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 Review Article
 Medical Progress 
 938
 ·
 September 28, 2000
 The New England Journal of Medicine
 M
 ULTIPLE
 S
 CLEROSIS
 J
 
OHN
 H. N
 
OSEWORTHY
 , M.D., C
 
LAUDIA
 L
 
UCCHINETTI
 , M.D.,M
 
OSES
 R
 
ODRIGUEZ
 , M.D.,
AND
 B
 
RIAN
 G. W
 
EINSHENKER
 , M.D.
 From the Department of Neurology, Mayo Clinic and Mayo Founda-tion, Rochester, Minn. Address reprint requests to Dr. Noseworthy at theDepartment of Neurology, Mayo Clinic and Mayo Foundation, 200 FirstSt., SW, Rochester, MN 55905.©2000, Massachusetts Medical Society.
 ORE than 100 years has passed sinceCharcot, Carswell, Cruveilhier, and othersdescribed the clinical and pathologicalcharacteristics of multiple sclerosis.
 1
 This enigmatic,relapsing, and often eventually progressive disorderof the white matter of the central nervous systemcontinues to challenge investigators trying to under-stand the pathogenesis of the disease and prevent itsprogression.
 2
 There are 250,000 to 350,000 patients with multiple sclerosis in the United States.
 3
 Multiplesclerosis typically begins in early adulthood and hasa variable prognosis. Fifty percent of patients will needhelp walking within 15 years after the onset of dis-ease.
 4
  Advanced magnetic resonance imaging (MRI)and spectroscopy may allow clinicians to follow thepathological progression of the disease and monitorthe 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 manifestationsof disease activity have been reduced by new therapies,although the degree of presumed long-term benefitfrom these treatments will require further study.
 CLINICAL COURSE AND DIAGNOSIS
  A patient’s presenting symptoms and the temporalevolution 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-
M
 cally begins in the second or third decade of life andhas a female predominance of approximately 2:1. Thetendency for corticosteroids to speed recovery fromrelapses often diminishes with time. Persistent signs of central nervous system dysfunction may develop aftera relapse, and the disease may progress between relaps-es (secondary progressive multiple sclerosis). Twenty percent of affected patients have primary progressivemultiple sclerosis, which is characterized by a gradu-ally progressive clinical course and a similar incidenceamong 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 afternoonand is accompanied by physiologic increases in body temperature. The onset of symptoms post partum andsymptomatic worsening with increases in body tem-perature (Uhthoff’s symptom) and pseudoexacerba-tions with fever suggest the diagnosis. Some patientshave 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, recurrentseizures, 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 quadriparesisand sensory loss, ataxic tremors, pain, sexual dysfunc-tion, spasticity, and other manifestations of centralnervous 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 worsensgradually, and quadriparesis, cognitive decline, visualloss, brain-stem syndromes, and cerebellar, bowel,bladder, and sexual dysfunction may develop.The diagnosis is based on established clinical and, when necessary, laboratory criteria.
 5
  Advances in cer-ebrospinal fluid analysis and MRI, in particular, havesimplified the diagnostic process (Fig. 1).
 6
 The relaps-ing forms are considered clinically definite when neu-rologic dysfunction becomes “disseminated in spaceand time.” Primary progressive multiple sclerosis may be suggested clinically by a progressive course thatlasts longer than six months, but laboratory studiesto obtain supportive evidence and efforts to exclude
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 MEDICAL PROGRESS
  Volume 343Number 13
 ·
 939
 
Figure 1.
 
MRI Scans of the Brain of a 25-Year-Old Woman with Relapsing–Remitting Multiple Sclerosis.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). Afterthe administration of gadolinium, many of the lesions demonstrate ring or peripheral enhancement, indicating the breakdown ofthe blood–brain barrier (Panel C). In Panel D, a parasagittal T
 
1
 
-weighted MRI scan shows multiple regions in which the signal isdiminished (referred to as “black holes”) in the periventricular white matter and corpus callosum. These regions correspond to thechronic lesions of multiple sclerosis.
BACD
Downloaded from www.nejm.org on September 26, 2009 . Copyright © 2000 Massachusetts Medical Society. All rights reserved.
 
 940
 ·
 September 28, 2000
 The New England Journal of Medicine
 other, potentially treatable illnesses are advised; forexample, structural or metabolic myelopathy can beidentified by appropriate laboratory studies, includingspinal MRI (Table 1). On MRI, findings of multifo-cal lesions of various ages, especially those involvingthe 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 presumedinflammatory demyelination (active lesions). When there is diagnostic uncertainty, repeatedMRI after several months may provide evidence thatthe lesions are “disseminated in time.” Cerebrospi-nal fluid analysis often shows increased intrathecalsynthesis of immunoglobulins of restricted specifici-ty (oligoclonal bands may be present, or the synthesisof IgG may be increased), with moderate lympho-cytic pleocytosis (almost invariably there are fewerthan 50 mononuclear cells). Physiologic evidence of subclinical dysfunction of the optic nerves and spinalcord (changes in visual evoked responses and soma-tosensory evoked potentials) may provide supportfor the conclusion that there is “dissemination inspace.”
 7
 Therefore, spinal MRI and evoked-potentialtesting may provide evidence of a second lesion thatcan confirm the diagnosis. Abnormalities detectedby testing of somatosensory evoked potentials andspinal MRI may clarify the diagnosis in patients withoptic 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 evokedresponses may support the diagnosis of multiple scle-rosis in patients with isolated brain-stem or spinalcord lesions.The course of multiple sclerosis in an individualpatient is largely unpredictable. Patients who have aso-called clinically isolated syndrome (e.g., optic neu-ritis, brain-stem dysfunction, or incomplete transversemyelitis) as their first event have a greater risk of bothrecurrent events (thereby confirming the diagnosisof clinically definite multiple sclerosis) and disability  within a decade if changes are seen in clinically asymp-tomatic regions on MRI of the brain.
 8
 The presenceof oligoclonal bands in cerebrospinal fluid slightly in-creases the risk of recurrent disease.
 9
 Studies of the natural history of the disease haveprovided important prognostic information that isuseful for counseling patients and planning clinicaltrials.
 4,10,11
 Ten percent of patients do well for morethan 20 years and are thus considered to have benignmultiple sclerosis. Approximately 70 percent will havesecondary progression.
 4
 Frequent relapses in the firsttwo years, a progressive course from the onset, malesex, 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-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, evenfor young patients with mild symptoms.
 12
 EPIDEMIOLOGIC FEATURES
 The prevalence of multiple sclerosis varies consid-erably around the world.
 13
 Kurtzke classified regionsof the world according to prevalence: a low preva-lence was considered less than 5 cases per 100,000persons, an intermediate prevalence was 5 to 30 per100,000 persons, and a high prevalence was morethan 30 per 100,000 persons.
 14
 The prevalence ishighest in northern Europe, southern Australia, andthe middle part of North America. There has been
 *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 humanT-cell lymphotropic virus type 1.‡In many patients with these variants, clinically definite multiple sclerosisdevelops or the course is indistinguishable from that of multiple sclerosis.
 T
 ABLE
 1.
 D
 IFFERENTIAL 
 D
 IAGNOSIS
 
OF
 M
 ULTIPLE
 S
 CLEROSIS
 .
 Metabolic disorders
 Disorders of B
 
12
 metabolism*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,* Lymedisease, meningovascular syphilis, Eales’ disease
  Vascular disorders
 Spinal dural arteriovenous fistula*Cavernous hemangiomataCentral nervous system vasculitis, including retinocochlear cerebral vasculitisCerebral autosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy 
 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 ataxiasSpondylotic and other myelopathies*
 Psychiatric disorders
 Conversion reaction, malingering
 Neoplastic diseases
 Spinal cord tumors,* central nervous system lymphomaParaneoplastic disorders
  Variants of multiple sclerosis
 ‡Optic neuritis; isolated brain-stem syndromes; transverse myelitis; acutedisseminated encephalomyelitis, Marburg disease; neuromyelitis optica
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