cme multiple sclerosis: advances in understanding, diagnosing, and

CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006 91

ROBERT J. FOX, MD*

Medical Director, Mellen Center for MultipleSclerosis Treatment and Research,Department of Neurology, The ClevelandClinic Foundation; Cleveland Clinic LernerSchool of Medicine, Case Western ReserveUniversity, Cleveland

FRANCOIS BETHOUX, MD†

Mellen Center for Multiple SclerosisTreatment and Research, Department ofNeurology, The Cleveland Clinic Foundation

MYLA D. GOLDMAN, MDMellen Center for Multiple SclerosisTreatment and Research, Department ofNeurology, The Cleveland Clinic Foundation

JEFFREY A. COHEN, MD‡

Mellen Center for Multiple SclerosisTreatment and Research, Department ofNeurology, The Cleveland Clinic Foundation

Multiple sclerosis: Advancesin understanding, diagnosing,and treating the underlying disease

REVIEW

■ ABSTRACT

Recent advances in our understanding of the diagnosis,imaging, pathology, and clinical monitoring of multiplesclerosis (MS) have significantly increased our ability tosuccessfully treat this often perplexing neurologicdisorder. Magnetic resonance imaging (MRI) is nowintegral to the diagnostic process. Treatment of MS canbe considered as three parallel pathways: treatment ofrelapses, symptom management, and long-termprevention of tissue injury.

■ KEY POINTS

Although MS often has a benign initial clinical course,pathological studies have found significant axonal injuryand tissue loss early in the disease.

Symptoms of MS can be subtle and are sometimesconfused with those of other disorders or are simplyattributed to emotional distress.

MRI has aided the diagnosis and management of MS andis a key outcome measure in early-phase clinical trials in MS.

Although corticosteroids are most effective immediatelyafter the onset of symptoms, we have often found them tobe at least partially effective when given several weeks—or even months—after the onset of clinical symptoms.

The choice of disease-modifying therapies remains aclinical judgment that involves consideration of patientpreference and concurrent symptomatic issues, includingspasticity, depression, or headaches.

Editor’s note: This review covers advances inthe pathophysiology, diagnosis, imaging, andtreatment of the underlying disorder. In a sep-arate article next month, the same authorswill address in greater detail the managementof the symptoms of multiple sclerosis.

DVANCES in diagnosis, imaging, patholo-gy, and clinical monitoring have signifi-

cantly improved our understanding of multi-ple sclerosis (MS). These advances have sup-ported the development of many effectivetherapies for MS that appear to slow the dis-ease course.

Although there have been setbacks in thedevelopment of therapies for relapsing-remit-ting MS and although there remains a paucityof treatments for progressive forms of MS, thefuture promises new hope for patients andclinicians struggling with this disease.

■ A DISEASE OF YOUNG ADULTS

MS, a chronic disorder affecting the brain,spinal cord, and optic nerve, is the leadingcause of nontraumatic disability among youngadults. About 300,000 to 350,000 people are

A

*Dr. Fox has indicated that he has served as a consultant or lecturer for theAccorda Therapeutics, Biogen Idec, Genentech, Merck, QuestorPharmaceuticals, Serono, and Teva Neuroscience corporations.†Dr. Bethoux has indicated that he has served as a lecturer for the BiogenIdec corporation.‡Dr. Cohen has indicated that he has served as a consultant for the BiogenIdec and Teva Neuroscience corporations and has received research supportfrom the Biogen Idec corporation.This work was supported by grants from the National Institutes of Health(NINDS K23 NS 47211 to RJF), National MS Society (RG 33548A2 to RJF, FP1521-A-1 to MDG), the Nancy Davis Center Without Walls (RJF and JAC),and Potiker Fellowship (MDG).

CREDITCME

on October 30, 2021. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

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92 CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 73 • NUMBER 1 JANUARY 2006

estimated to have MS in the United States,incurring a cost of about $10 billion per year.1Up to 2 million people are affected world-wide. Women with MS outnumber men by 2to 1. Symptoms typically first develop in thethird or fourth decade, but progressivemyelopathy due to previously unrecognizedMS may not manifest until the seventh oreighth decade.

■ SYMPTOMS VARY

MS inflammation can occur anywhere in thebrain, spinal cord, or optic nerve, and theresulting symptoms can involve a single neu-rologic function or a combination of them.

Sensory symptoms are among the mostcommon presenting symptoms of MS.2Sensory symptoms can consist of an absence ofsensation (frank numbness) or can involvepositive, uncomfortable sensations, includingpain or tingling (paresthesias). Numbness isusually vague and difficult for patients todescribe, occasionally being severe enough toimpair functional use of an arm or leg despiteexcellent strength and coordination. Sensoryexamination is often normal, which con-tributes to the frequent misattribution of thesesymptoms to emotional distress.

Motor symptoms in MS typically involveweakness and spasticity. Weakness is usuallyaccompanied by numbness, and spasticityoften manifests during the recovery period fol-lowing an exacerbation. Spasticity can alsodevelop without a previously recognizedepisode of weakness, particularly in the legs.

Coordination abnormalities can includedifficulties in hand dexterity or gait. Gait dif-ficulties can develop from weakness, dyscoor-dination, spasticity, sensory loss, or a combi-nation of any of these symptoms.

Visual difficulties are another commonpresentation of MS. Optic neuritis arises frominflammation of the optic nerve, and visualdeficits can vary from subtle visual distortionto complete visual loss. Retro-orbital pain orsoreness with eye movement is common.Ocular dyscoordination from focal brainsteminflammation (most typically an internuclearophthalmoplegia) causes diplopia that resolveswhen either eye is covered.

Bladder dysfunction. MS plaques in the

spinal cord commonly cause bladder overac-tivity, which can manifest as frequency orurgency. Bladder function can also be under-active, with failure to properly store andempty.

Bowel symptoms of urgency and consti-pation are also common.

Sexual dysfunction can include erectiledysfunction in men and altered libido andgenital sensation in both men and women.

Cognitive dysfunction can occur through-out the disease course and often involves prob-lems with concentration, processing speed,executive function (eg, planning), and visuo-spatial abilities. Formal neuropsychologicaltesting can help identify specific deficits and ishelpful to clarify a patient’s self-report of cog-nitive symptoms or to document impairment.Depression is common and can present withprimarily cognitive symptoms.

Fatigue is reported by up to 90% of MSpatients and is very common at the time ofdiagnosis. Fatigue may refer to early musclefatigue with exertion or generalized lassitudeindependent of exertion. Paradoxically, symp-toms of fatigue are inversely proportional tothe degree of clinical disability and theamount of brain injury measured on magneticresonance imaging (MRI).3

■ DISEASE CLASSIFICATIONS

MS is classified on the basis of both the initialand the current clinical disease course. Theseclassifications do not represent separate anddistinct disease pathophysiologies, but ratherprovide a framework for organizing anapproach to diagnosis and long-term manage-ment. The disease course and tempo varytremendously among patients.

Relapsing-remitting MSAbout 85% of MS patients experience relaps-ing neurologic symptoms during their initialdisease course, and this form is called relapsing-remitting MS.4 During episodes of inflamma-tion, acute symptoms typically develop overseveral days, become maximal after 1 to 2weeks, and gradually resolve over severalweeks or months. Residual symptoms may per-sist indefinitely, especially sensory symptoms.Patients presenting with only a single isolated

Up to 90%of MS patientsreport havingfatigue

MULTIPLE SCLEROSIS FOX AND COLLEAGUES



episode of inflammation are classified as hav-ing a clinically isolated syndrome.

Secondary progressive MSAfter 10 to 20 years of relapsing-remitting MS,intermittent relapses typically become infre-quent and are usually replaced by gradual wors-ening of neurologic symptoms over months toyears.5 This stage, called secondary progressiveMS, probably represents a neurodegenerativeprocess initiated by earlier episodes of tissueinjury (FIGURE 1). Clinical relapses can stilloccur during secondary progressive MS, partic-ularly during the early transition from relaps-ing-remitting to secondary progressive MS.

Primary progressive MSAbout 15% of MS patients present with grad-ually progressive neurologic symptoms fromthe onset, called primary progressive MS. Thisgroup is probably a mixture of patients withsecondary progressive MS in whom previousfoci of inflammation did not affect white mat-ter areas that would cause symptoms if affect-ed or in whom clinical relapses were not rec-ognized or remembered. Other patients withprimary progressive MS probably have a pri-mary neurodegenerative process with sec-ondary inflammation.

Devic diseaseInflammation restricted to the optic nerve andspinal cord and sparing the brain is called neu-romyelitis optica, or Devic disease. It remainsdebated whether Devic disease is a separateentity from MS or simply an MS variant.

Recent studies have identified an antibodythat binds brain microvessels and meninges,called NMO-IgG, and this antibody appears tobe a sensitive and specific indicator of Devicdisease.6 Identification of this specific anti-body implicates a primary humoral immunemechanism in Devic disease.

■ DIAGNOSIS BASED ONMULTIPLE EPISODES

Although several diagnostic criteria for MShave been used over the last several decades,they are all unified by the underlying conceptof multiple episodes of inflammation dissemi-nated in time and space.

The diagnostic criteria for MS wereupdated recently and now incorporate MRI ofthe brain and spine and other paraclinicaltesting to fulfill the “dissemination in timeand space” criteria for definite MS (TABLE 1).7Specifically, after a single clinical episode ofinflammation such as optic neuritis, a newMRI lesion 3 months or more after the firstMRI fulfills the requirement for disseminationin time. Although somewhat complicated,these updated criteria have increased sensitiv-ity in diagnosing MS at an early stage.

MRI is an important toolMRI is an important tool in evaluating MSpatients. Affected patients typically have mul-tiple hyperintense lesions in the cerebralwhite matter on T2-weighted images.

However, T2 lesions in the deep cerebralwhite matter and anterior and posterior to the


Preclinicalphase

Relapsing-remitting phase

Secondary progressive phase

Brain volume

MRI activity

? years 10-20 years 20 + years

Disease burden

Clinical disability

FIGURE 1. Typical clinical and magnetic resonanceimaging (MRI) course of multiple sclerosis. MRI activity(vertical arrows) indicates an inflammatory lesionmeasured on brain MRI. MRI activity typically is morefrequent than clinical relapses (spikes in clinicaldisability). Loss of brain volume, or atrophy, is measuredon MRI and indicates permanent tissue damage.Atrophy is observed early in the disease and continuesto progress after inflammatory activity has becomequiescent. The early inflammatory activity is thought tobe replaced later by a neurodegenerative process.

ADAPTED FROM FOX RJ, COHEN JA. MULTIPLE SCLEROSIS: THE IMPORTANCE OF EARLYRECOGNITION AND TREATMENT. CLEVE CLIN J MED 2001; 68:157–170.

Natural history of multiple sclerosis




lateral ventricles are not specific for MS andare often seen in many other conditions,including vascular disease (hypertension, dia-betes), migraine, and aging. Lesions are morespecific for MS if they are in the corpus callo-sum, juxtacortical area, brainstem, or adjacentto the body of the lateral ventricles.

Lesions are often round or ovoid, orient-ed perpendicularly to the lateral ventricle (FIG-

URE 2) and are also referred to as “Dawson fin-gers.” Active inflammatory lesions demon-

strate gadolinium enhancement, which indi-cates breakdown of the blood-brain barrier.Cumulative inflammatory tissue injury leadsto tissue destruction, which can be appreciat-ed on imaging as spinal cord and brain atro-phy.

Atypical presentationsSome patients present without specific symp-toms of an MS relapse but have classic MRIfindings of MS. Cerebrospinal fluid studies

The updatedcriteria haveincreasedsensitivity indiagnosingMS at anearly stage

International Panel criteriafor the diagnosis of multiple sclerosis

CLINICAL PRESENTATION ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS

Two or more attacks; Noneobjective clinical evidenceof 2 or more lesions

Two or more attacks; Dissemination in space, demonstrated by:objective clinical evidence MRI,* orof 1 lesion 2 or more MRI lesions plus positive CSF, or

Another clinical attack

One attack; Dissemination in time, demonstrated by:objective clinical evidence New MRI lesion, orof 2 or more lesions Second clinical attack

One attack; Dissemination in space, demonstrated by:objective clinical evidence MRI,* orof 1 lesion Two or more MRI lesions plus positive CSF;(clinically isolated syndrome) And dissemination in time, demonstrated by:

New MRI lesion, orSecond clinical attack

Insidious neurologic progression Positive CSF, and dissemination in space, demonstrated by:suggestive of MS ≥ 9 brain lesions, or(ie, primary progressive MS) ≥ 2 spinal cord lesions, or

4–8 brain lesions and 1 spinal cord lesion;or

Abnormal visual evoked potentials, and 4–8 brain lesions;or

> 4 brain lesions plus 1 spinal cord lesion; orDissemination in time, demonstrated by MRI;

orContinued progression for 1 year

MRI = magnetic resonance imaging, CSF = cerebrospinal fluid*MRI criterion for dissemination in space is a single gadolinium-enhancing lesion or nine T2 lesions, in appropriate locations

FROM MCDONALD WI, COMPSTON A, EDAN G, ET AL. RECOMMENDED DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS: GUIDELINES FROM THEINTERNATIONAL PANEL ON THE DIAGNOSIS OF MULTIPLE SCLEROSIS. ANN NEUROL 2001; 50:121–127.

T A B L E 1




and visual evoked potentials can further sup-port the diagnosis of MS in these patients.

Diagnostic criteria continue to requirethat alternative diagnoses are excluded.Therefore, the diagnosis of MS is ultimately aclinical decision that involves weighing fac-tors that support it and those that fail to sup-port it or point to the possibility of an alter-native diagnosis.

A limitation in even the most recentdiagnostic criteria is that patients with a clin-ical isolated syndrome with multiple lesionson a single brain MRI do not fulfill the dis-semination-in-time criteria. However, severalclinical trials have demonstrated that thesepatients may benefit from MS therapies,8,9

and so clinical judgment is particularly impor-tant when evaluating and treating patients atthis very early stage of disease.

Excluding other diagnosesThere is little consensus about which addi-tional studies, particularly blood tests, shouldbe obtained to exclude other diagnoses. Thedifferential diagnosis for a patient with symp-toms suggestive of MS is extensive, but mostcan be excluded on the basis of clinical andradiologic assessments.

Routine laboratory studies could includemeasuring vitamin B12 and thyroid-stimulat-ing hormone levels, serologic testing forsyphilis, and a complete blood cell count.The antinuclear antibody (ANA) titer anderythrocyte sedimentation rate are useful toscreen for connective tissue disorders,although a low-positive ANA titer can beseen in approximately 25% of MS patientsand appears to have no impact on the long-term disease course.10 Lyme disease titerscan be useful in the appropriate geographicsetting.

■ PATHOPHYSIOLOGY:INJURY OCCURS EARLY

Most clinical relapses are followed by a full ornearly full recovery over the ensuing weeks ormonths, particularly early in the disease.Previously, this clinical improvement wasthought to reflect remyelination, and notuntil the secondary progressive MS stage wasthis cycle of inflammation and recoverythought to break down. In the past decade,however, pathologic studies have revealed sig-nificant permanent tissue injury during theinitial stages of inflammation.


Laboratorystudies forsuspected MScould includevitamin B12,TSH, syphillisserology, CBC,ANA, and ESR

FIGURE 2. Typical T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI imagesfrom an MS patient, illustrating different types of cerebral lesions.

Periventricular

More specific for MS Nonspecific for MS

Subcortical Deep whitematterPerpendicular

to ventricle

Anterior/posteriorhorns of lateralventricle




In acute inflammatory lesions, there is anaverage of 11,000 transected axons per mm3,compared with an average of 1 transectedaxon per mm3 in unaffected controls.11 Mosttissue injury occurs early in the disease courseand can involve the spinal cord and cerebralgray matter.12,13 Gray matter involvementbroadens the previous concept of MS as a“white matter disease.”

Functional MRI studies have revealedincreased cortical recruitment during simplemotor tasks in MS patients. Even in patientswith only a single episode of transversemyelitis and minimal brain lesions, therecan be significant functional reorganizationof the cerebral cortex.14 These functionalMRI studies suggest that recovery from aclinical relapse may involve more than justremyelination. Accordingly, secondary pro-gressive MS may develop when multifocaltissue injury outstrips this compensatoryadaptation.

Pathologic studies have also helped us tounderstand secondary progressive MS. Themyelin sheath is an extension of oligoden-drocytes, and axons denuded of their myelinsheath probably have impaired survival.Oligodendrocyte progenitor cells are locatedin the periventricular regions and canmigrate into areas of tissue injury andreplace injured myelin sheath. In some

patients, these cells can successfully remyeli-nate, while in others these cells extendprocesses to the axons but are unable toproperly remyelinate (FIGURE 3). Importantly,these cells can be observed after decades ofdisease, so improving their ability toremyelinate is a potential therapeutic targetin secondary progressive MS.

Previous models of MS implicated a T-cell pathogenesis, but there is growingrecognition of monocyte, macrophage, andhumoral mechanisms. Other pathologicstudies have described specific, stereo-typed immunopathologies within inflam-matory lesions of MS patients that utilizevarious components of the immune sys-tem.15 Despite pathologic heterogeneitybetween patients, individual patients tendto demonstrate only one immunopatholo-gy within all of their lesions. These differ-ent immunopathologies may explain thedifferential response to MS treatmentsbetween patients, although methods toidentify a patient’s specific immunopathol-ogy short of brain biopsy have not yet beendeveloped.

The immune targets in MS have remainedelusive. Cross-reactivity between an infectiousagent and endogenous central nervous systemprotein is suspected, but no single agent hasbeen conclusively demonstrated.16

Different MSpatients havedifferentimmuno-pathologicprocesses

FIGURE 3. A premyelinating oligodendrocyte (red) showing effective myelination (arrows,left), and another showing ineffective remyelination despite appropriate axial extensions.Scale bar represents 20 µm.

FROM CHANG A, TOURTELLOTTE WW, RUDICK R, TRAPP BD. PREMYELINATING OLIGODENDROCYTES IN CHRONIC LESIONS OF MULTIPLE SCLEROSIS.N ENGL J MED 2002; 346:165–173.




■ CLINICAL MONITORING

MS Functional Composite scoreClinical monitoring is an ongoing challengein the management of MS patients. Since MSaffects almost all neurologic functions, it isvery difficult to quantify clinical impairmentand monitor therapeutic efficacy.

A task force of the National MultipleSclerosis Society developed a new clinicalmeasure called the MS Functional Composite(MSFC),17 composed of measures of ambula-tion, arm and hand function, and cognition.Results from the three individual measures arecombined into a single composite score.Studies have found that the MSFC has greaterreliability, sensitivity, and statistical validitythan the traditional Kurtzke ExpandedDisability Status Scale (EDSS), and theMSFC has been used successfully in severallarge clinical trials to measure disability.18 Thequalitative tests that make up the MSFC alsocan be useful for following individual patientsin clinical practice.

MRI for monitoring disease activityMRI is a useful tool to monitor ongoing dis-ease activity in MS patients and has beenintegrated into general clinical practice.Gadolinium-enhancing lesions and new T2

lesions are typical primary outcomes of phaseII clinical trials in relapsing-remitting MS. Inclinical practice, MRI can confirm diseaseactivity in patients for whom disease activityis unclear, and persistent MRI activity afterstarting MS medications can predict long-term clinical activity.19

Advanced methods of MRI, ie, diffusiontensor imaging, magnetization transfer imag-ing, and spectroscopy, hold promise in assess-ing tissue injury more accurately and in char-acterizing its recovery following treatment.

■ TREATING RELAPSES AND SYMPTOMSAND PREVENTING TISSUE INJURY

Treatment of MS can be considered as threeparallel pathways: treatment of relapses,symptom management, and long-term pre-vention of tissue injury. Effective manage-ment of MS should include consideration ofeach of these three areas. We will discusssymptom management in detail in a separatearticle in this journal.20

Treatment of MS relapsesThe neuronal injury in acute MS lesions wasnot previously appreciated because mostrelapses are followed by complete clinicalrecovery, even without treatment with acute


The MSFC scorecombinesmeasuresof ambulation,arm and handfunction,and cognition

Common side effects of high-dose corticosteroids

Metallic taste—candy may help

Insomnia—over-the-counter sleep aids and short-acting benzodiazepines can be helpful

Altered mood—nervousness, restlessness, irritability; rarely, mania

Indigestion/heartburn—minimize aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), caffeine

Fluid retention—minimize salt intake

Potassium depletion (muscle weakness, fatigue)—increase dietary potassium if necessary(eg, bananas, orange juice)

Flushing in face, neck, or chest

Tachycardia

Headaches—use acetaminophen; avoid aspirin and NSAIDs because of possible gastritis

Acute adrenal insufficiency—very rare, but may be prevented by oral prednisone taper

Avascular necrosis—very rare

T A B L E 2




anti-inflammatory therapy. Controlled trialshave found that corticosteroid treatment has-tens recovery, and that high-dose cortico-steroids are more effective than moderate-doseregimens.21,22

Although corticosteroids are most effec-tive immediately after the onset of symptoms,we have often found them to be at least par-tially effective when given several weeks—oreven months—after the onset of clinicalsymptoms. The risks from a short exposure tocorticosteroids appear to be reasonable rela-tive to the benefits, although side effects fromcorticosteroids are common (TABLE 2).

Infections can precipitate relapses andblunt the effectiveness of corticosteroids.

Bladder infections are particularly common.Physical therapy can also be beneficial duringrecovery from a clinical relapse.

Corticosteroid dose. The optimal dose ofcorticosteroids is unknown, but our typicalpractice is to give a 3-day course of methyl-prednisolone 1,000 mg intravenously daily,followed by a 12-day prednisone taper.Extending the methylprednisolone course canbe considered, particularly if there is a poorresponse to the initial 3-day course or if pro-longed treatment was necessary previously.There is evidence that equivalent doses of oralcorticosteroids have acceptable pharmacoki-netics and tolerability, but definitive studies ofthis route of administration are lacking.23

Brief description of MS therapiesapproved by the US Food and Drug Administration

INTERFERON BETA-1 (Avonex, Betaseron, Rebif)Identical or nearly identical to human interferon beta-1Alters inflammatory response through specific receptorsInjection:

Avonex (intramuscular injection once a week)Betaseron (subcutaneous injection every other day)Rebif (subcutaneous injection three times a week)

Common adverse effectsFlu symptoms—myalgia, fever, fatigue, chillsSkin reaction (subcutaneous preparations only)Antibodies (with subcutaneous more than intramuscularpreparations)

Uncommon adverse effectsAminotransferase elevationsAnemiaDepression

Pregnancy category C

GLATIRAMER ACETATE (Copaxone)Complex random mixture of four polypeptides: ala, glu, lys, tyrPotential immunochemical mimic of myelin proteinsAlters antigen-specific immune responseInjection: subcutaneous dailyCommon adverse effects

Skin reactionsUncommon adverse effects

Systemic reaction (chest pain, shortness of breath,palpitations, vasodilation)

AnaphylaxisPregnancy category B

MITOXANTRONE (Novantrone)Synthetic anthracenedioneInhibits DNA replication, which reduces immune cell

proliferationInfusion: once every 3 months to maximum dose of

100–120 mg/m2

Common adverse effectsBlue sclera, urineAlopecia (usually mild)NauseaLeukopenia

Uncommon adverse effectsDecreased cardiac functionMenstrual irregularitiesVomitingVery rarely: leukemia

Pregnancy category D

NATALIZUMAB (Tysabri)Monoclonal antibody that inhibits cell trafficking from

circulation into central nervous systemInfusion: monthlyCommon adverse effects

HeadacheFatigueArthralgia

Uncommon adverse effectsDepressionAllergic reactionsCholelithiasisProgressive multifocal leukoencephalopathy

Pregnancy category C

T A B L E 3




Similarly, the need for prednisone taperremains unknown.

Mild relapses. Some relapses involve onlymild sensory symptoms, which are not trou-blesome to the patient. Given the known tis-sue damage from MS inflammation, treatmentof these mild relapses could be considered,especially if there are new or enhancinglesions on MRI of the brain or spine.

Long-term MS therapiesFour medications approved by the US Foodand Drug Administration (FDA) are current-ly available as first-line therapy for relapsingremitting MS (TABLE 3):• Interferon beta-1a (two preparations:

Avonex 30 µg intramuscularly once aweek, and Rebif 44 µg subcutaneouslythree times a week)

• Interferon beta-1b (Betaseron 250 µg sub-cutaneously every other day)

• Glatiramer acetate (Copaxone 20 mg sub-cutaneously daily).24–27

Mechanism of action. The precise mecha-nism of action for each therapy is unknown.The interferon therapies may work by modulat-ing T cells and B cells and altering expression ofany of a number of cytokines. Glatirameracetate is a random polypeptide based on theamino acid structure of a myelin protein and ishypothesized to alter autoreactive regulatory Tcells, thereby suppressing immune responses tomyelin and other brain antigens.28

All four treatments are reasonable optionsfor initial treatment of relapsing-remittingMS. In phase III clinical trials, all of thesemedications decreased clinical relapses over 2years by about 30% and reduced the develop-ment of new brain lesions on MRI. Severaltrials were large enough to demonstrate areduction in progression of disability as mea-sured by the EDSS, and several therapies havebeen shown to slow the progression of brainatrophy.

Interferon dose. Some studies have sug-gested that high-dose, high-frequency inter-feron preparations (ie, Rebif, Betaseron) aremore effective than the low-dose, low-fre-quency preparation (Avonex), but this advan-tage appears to be limited to the first 6 monthsof treatment and disappears thereafter.29,30

High-dose, high-frequency interferon prepa-

rations are associated with a higher incidenceof skin reactions (redness, swelling, pain),aminotransferase elevations, anemia, andneutralizing antibodies. Therefore, theincreased initial efficacy of these preparationsneeds to be weighed against their tolerabilityand side effects as well as their similar long-term efficacy compared with the low-dose,low-frequency preparation. Accordingly, theoptimal interferon dose for long-term man-agement of relapsing remitting MS remainsunclear. All interferon preparations can wors-en spasticity, depression, and headaches.

Glatiramer acetate appears to modulatethe immune response more than it decreasesinflammation. Accordingly, it has a less robusteffect than interferons on imaging measures ofactive inflammation, despite a comparablereduction in clinical relapses. Glatirameracetate is not associated with aminotrans-ferase elevations, anemia, depression, neutral-izing antibodies, or worsening spasticity.Randomized, controlled trials comparing glati-ramer acetate to interferons are under way.

The choice of disease-modifying therapiesremains a clinical judgment that involvesconsideration of patient preference and con-current symptomatic issues, including spastic-ity, depression, or headaches.

ChemotherapyMitoxantrone (Novantrone) is a synthet-

ic anthracenedione with demonstrated effica-cy in several cancers. It arrests the cell cycleand interferes with DNA repair and RNAsynthesis.

Mitoxantrone is effective in reducingclinical relapses and progression of disabilityin patients with worsening relapsing-remittingMS and secondary progressive MS.31 Becausethere is little inflammation in the later stagesof secondary progressive MS, the use of mitox-antrone in secondary progressive MS is gener-ally targeted to patients in its early stages whohave ongoing inflammation (ie, clinicalrelapses or gadolinium-enhancing lesions onbrain MRI). Mitoxantrone is labeled for intra-venous infusion every 3 months, althoughmonthly induction for 3 months is sometimesused in very active disease.

Mitoxantrone-associated cardiotoxicityincludes decreased ejection fraction and con-


Interferon betaand glatirameracetatereduced clinicalrelapses over2 years byabout 30%




gestive heart failure. The risk of cardiotoxicityappears proportional to the total lifetime,cumulative dose of the medication, but canoccur at any time during mitoxantrone treat-ment.32 Multiple gated acquisition scanning(MUGA) or echocardiography should be per-formed prior to each infusion of mitoxantroneto monitor ejection fraction. Mitoxantroneshould not be given if there is a decrease in theejection fraction to below 50% or a 5% ormore decline from baseline measures, exceptin consultation with a cardiologist.

Blood cancers, particularly secondaryacute myelogenous leukemia, have been rarelyassociated with mitoxantrone.

Because of these adverse effects, mitox-antrone is usually reserved for patients whohave not responded sufficiently to or couldnot tolerate interferon beta-1 and glatirameracetate treatments.

Cyclophosphamide (Cytoxan) is an alky-lating agent related to nitrogen mustards andhas been used extensively in various autoim-mune disorders, including MS.33 A recentplacebo-controlled trial combining monthlycyclophosphamide and corticosteroids withinterferons has confirmed its efficacy in reduc-ing clinical relapses and MRI lesions.34

Common side effects include mild to moder-ate alopecia, infertility, nausea, and infections.Uncommon complications include hemor-rhagic cystitis, bladder cancer, and possiblyother cancers. Aggressive hydration can mini-mize cystitis, and bladder cancer screeningshould be considered with chronic use.

Oral chemotherapies. Methotrexate(Rheumatrex) and azathioprine (Imuran) aresometimes used when standard therapies areineffective, although data from controlledclinical trials are scant. The preferential effectof azathioprine on the humoral immune sys-tem has led to its frequent use in Devic dis-ease. Mycophenolate mofetil (Cellcept),another oral agent, has shown reasonable effi-cacy and tolerability in preliminary studies.35

Treating breakthrough disease activityAlthough there is general consensus thatpatients with relapsing MS should considertreatment with one of the four injectableimmunomodulating medications,36,37 there islittle consensus on the appropriate treatment

for patients who demonstrate breakthroughdisease activity on a standard MS therapy.Even the definition of breakthrough diseaseactivity is not clear, although most cliniciansintegrate clinical relapse rate, recovery fromrelapses, and MRI measures of ongoing inflam-mation (gadolinium-enhancing lesions or newT2 lesions) into this judgment.

Treatment options for patients withbreakthrough disease activity include switch-ing from one injectable therapy to anotherand adding medications with or without aninjectable therapy (ie, bimonthly pulse intra-venous methylprednisolone, oral methotrex-ate, mycophenolate mofetil, or azathioprine).Several large clinical trials are evaluatingthese combination therapy approaches.Treatment with intravenous chemotherapysuch as mitoxantrone or cyclophosphamidecan also be considered.

NatalizumabNatalizumab (Tysabri) is a monoclonal anti-body that blocks very late antigen-4 (VLA-4),which is a cell-trafficking adhesion moleculeon the surface of circulating leukocytes. Twolarge clinical trials found that natalizumabreduced the clinical relapse rate by 53% to68% over 2 years, and also reduced the pro-gression of clinical disability and developmentof new brain lesions on MRI.38–40

Safety. Initial safety reports indicated thatnatalizumab was generally well tolerated.Allergic hypersensitivity (ie, generalizedurticaria) was occasionally observed (in 1.7%to 4.0%), with about half of the reactionsdeveloping after the second infusion.However, natalizumab was withdrawn fromclinical use 3 months after its initial FDAapproval because of two cases of progressivemultifocal leukoencephalopathy (PML) dur-ing the patients’ 3rd year of natalizumab ther-apy.41,42 A third case of PML was identified ina patient treated in a clinical trial for Crohndisease.43

PML is a demyelinating brain disordercaused by the ubiquitous JC virus. In the set-ting of immune compromise (ie, solid-organtransplantation, late-stage acquired immunedeficiency syndrome), the JC virus infects thebrain and causes widespread demyelinationand tissue destruction. In most cases, PML is


MUGA or echoshould bedone beforeeachmitoxantroneinfusion tomonitorejectionfraction



fatal, although correcting the immunosup-pressed state has stabilized some patients withPML. The magnitude of PML risk, treatmentoptions, and long-term prognosis for MSpatients developing PML in association withnatalizumab remain unclear.

Natalizumab is significantly more effec-tive than the interferon or glatiramer acetatetherapies, but also has potentially fatal com-plications. The experience with natalizumabhighlights the potential risks for rare andunanticipated serious complications fromnovel, potent therapies. Natalizumab wasapproved by the FDA under both expeditedreview and accelerated approval processes,leading to discussion of whether these reviewmechanisms are appropriate for novel treat-ments. However, PML was not detected dur-ing several large-scale pivotal trials but onlyduring the open-label safety extension study.Therefore, we feel this experience probablyattests more to the importance of detailed,long-term safety follow-up studies and theneed for a more comprehensive post-market-ing surveillance system than to the perils ofaccelerated FDA review.

Treatment of progressive MSTreating progressive forms of MS, includingsecondary progressive MS and primary pro-gressive MS, has remained a challenge.Clinical trials of interferon beta-1 therapieshave produced mixed results depending on thestage of secondary progressive MS: the earlierstage of secondary progressive MS appears torespond better, while the middle and laterstages responsed only minimally. These resultsconform to the emerging degenerative patho-genesis concepts of secondary progressive MS.

Clinical trials of anti-inflammatory thera-pies in primary progressive MS have been sim-ilarly disappointing. Intermittent pulses ofhigh-dose corticosteroids or weekly oralmethotrexate are sometimes effective in slow-ing the course of progressive disease, and sev-eral randomized clinical trials support theiruse in this setting.44–46

Future therapies in MSAdvances in our understanding of theimmunopathogenic mechanism of MS havespurred the development of many novelapproaches to treating MS.47 Generalimmunosuppressants are associated with wide-spread immunosuppression and generallyunfavorable safety profiles. Inhibiting anti-gen-specific immune activation requiresknowledge of the driving antigenic determi-nant, which remains unclear in MS and like-ly varies from patient to patient.

Despite the PML complication seen withnatalizumab, there remains great interest incell-trafficking approaches, including inhibi-tion of chemokine receptors such as CCR2, aswell as the lymphocyte receptor for sphingo-sine-1-phosphate. Previous attempts to neu-tralize immune effector mechanisms in MSsuch as TNF-alpha have been unsuccessful,but approaches targeting cytokine receptorsfor interleukin (IL)-1, IL-2, IL-12/23 appearpromising.

Identification of the NMO antibody hasfueled interest in humoral immune therapies,including the B-cell depletion therapy ritux-imab.48 Transplantation of hematopoieticstem cells constitutes an attempt to reset anaberrant immune system, but significant toxi-cities will limit this approach to only the mostsevere MS cases.

Oral therapies for long-term MS treat-ment remain elusive, but several potentialapproaches have emerged. Statin medicationsaffect immune cell signaling pathways, and iffound to be effective, could rapidly be inte-grated into current treatment.

Treatment of progressive MS will likelyrequire neuroprotective approaches, andthese may be beneficial in early disease, too.Neurotrophic cytokines, erythropoietin,and corticosteroids all show potential effi-cacy as neuroprotective therapies. However,clinical trial methodology to screen candi-date therapies and eventually provide con-vincing evidence for efficacy has not beenestablished.


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ADDRESS: Robert J. Fox, MD, Mellen Center, U10, The Cleveland ClinicFoundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected].





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