-old woman with relapsing-remitting multiple sclerosis. (A) An MRI image shows multiple ovoid and confluent hyperintense lesions in the white matter surrounding the ventricles (the ventricles appear in the center of this image as a dark butterfly shape; they are the spaces through which cerebrospinal fluid [CSF] flows). (B) Nine months later, the number and size of the lesions have increased substantially. (C) After the administration of gadolinium, many of the lesions demonstrate ring or peripheral enhancement, indicating the breakdown of the blood-brain barrier. (D) A parasagittal T1-weighted MRI scan shows multiple regions in which the signal is diminished (referred to as “black holes”) in the periventricular white matter and corpus callosum. These regions correspond to the chronic lesions of multiple sclerosis. SOURCE: Reprinted with permission from Noseworthy et al.154 Copyright 2000 Massachusetts Medical Society. All rights reserved.

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Page 38 process (Table 2.4). Magnetic resonance imaging is a technique that creates cross-sectional images of the brain using a magnetic field and radio waves (Box 2.1). It is a versatile, powerful, and sensitive tool for measuring abnormalities in the brain. This is especially valuable with MS, because so much of the pathological activity of the disease is neurologically asymptomatic. Indeed, until neuroimaging results proved otherwise, the disease appeared to be quiescent during remissions. Neuroimaging has revealed a previously unsuspected level of activity and pathology throughout the course of disease. Contrast-Enhanced Lesions. Contrast agents are used in MRI in cases where contrast between two tissues is poor. The contrasting agent, gadolinium, is normally excluded from the brain by the blood-brain barrier. Its presence in the TABLE 2.4 Information Provided by Neuroimaging Observation or Method What it Reveals T1 gadolinium-enhancing lesions Detects blood-brain barrier leakage, inflammatory disturbances, and recent (≤6 weeks) activity, with lesion formation. T2 hyperintense lesions Provides total burden of disease measure, including reversible and irreversible pathologies. Most predictive of disease course in early MS. T1 hypointense lesions (black holes) Reflects more severe tissue pathology, including axon loss, and correlates with disability. Atrophy Reflects axon loss, as well as other tissue component loss. Correlates with disability. Atrophy is detectable in both brain and spinal cord of MS patients. CNS atrophy is ongoing and accelerated compared to normal age-related changes. MR spectroscopy measure of N-acetyl aspartate levels Decreased NAA levels reflect axon damage. Often shows abnormalities in normal brain tissue. Can be measured in whole brain (NAA) or in region of interest. Magnetization transfer imaging and magnetization transfer ratio Indicates more severe lesions, with tissue destruction. Abnormalities noted within both lesions and normal-appearing CNS tissue. Marker for disability. Can be measured in whole brain or in region of interest. Diffusion-weighted MRI Detects abnormalities in both lesions and normal-appearing CNS tissue. Detects white matter changes. High field MRI Increased sensitivity for MS lesions. Can be used in conjunction with MS spectroscopy or magnetization transfer imaging. Functional MRI Measures critical circuitry involved in response to injury, activation, loss of function, and recovery of function.

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Page 39 brain, therefore, indicates a breakdown of the blood-brain barrier. Gadolinium-enhancing activity on MRI correlates with clinical relapses and predicts increased risk or further disease activity. However, since most new brain MRI lesions are clinically silent, gadolinium-enhanced lesions are seen more often than clinical relapses. T2-Weighted Hyperintense Lesions. In T2-weighted images, MS lesions appear as very bright white areas against a gray or more neutral background and are the most readily visualized MS lesions by MRI. They reflect lesions with different pathology and of various ages, and reversible as well as irreversible abnormalities. T2-weighted hyperintense lesions can be used to measure the total lesion volume (burden-of-disease). The variable pathology, which is not distinguished in T2 burden-of-disease measures, is probably a determinant of associated disability. Only a modest relationship has been observed between T2 burden of disease and clinical disability in relapsing and secondary progressive MS. However, in patients with clinically isolated syndromes who are in the early stages of MS, T2 burden-of-disease has been correlated with the development of MS, as well as the clinical subtype of MS and disability 10 years later. The magnitude of T2 burden-of-disease changes very early in the disease process and may be valuable for predicting subsequent course. Atrophy. Atrophy of both brain and spinal cord can be detected in MS patients, including relapsing patients with minimal neurologic deficits.200 Both axon and myelin loss contribute to tissue atrophy. Recent studies suggest that CNS atrophy may be the best neuroimaging correlate for clinical disability (reviewed in 1999 by Trapp et al.213). A number of different methodologies are used to measure atrophy. Current advances involve measurement of the whole brain and improved automation, but the optimal technique has not been decided. MR Spectroscopy. Axonal injury can be measured on proton MR spectroscopy by estimating N-acetyl aspartate (NAA) levels in brain tissue. NAA is a molecule that is virtually confined to axons and neurons. Levels of NAA can fluctuate, suggesting that they can be used to measure reversible as well as irreversible damage. Persistent reduction of NAA on MR Spectroscopy correlates with axon loss, damage, or dysfunction. Reduced NAA is found not only within MS lesions but also in the normal-appearing white matter of relapsing-remitting, secondary progressive, and primary progressive MS patients. The reduction in NAA is more severe in secondary progressive MS than in relapsing MS. In addition, NAA decrease in cerebellar white matter has been correlated with clinical ataxia.51 NAA can be measured in a discrete region of interest within the brain. Recently, whole-brain NAA has been measured in MS. This appears to be a more meaningful neuroimaging marker to evaluate axon damage. MR spectroscopy can also be used to measure lipid changes within both lesions and normal-

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Page 104transgenes are integrated into defined loci through homologous recombination, will likewise overcome the problems of uneven gene copy numbers in replicate animals and disparate sites of integration in the genome. REFERENCES 1. Acheson ED. 1977. Epidemiology of multiple sclerosis. Br Med Bull.; 33: 9-14. 2. Adelmann M, Wood J, Benzel I, et al. 1995. The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat. J Neuroimmunol.; 63: 17-27. 3. Agresti C, D'Urso D, Levi G. 1996. Reversible inhibitory effects of interferon-gamma and tumour necrosis factor-alpha on oligodendroglial lineage cell proliferation and differentiation in vitro. Eur J Neurosci.; 8: 1106-16. 4. Akassoglou K, Bauer J, Kassiotis G, et al. 1998. Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am J Pathol.; 153: 801-13. 5. Albert LJ, Inman RD. 1999. Molecular mimicry and autoimmunity. N Engl J Med.; 341: 2068-74. 6. Allain H, Schuck S. 1998. Observations on differences between interferons to treat multiple sclerosis. Journal of Clinical Research; 1: 381-392. 7. Allegretta M, Nicklas JA, Sriram S, Albertini RJ. 1990. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science.; 247: 718-21. 8. Amato MP, Ponziani G, Bartolozzi ML, Siracusa G. 1999. A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci.; 168: 96-106. 9. Antel JP, Becher B, Owens T. 1996. Immunotherapy for multiple sclerosis: from theory to practice. Nat Med.; 2: 1074-5. 10. Apple RJ, Erlich HA. 1996. HLA class II genes: structure and diversity. Browning M, McMichael A, eds. HLA and MHC: Genes, Molecules and Function. Oxford: BIOS Scientific Publishers Limited; 97-109. 11. Arbiser JL, Kraeft SK, van Leeuwen R, et al. 1998. Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy. Mol Med.; 4: 665-670. 12. Ascherio A. 1997. Antimetabolites and an optic neuropathy epidemic in Cuba. Am J Clin Nutr.; 65: 1092-1093. 13. Baerwald KD, Corbin JG, Popko B. 2000. Major histocompatibility complex heavy chain accumulation in the endoplasmic reticulum of oligodendrocytes results in myelin abnormalities. J Neurosci Res.; 59: 160-9. 14. Barkhof F, Filippi M, Miller DH, et al. 1997. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain.; 120 : 2059-69. 15. Benjamini E, Leskowitz S. 1991. Immunology: a Short Course. NY: Wiley-Liss, Inc. 16. Benveniste EN. 1997. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med.; 75: 165-73. 17. Bernard CC, Johns TG, Slavin A, et al. 1997. Myelin oligodendrocyte glycoprotein: a novel candidate autoantigen in multiple sclerosis. J Mol Med.; 75: 77-88. 18. Berti R, Jacobson S. 1999. Role of viral infection in the aetiology of multiple sclerosis. Status of current knowledge and therapeutic implications. CNS Drugs.; 12: 1-7. 19. Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. 1998. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol.; 161: 3299-306.

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