`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`Review Article
`
`Medical Progress
`
`M
`
`ULTIPLE
`
` S
`
`CLEROSIS
`
`J
`OHN
`
` L
`, M.D., C
` H. N
`UCCHINETTI
`LAUDIA
`OSEWORTHY
`M
` R
`, M.D.,
`OSES
`ODRIGUEZ
` B
` G. W
`, M.D.
`RIAN
`EINSHENKER
`
`AND
`
`, M.D.,
`
`M
`
`ORE than 100 years has passed since
`Charcot, Carswell, Cruveilhier, and others
`described the clinical and pathological
`characteristics of multiple sclerosis.
` This enigmatic,
`1
`relapsing, and often eventually progressive disorder
`of the white matter of the central nervous system
`continues to challenge investigators trying to under-
`stand the pathogenesis of the disease and prevent its
`progression.
` There are 250,000 to 350,000 patients
`2
`with multiple sclerosis in the United States.
` Multiple
`3
`sclerosis typically begins in early adulthood and has
`a variable prognosis. Fifty percent of patients will need
`help walking within 15 years after the onset of dis-
`ease.
` Advanced magnetic resonance imaging (MRI)
`4
`and spectroscopy may allow clinicians to follow the
`pathological progression of the disease and monitor
`the response to treatment. Recent progress has oc-
`curred in understanding the cause, the genetic com-
`ponents, and the pathologic process of multiple scle-
`rosis. The short-term clinical and MRI manifestations
`of disease activity have been reduced by new therapies,
`although the degree of presumed long-term benefit
`from these treatments will require further study.
`CLINICAL COURSE AND DIAGNOSIS
`A patient’s presenting symptoms and the temporal
`evolution of the clinical findings may suggest the cor-
`rect diagnosis. In relapsing–remitting multiple scle-
`rosis — the type present in 80 percent of patients —
`symptoms and signs typically evolve over a period of
`several days, stabilize, and then often improve, spon-
`taneously or in response to corticosteroids, within
`weeks. Relapsing–remitting multiple sclerosis typi-
`
`From the Department of Neurology, Mayo Clinic and Mayo Founda-
`tion, Rochester, Minn. Address reprint requests to Dr. Noseworthy at the
`Department of Neurology, Mayo Clinic and Mayo Foundation, 200 First
`St., SW, Rochester, MN 55905.
`©2000, Massachusetts Medical Society.
`
`cally begins in the second or third decade of life and
`has a female predominance of approximately 2:1. The
`tendency for corticosteroids to speed recovery from
`relapses often diminishes with time. Persistent signs of
`central nervous system dysfunction may develop after
`a relapse, and the disease may progress between relaps-
`es (secondary progressive multiple sclerosis). Twenty
`percent of affected patients have primary progressive
`multiple sclerosis, which is characterized by a gradu-
`ally progressive clinical course and a similar incidence
`among men and women.
`Relapsing–remitting multiple sclerosis typically
`starts with sensory disturbances, unilateral optic neu-
`ritis, diplopia (internuclear ophthalmoplegia), Lher-
`mitte’s sign (trunk and limb paresthesias evoked by
`neck flexion), limb weakness, clumsiness, gait ataxia,
`and neurogenic bladder and bowel symptoms. Many
`patients describe fatigue that is worse in the afternoon
`and is accompanied by physiologic increases in body
`temperature. The onset of symptoms post partum and
`symptomatic worsening with increases in body tem-
`perature (Uhthoff ’s symptom) and pseudoexacerba-
`tions with fever suggest the diagnosis. Some patients
`have recurring, brief, stereotypical phenomena (par-
`oxysmal pain or paresthesias, trigeminal neuralgia, ep-
`isodic clumsiness or dysarthria, and tonic limb postur-
`ing) that are highly suggestive of multiple sclerosis.
`Prominent cortical signs (aphasia, apraxia, recurrent
`seizures, visual-field loss, and early dementia) and ex-
`trapyramidal phenomena (chorea and rigidity) only
`rarely dominate the clinical picture. Eventually, cog-
`nitive impairment, depression, emotional lability, dys-
`arthria, dysphagia, vertigo, progressive quadriparesis
`and sensory loss, ataxic tremors, pain, sexual dysfunc-
`tion, spasticity, and other manifestations of central
`nervous system dysfunction may become troublesome.
`Patients who have primary progressive multiple scle-
`rosis often present with a slowly evolving upper-
`motor-neuron syndrome of the legs (“chronic pro-
`gressive myelopathy”). Typically, this variant worsens
`gradually, and quadriparesis, cognitive decline, visual
`loss, brain-stem syndromes, and cerebellar, bowel,
`bladder, and sexual dysfunction may develop.
`The diagnosis is based on established clinical and,
`when necessary, laboratory criteria.
` Advances in cer-
`5
`ebrospinal fluid analysis and MRI, in particular, have
`simplified the diagnostic process (Fig. 1).
` The relaps-
`6
`ing forms are considered clinically definite when neu-
`rologic dysfunction becomes “disseminated in space
`and time.” Primary progressive multiple sclerosis may
`be suggested clinically by a progressive course that
`lasts longer than six months, but laboratory studies
`to obtain supportive evidence and efforts to exclude
`
`938
`
`·
`
`September 28, 2000
`
`1
`
`Hopewell EX1006
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDICAL PROGRESS
`
`A
`
`C
`
`B
`
`D
`
` MRI Scans of the Brain of a 25-Year-Old Woman with Relapsing–Remitting Multiple Sclerosis.
`Figure 1.
`An axial FLAIR (fluid-attenuated inversion recovery) image shows multiple ovoid and confluent hyperintense lesions in the periven-
`tricular white matter (Panel A). Nine months later, the number and size of the lesions have substantially increased (Panel B). After
`the administration of gadolinium, many of the lesions demonstrate ring or peripheral enhancement, indicating the breakdown of
`the blood–brain barrier (Panel C). In Panel D, a parasagittal T
`-weighted MRI scan shows multiple regions in which the signal is
`1
`diminished (referred to as “black holes”) in the periventricular white matter and corpus callosum. These regions correspond to the
`chronic lesions of multiple sclerosis.
`
`2
`
`Volume 343 Number 13
`
`·
`
`939
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`other, potentially treatable illnesses are advised; for
`example, structural or metabolic myelopathy can be
`identified by appropriate laboratory studies, including
`spinal MRI (Table 1). On MRI, findings of multifo-
`cal lesions of various ages, especially those involving
`the periventricular white matter, brain stem, cerebel-
`lum, and spinal cord white matter, support the clin-
`ical impression. The presence of gadolinium-enhanc-
`ing lesions on MRI indicates current sites of presumed
`inflammatory demyelination (active lesions).
`When there is diagnostic uncertainty, repeated
`MRI after several months may provide evidence that
`the lesions are “disseminated in time.” Cerebrospi-
`nal fluid analysis often shows increased intrathecal
`synthesis of immunoglobulins of restricted specifici-
`ty (oligoclonal bands may be present, or the synthesis
`of IgG may be increased), with moderate lympho-
`cytic pleocytosis (almost invariably there are fewer
`than 50 mononuclear cells). Physiologic evidence of
`subclinical dysfunction of the optic nerves and spinal
`cord (changes in visual evoked responses and soma-
`tosensory evoked potentials) may provide support
`for the conclusion that there is “dissemination in
`space.”
` Therefore, spinal MRI and evoked-potential
`7
`testing may provide evidence of a second lesion that
`can confirm the diagnosis. Abnormalities detected
`by testing of somatosensory evoked potentials and
`spinal MRI may clarify the diagnosis in patients with
`optic neuritis alone or isolated brain-stem abnormal-
`ities and in those suspected of having unifocal cere-
`bral multiple sclerosis on the basis of MRI. If posi-
`tive, abnormalities detected by tests of visual evoked
`responses may support the diagnosis of multiple scle-
`rosis in patients with isolated brain-stem or spinal
`cord lesions.
`The course of multiple sclerosis in an individual
`patient is largely unpredictable. Patients who have a
`so-called clinically isolated syndrome (e.g., optic neu-
`ritis, brain-stem dysfunction, or incomplete transverse
`myelitis) as their first event have a greater risk of both
`recurrent events (thereby confirming the diagnosis
`of clinically definite multiple sclerosis) and disability
`within a decade if changes are seen in clinically asymp-
`tomatic regions on MRI of the brain.
` The presence
`8
`of oligoclonal bands in cerebrospinal fluid slightly in-
`creases the risk of recurrent disease.
`9
`Studies of the natural history of the disease have
`provided important prognostic information that is
`useful for counseling patients and planning clinical
` Ten percent of patients do well for more
`trials.
`4,10,11
`than 20 years and are thus considered to have benign
`multiple sclerosis. Approximately 70 percent will have
`secondary progression.
` Frequent relapses in the first
`4
`two years, a progressive course from the onset, male
`sex, and early, permanent motor or cerebellar find-
`ings are independently, but imperfectly, predictive of
`a more severe clinical course. Women and patients
`with predominantly sensory symptoms and optic neu-
`
`940
`
`·
`
`September 28, 2000
`
`3
`
`T
`
`ABLE
`
` 1.
`
` D
`
`IFFERENTIAL
`
` D
`
`IAGNOSIS
`
`
`
`OF
`
` M
`
`ULTIPLE
`
` S
`
`CLEROSIS
`
`.
`
`Metabolic disorders
`Disorders of B
` metabolism*
`12
`Leukodystrophies
`Autoimmune diseases
`Sjögren’s syndrome, systemic lupus erythematosus, Behçet’s disease, sar-
`coidosis, chronic inflammatory demyelinating polyradiculopathy associat-
`ed with central nervous system demyelination, antiphospholipid-anti-
`body syndrome
`Infections
`†
`HIV-associated myelopathy* and HTLV-1–associated myelopathy,* Lyme
`disease, meningovascular syphilis, Eales’ disease
`Vascular disorders
`Spinal dural arteriovenous fistula*
`Cavernous hemangiomata
`Central nervous system vasculitis, including retinocochlear cerebral
`vasculitis
`Cerebral autosomal dominant arteriopathy with subcortical infarcts and
`leukoencephalopathy
`Genetic syndromes
`Hereditary ataxias and hereditary paraplegias*
`Leber’s optic atrophy and other mitochondrial cytopathies
`Lesions of the posterior fossa and spinal cord
`Arnold–Chiari malformation, nonhereditary ataxias
`Spondylotic and other myelopathies*
`Psychiatric disorders
`Conversion reaction, malingering
`Neoplastic diseases
`Spinal cord tumors,* central nervous system lymphoma
`Paraneoplastic disorders
`Variants of multiple sclerosis
`‡
`Optic neuritis; isolated brain-stem syndromes; transverse myelitis; acute
`disseminated encephalomyelitis, Marburg disease; neuromyelitis optica
`
`*This disorder or group of disorders is of particular relevance in the dif-
`ferential diagnosis of progressive myelopathy and primary progressive mul-
`tiple sclerosis.
`†HIV denotes human immunodeficiency virus, and HTLV-1 human
`T-cell lymphotropic virus type 1.
`‡In many patients with these variants, clinically definite multiple sclerosis
`develops or the course is indistinguishable from that of multiple sclerosis.
`
`ritis have a more favorable prognosis. Life expectan-
`cy may be shortened slightly; in rare cases, patients
`with fulminant disease die within months after the on-
`set of multiple sclerosis. Suicide remains a risk, even
`for young patients with mild symptoms.
`12
`EPIDEMIOLOGIC FEATURES
`The prevalence of multiple sclerosis varies consid-
`erably around the world.
` Kurtzke classified regions
`13
`of the world according to prevalence: a low preva-
`lence was considered less than 5 cases per 100,000
`persons, an intermediate prevalence was 5 to 30 per
`100,000 persons, and a high prevalence was more
`than 30 per 100,000 persons.
` The prevalence is
`14
`highest in northern Europe, southern Australia, and
`the middle part of North America. There has been
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDICAL PROGRESS
`
`a trend toward an increasing prevalence and incidence,
`particularly in southern Europe.
` Even in areas with
`15,16
`uniform methods of ascertainment and high preva-
`lence, such as Olmsted County, Minnesota, the in-
`cidence has increased from 2 to 6 per 100,000 dur-
`ing the past century.
` However, the incidence has
`17
`actually declined in some,
` but not all,
` areas of
`18,19
`20
`northern Europe. Stable or declining rates have been
`reported most often in regions with high prevalence
`and incidence. The extent to which the observed in-
`creases in incidence are explained by an enhanced
`awareness of the disease and improved diagnostic
`techniques is uncertain. There is a large reservoir of
`mild cases, the recognition of which may depend
`heavily on the zeal and resources of the investigator.
`The reasons for the variation in the prevalence and
`incidence of multiple sclerosis worldwide are not un-
`derstood. Environmental and genetic explanations
`have been offered, and both factors probably have a
`role. The occurrence of rapid shifts in the incidence
`of multiple sclerosis, if not artifactual, is an argu-
`ment for an environmental influence, as is the equiv-
`ocal, but suggestive, evidence of the clustering of cases
`in terms of both geography and time and of epidem-
`ics, especially on the Faroe Islands.
` The apparent
`21
`change in the frequency of multiple sclerosis among
`people
` and their offspring
` who migrate to and
`22,23
`24
`from high-prevalence areas is another factor that has
`been presented to support the existence of an envi-
`ronmental factor. However, each of these relations
`has potential confounders that preclude the drawing
`of a definite conclusion regarding the importance of
`environmental factors.
` The nature of putative envi-
`25
`ronmental factors remains unclear in numerous case–
`control studies. Studies that show that the incidence
`of multiple sclerosis among the adopted children of
`patients with multiple sclerosis is not higher than ex-
`pected seem to argue against the possibility that a
`transmissible factor is primarily responsible for the
`increased risk of the disease among relatives and in-
`stead suggest that genetic factors may be responsible.
`26
`GENETIC FACTORS
`Evidence that genetic factors have a substantial ef-
`fect on susceptibility to multiple sclerosis is unequiv-
`ocal. The concordance rate of 31 percent among
`monozygotic twins is approximately six times the rate
`among dizygotic twins (5 percent).
` The absolute risk
`27
`of the disease in a first-degree relative of a patient with
`multiple sclerosis is less than 5 percent; however, the
`risk in such relatives is 20 to 40 times the risk in the
`general population.
` Since 1973, it has been recog-
`28
`nized that the presence of the HLA-DR2 allele sub-
`stantially increases the risk of multiple sclerosis.
`29
`This effect has been found in all populations, with the
`exception of that in Sardinia.
` The magnitude of the
`30
`relative risk depends on the frequency of the HLA-
`DR2 allele in the general population. Given the high
`
`frequency of this allele in the population, the risk at-
`tributable to the HLA-DR2 allele is considerable. Pop-
`ulations with a high frequency of the allele (e.g., those
`in Scotland) have the highest risk of multiple sclerosis.
`The mode of transmission of genetic susceptibility
`to multiple sclerosis is complex. Most cases are sporad-
`ic, despite the clear excess risk among the relatives of
`patients. Investigators have used the usual genetic
`approaches to identify genes associated with an in-
`creased risk of multiple sclerosis.
`Studies of candidate genes have targeted individu-
`al genes with microsatellite markers with use of asso-
`ciation and linkage strategies. For some genetic re-
`gions, such as the HLA region on chromosome 6, it
`has been difficult to identify the specific polymor-
`phism that predisposes persons to the disease, given
`the high degree of linkage disequilibrium at that locus.
`Candidate-gene studies were followed by four stud-
`ies in which the entire genome was scanned.
` Re-
`31-34
`gions of interest have been identified, although none
`have been linked to the disease with certainty. Con-
`sidering the rather large number of patients evaluated
`in such studies, one might conclude tentatively that no
`single gene, except possibly those for HLA antigens,
`35
`exerts a strong effect.
`Further refinement of the linkage map is in prog-
`ress.
` Whether this approach will prove powerful
`36
`enough to identify genes with a relatively weak effect
`is difficult to predict. To enhance the detection of
`genes with a weak effect, investigators have begun to
`use strategies involving linkage-disequilibrium map-
`ping and transmission-disequilibrium testing. In these
`approaches, putative causative alleles or marker al-
`leles and haplotypes are assessed to determine wheth-
`er they are associated with the disease at a popula-
`tion level or whether they are associated with a
`higher-than-expected rate of transmission of disease
`from heterozygous parents to their children. This ef-
`fort will involve a major expenditure of resources to
`achieve genome-wide coverage. The development of
`novel analytic techniques for these types of genetic
`data sets makes such an undertaking feasible.
`37
`The severity and course of multiple sclerosis may
`also be influenced by genetic factors. Epidemiologic
`evidence to support this premise comes from studies
`examining the rate of concordance for measures that
`describe and quantitate variations in the course of
`disease, including the age at onset, the proportion
`of patients in whom the disease progresses, and the
` HLA-DR and DQ
`extent of disability over time.
`38
`polymorphisms are not associated with the course and
`severity of multiple sclerosis, despite their substantial
`contribution to disease susceptibility.
` Recently, vari-
`39
`ants of the interleukin-1
`–receptor and interleukin-1–
`b
`receptor antagonist genes,
` immunoglobulin Fc re-
`40
`ceptor genes,
` and apolipoprotein E gene
` have been
`41
`42
`associated with the course of the disease, but these
`findings await confirmation.
`
`4
`
`Volume 343 Number 13
`
`·
`
`941
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`PATHOLOGICAL FEATURES
`AND PATHOGENESIS
`Multiple sclerosis is generally believed to be an im-
`mune-mediated disorder that occurs in genetically sus-
`ceptible people (Fig. 2).
` However, the sequence of
`43
`events that initiates the disease remains largely un-
`known. Given the considerable clinical, genetic, MRI,
`and pathological heterogeneity of multiple sclerosis,
`perhaps more than one pathogenetic mechanism con-
`tributes to tissue injury. This possibility has therapeutic
`implications, because more than one approach to treat-
`ment may be required to treat this disease effectively.
`The pathological hallmark of chronic multiple scle-
`rosis is the demyelinated plaque, which consists of a
`well-demarcated hypocellular area characterized by
`the loss of myelin, relative preservation of axons, and
`the formation of astrocytic scars (Fig. 3). Lesions have
`a predilection for the optic nerves, periventricular
`white matter, brain stem, cerebellum, and spinal cord
`white matter, and they often surround one or several
`medium-sized vessels. Although the lesions are usu-
`ally round or oval, they often have finger-like exten-
`sions along the path of small or medium-sized blood
`vessels (Dawson’s fingers). Inflammatory cells are typ-
`ically perivascular in location, but they may diffusely
`infiltrate the parenchyma. The composition of the
`inflammatory infiltrate varies depending on the stage
`of demyelinating activity. In general, it is composed
`
`of lymphocytes and macrophages; the latter predomi-
`nate in active lesions.
`For meaningful conclusions to be drawn regarding
`the earliest immunologic and molecular events con-
`tributing to the formation of lesions, only actively de-
`myelinating plaques should be considered. Identifying
`myelin-degradation products in macrophages is the
`most reliable method of identifying active lesions (Fig.
`4).
` When stringent criteria are used to define lesion-
`44
`al activity, the frequency of active plaques in patients
`with chronic multiple sclerosis is extremely low. Al-
`though remyelination is minimal in lesions associated
`with chronic multiple sclerosis, plaques in acute and
`early multiple sclerosis may have extensive remyeli-
`nation (referred to as shadow plaques) (Fig. 5). Fur-
`thermore, the lesions of chronic multiple sclerosis
`reportedly contain substantial numbers of oligoden-
`drocyte precursor cells.
` Thus, central nervous sys-
`45
`tem myelin can be repaired, and mechanisms that
`promote endogenous remyelination may represent a
`feasible therapeutic strategy.
`Early symptoms of multiple sclerosis are widely
`believed to result from axonal demyelination, which
`leads to the slowing or blockade of conduction. The
`regression of symptoms has been attributed to the
`resolution of inflammatory edema and to partial re-
`myelination. However, inflammatory cytokines may
`inhibit axonal function, and the recovery of function
`
` Possible Mechanisms of Injury and Repair in Multiple Sclerosis.
`Figure 2 (facing page).
`Genetic and environmental factors (including viral infection, bacterial lipopolysaccharides, superantigens, reactive metabolites, and
`metabolic stress) may facilitate the movement of autoreactive T cells and demyelinating antibodies from the systemic circulation
`into the central nervous system through disruption of the blood–brain barrier. In the central nervous system, local factors (including
`viral infection and metabolic stress) may up-regulate the expression of endothelial adhesion molecules, such as intercellular adhe-
`sion molecule 1 (ICAM-1), vascular-cell adhesion molecule 1 (VCAM-1), and E-selectin, further facilitating the entry of T cells into
`the central nervous system. Proteases, including matrix metalloproteinases, may further enhance the migration of autoreactive im-
`mune cells by degrading extracellular-matrix macromolecules. Proinflammatory cytokines released by activated T cells, such as
`interferon-
` and tumor necrosis factor
` (TNF-
`), may up-regulate the expression of cell-surface molecules on neighboring lympho-
`g
`b
`b
`cytes and antigen-presenting cells. Binding of putative multiple sclerosis (MS) antigens, such as myelin basic protein, myelin-asso-
`ciated glycoprotein, myelin oligodendrocyte glycoprotein (MOG), proteolipid protein,
`B-crystallin, phosphodiesterases, and S-100
`a
`protein, by the trimolecular complex — the T-cell receptor (TCR) and class II major-histocompatibility-complex (MHC) molecules on
`antigen-presenting cells — may trigger either an enhanced immune response against the bound antigen or anergy, depending on
`the type of signaling that results from interactions with surface costimulatory molecules (e.g., CD28 and CTLA-4) and their ligands
`(e.g., B7-1 and B7-2). Down-regulation of the immune response (anergy) may result in the release of antiinflammatory cytokines
`(interleukin-1, interleukin-4, and interleukin-10) from CD4+ T cells, leading to the proliferation of antiinflammatory CD4+ type 2 help-
`er T (Th2) cells. Th2 cells may send antiinflammatory signals to the activated antigen-presenting cells and stimulate pathologic or
`repair-enhancing antibody-producing B cells. Alternatively, if antigen processing results in an enhanced immune response, proin-
`flammatory cytokines (e.g., interleukin-12 and interferon-
`) may trigger a cascade of events, resulting in the proliferation of proin-
`g
`flammatory CD4+ type 1 helper T (Th1) cells and ultimately in immune-mediated injury to myelin and oligodendrocytes. Multiple
`mechanisms of immune-mediated injury of myelin have been postulated: cytokine-mediated injury of oligodendrocytes and myelin;
`digestion of surface myelin antigens by macrophages, including binding of antibodies against myelin and oligodendrocytes (i.e.,
`antibody-dependent cytotoxicity); complement-mediated injury; and direct injury of oligodendrocytes by CD4+ and CD8+ T cells.
`This injury to the myelin membrane results in denuded axons that are no longer able to transmit action potentials efficiently within
`the central nervous system (loss of saltatory conduction). This slowing or blocking of the action potential results in the production
`of neurologic symptoms. The exposed axon segments may be susceptible to further injury from soluble mediators of injury (in-
`cluding cytokines, chemokines, complement, and proteases), resulting in irreversible axonal injury (such as axonal transection and
`terminal axon ovoids). There are several possible mechanisms of repair of the myelin membrane, including resolution of the in-
`flammatory response followed by spontaneous remyelination, spread of sodium channels from the nodes of Ranvier to cover de-
`nuded axon segments and restore conduction, antibody-mediated remyelination, and remyelination resulting from the proliferation,
`migration, and differentiation of resident oligodendrocyte precursor cells. Adapted from a drawing by the Mayo Foundation.
`
`942
`
`·
`
`September 28, 2000
`
`5
`
`

`

`
`
`
`
`
`
`
`MEDICAL PROGRESS
`
`Autoreactive T cell
`
`Endothelial cells
`
`Adhesion
`
`Demyelinating antibodies(cid:2)
`Anti-MOG?
`ICAM-1, VCAM-1,(cid:2)
`E-selectins up-regulated
`
`Systemic circulation
`
`Blood–brain barrier
`
`Activated antigen-(cid:2)
`presenting cell(cid:2)
`(astrocytes, microglia,(cid:2)
`macrophages)
`
`Penetration(cid:2)
`(matrix metalloproteinases)
`
`(cid:2)
`Interferon-g
`TNF-b
`
`(cid:2)
`B7-1, B7-2
`
`CD28 Immune response
`CTLA-4 Anergy
`
`Basement(cid:2)
`membrane
`
`Central(cid:2)
`nervous system
`
`Oligodendrocyte(cid:2)
`precursor cell
`
`TCR
`
`CD4+ T cell
`
`Antiinflammatory signaling(cid:2)
`Interleukin-4, 10, 13
`
`Activated(cid:2)
`B cell
`
`Class II MHC(cid:2)
`molecule
`Putative(cid:2)
`MS antigen
`
`(cid:2)
`
`CD4+(cid:2)
`Th1 cell
`(cid:2)
`TNF-a,
`Interferon-g
`
`
`
`Interleukin-12(cid:2)
`Interferon-g
`
`
`Interleukin-1, 4, 10(cid:2)
`(cid:2)
`
`CD4+(cid:2)
`Th2 cell
`
`(cid:2)
`Interleukin-(cid:2)
`4, 5, 6, 10, 13
`
`Antibodies
`
`Cytokine-mediated(cid:2)
`injury
`
`Macrophage
`
`Complement
`
`Neuronal(cid:2)
`cell body
`
`Glial growth(cid:2)
`factors?
`
`Surface Ig
`
`Proliferation(cid:2)
`Migration(cid:2)
`Differentiation(cid:2)
`Remyelination
`
`Normal(cid:2)
`myelin sheath
`
`Remyelinated(cid:2)
`areas
`
`Immune-(cid:2)
`mediated injury
`
`Class I MHC(cid:2)
`molecule
`
`Class I–restricted(cid:2)
`CD8+ T cell(cid:2)
`up-regulated by(cid:2)
`interferon-g
`
`Antibody-mediated injury(cid:2)
`(cid:2)
`(cid:2)
`(cid:2)
`
`Antibody-mediated(cid:2)
`remyelination?
`
`Primary(cid:2)
`oligodendrogliopathy
`
`Oligodendrocyte
`
`Terminal(cid:2)
`axon ovoid
`
`Increased(cid:2)
`sodium-channel(cid:2)
`density
`
`Degeneration(cid:2)
`of inner glial loop
`
`Postsynaptic neuron
`
`6
`
`Volume 343 Number 13
`
`·
`
`943
`
`

`

`The New England Journal of Medicine
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A
`
`B
`
` Photomicrographs of a Chronic Multiple Sclerosis
`Figure 3.
`Plaque.
`In Panel A, a well-demarcated hypocellular region of myelin
`loss is evident in the periventricular white matter (luxol fast
`blue and periodic acid–Schiff myelin stain, ¬15). In Panel B,
`neurofilament staining for axons in the same lesion demon-
`strates a reduction in axonal density (¬15).
`
`may result from the redistribution of sodium chan-
`nels across segments of demyelinated axons.
` Irre-
`46,47
`versible axonal injury, gliotic scarring, and exhaustion
`of the oligodendrocyte progenitor pool may result
`from repeated episodes of disease activity and lead to
`progressive loss of neurologic function. Axonal inju-
`ry may occur not only in the late phases of multiple
`sclerosis but also after early episodes of inflammatory
`demyelination.
` The pathogenesis of this early ax-
`48-50
`onal injury is still unclear.
`Experimental in vitro and in vivo models of in-
`flammatory demyelination suggest that diverse disease
`processes, including autoimmunity and viral infection,
`
`944
`
`·
`
`September 28, 2000
`
`7
`
`A
`
`B
`
` Photomicrographs of an Actively Demyelinating Mul-
`Figure 4.
`tiple Sclerosis Lesion (Immunocytochemical Staining of Myelin
`Oligodendrocyte Glycoprotein [Brown] with Hematoxylin Coun-
`terstaining of Nuclei [Blue]).
`In Panel A, at the active edge of a multiple sclerosis lesion (in-
`dicated by the asterisk), the products of myelin degradation are
`present in numerous macrophages (arrowheads) (¬100). In Pan-
`el B (¬100), macrophages containing myelin debris (arrowheads)
`are interdigitated with degenerating myelin sheaths.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEDICAL PROGRESS
`
`protein is present on the outer lamellae of the myelin
`sheath). Antibodies against both myelin oligodendro-
`cyte glycoprotein and myelin basic protein can be
`found in the brains of patients with multiple sclero-
`sis.
` Deposits of immunoglobulin and activated com-
`57
`plement may be present in multiple sclerosis lesions
`in which myelin is being degraded.
` Taken together,
`58
`these observations suggest that an antibody-mediated
`process may have an important role in the pathogen-
`esis of multiple sclerosis.
`Other factors may also help degrade myelin and
`damage oligodendrocytes. Activated macrophages and
`microglial cells may mediate such activity by produc-
`ing proinflammatory cytokines (such as tumor necro-
`sis factor
` and interferon-
`), generating reactive ox-
`a
`g
`ygen or nitrogen species, producing excitatory amino
`acids, activating complement components, or releas-
`ing proteolytic and lipolytic enzymes. Other factors
`potentially toxic to oligodendroglial cells include sol-
`uble T-cell products (such as perforin), the interaction
`of Fas antigen with Fas ligand, cytotoxicity mediated
`by the interaction of CD8+ T cells with class I ma-
`jor-histocompatibility-complex (MHC) antigens on
`antigen-presenting cells, and persistent viral infec-
`tion.
` Human herpesvirus type 6 can cause a con-
`54
`dition that mimics multiple sclerosis
` and appears in
`59
`oligodendrocytes within multiple sclerosis tissue in
`some patients, but not in control tissue.
` A direct
`60
`causal link, however, remains to be confirmed. In
`one study,
`
`Chlamydia pneumoniae was isolated from
`64 percent of patients with multiple sclerosis, as
`compared with 11 percent of control patients with
`other neurologic diseases, and it was detected in cer-
`ebrospinal fluid by a polymerase-chain-reaction assay
`in 97 percent of patients with multiple sclerosis, as
`compared with 18 percent of control patients.
`61
`These results have yet to be confirmed in other lab-
`oratories.
`62
`Various pathogenic mechanisms may be involved
`in multiple sclerosis. There is an important degree of
`variability among patients in the structural and im-
`munologic features of the lesions of multiple sclero-
`sis.
` The extent of survival of oligodendrocytes varies
`63
`from patient to patient but is uniform within a given
`patient, suggesting that the focus of injury (myelin,
`mature oligodendrocyte, or progenitor cell) varies
`among patients.
` Although most lesions are charac-
`49
`terized by an inflammatory reaction, composed main-
`ly of T lymphocytes and macrophages, diverse pat-
`
`terns of myelin destruction have been described.
`64
`In some lesions, the presence of immunoglobulins
`and activated terminal complement components sug-
`gests that demyelinating antibodies have a pathogenic
`role. In others, a primary oligodendrocyte dystrophy
`manifested by the selective loss of myelin-associated
`glycoprotein and apoptosis of oligodendrocytes has
`been seen. Finally, in other cases, a small rim of ne-
`crotic oligodendrocytes has been found in the nor-
`
`8
`
`Volume 343 Number 13
`
`·
`
`945
`
` Remyelination in a Lesion Associated with Chronic
`Figure 5.
`Multiple Sclerosis.
`The area stained pale blue (indicated by the asterisk) repre-
`sents a region of partial remyelination (a shadow plaque) along
`the periventricular edge of a lesion in a patient with chronic
`multiple sclerosis (luxol fast blue and periodic acid–Schiff my-
`elin stain, ¬15). NAWM denotes normal-appearing white matter.
`
`may induce multiple sclerosis–like inflammatory de-
`myelinated plaques. Activated CD4+ T cells specific
`for one or more self antigens are believed to adhere
`to the luminal surface of endothelial cells in central
`nervous system venules and migrate into the central
`nervous system at the time of disruption of the
`blood–brain barrier. This process is followed by an
`amplification of the immune response after the recog-
`nition of target antigens on antigen-presenting cells.
`The existence of T cells that are reactive to several
`putative self myelin and non-myelin “multiple sclerosis
`antigens,” including myelin basic protein, myelin-asso-
`ciated glycoprotein, myelin oligodendrocyte glycopro-
`tein, proteolipid protein,
`B-crystallin, phosphodi-
`a
`esterases, and S-100 protein, has been proposed.
`51-53
`Additional amplification