Multiple Sclerosis - LiveWiseMS...Chapter 11 Multiple Sclerosis 193 1845. Charcot is generally credited with the first comprehensive account of the clinical and pathologic features

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PETER A. CALABRESI AND SCOTT D. NEWSOME

11 Multiple Sclerosis

k e y p o i n t s

• Multiple sclerosis (MS) is an immune-mediated,multiphasic, mutifocal disease of the central nervoussystem.

• The primary etiology of MS is unknown; however, thedisease has features of inflammation, demyelination,axonal injury, and neurodegeneration.

• Visual dysfunction, sensory disturbances, and gaitimpairment are very common presenting symptoms.

• MRI is the single most useful test in confirming thediagnosis of MS.

• Early and accurate diagnosis is paramount.

• Initiating early disease-modifying treatment caninfluence the clinical course.

• Symptomatic therapy can greatly improve MS patients’quality of life.

ultiple sclerosis(MS) is a neurodegenerative disease with earlyintense inflammation of the central nervoussystem (CNS). The primary etiology of MS re-mains unknown and is likely multifactorial.The disease is characterized pathologically byinflammatory infiltrates and demyelination,followed by varying degrees of secondary ax-onal degeneration.

■ SPECIAL CLINICAL POINT: Multiplesclerosis is the most common nontraumaticcause of neurologic disability in young adultsand affects approximately 400,000 people in theUnited States. An estimated 200 people perweek are newly diagnosed.

MS affects women two to three times morecommonly than men. Most patients start with

a period of unpredictable relapses and remis-sions, which in the majority is followed by anaccumulation of neurologic dysfunction and achronic progressive course. The life expectancyhas been shown to be only 6 to 7 years lessthan that for a control population without MS,but the emotional and economic cost to societyas a result of the disability is enormous.

HISTORY

The earliest account of a disease that appearslikely to have been MS is found in writingsfrom the 14th century, describing the illness ofa Dutch nun, “Blessed Lidwina of Schiedam.”The earliest pathologic descriptions by Carswelland Cruveilhier date to between 1838 and

M

Chapter 11 Multiple Sclerosis■

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1845. Charcot is generally credited with thefirst comprehensive account of the clinical andpathologic features of MS, which was pub-lished in 1868.

EPIDEMIOLOGY

Epidemiologic studies have shown that MS hasan unequal geographic distribution, with largeregional and ethnic variations in the prevalenceof disease (Fig. 11.1). MS is rare in the tropicsand increases in frequency at higher latitudesnorth and south of the equator. The prevalencein the United States is reported at 57.8 per100,000 and is almost twice as common in theNorthern as compared to the Southern UnitedStates. The prevalence rate has been increasing,probably because of better recognition of MSand improved treatment of complications witha correspondingly increased longevity ofthose affected. Prevalence rates of less than5 per 100,000 are found in Asia, Africa (exceptEnglish-speaking whites in South Africa), andnorthern South America. MS is also said to bemuch less common among Eskimos, Gypsies,and African Americans. However, these pat-terns may be changing with increased travel;cases of MS have been reported in nativeAfricans who have not traveled out of the

country, and the prevalence of African Americanswith MS has not been reexamined adequatelyin the magnetic resonance imaging (MRI) eraof diagnosis.

Migration studies suggest that the risk of ac-quiring MS is related to the location in whichone has lived before puberty. Individuals migrat-ing from high- to low-risk areas decreased theirexpected risk of developing MS, as determinedfrom their area of birth. Conversely, migrationfrom low- to high-risk areas increased the risk ofacquiring MS. The reliability of migration stud-ies has been questioned, and no definite conclu-sions can be made from these data.

Numerous instances of MS clusters havebeen reported. Several clusters have been re-lated to exposure to heavy metals and caninedistemper virus, but no conclusive link hasbeen established. Genetic studies strongly sug-gest that the disease is polygenic and that ge-netic factors may have a stronger influence indetermining susceptibility to MS than environ-mental factors.

PATHOLOGY OF MULTIPLE SCLEROSIS

Classic descriptions of the MS lesion as pre-dominantly demyelinating with relative spar-ing of axons still hold true today. Modern tools

FIGURE 11.1 Map of the world depicting areas of high prevalence (30+/100,000, solid), mediumprevalence (5–29/100,000, dotted), and low prevalence (0–4/100,000, dashed). White areas areregions without data or people. (From Kurtzke JF, Wallin MT. Epidemiology. In: Burks JS, Johnson KP,eds. Multiple sclerosis: diagnosis, medical management, and rehabilitation. New York: Demos MedicalPublishing; 2000. Reproduced with permission from Demos Medical Publishing.)


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have afforded more detailed descriptions of theimmunologic and structural events occurringwithin lesions and have reemphasized the sec-ondary axonal degenerative stage of the lesion.Major advances in the classification of MSpathology have been made from biopsy andrapid autopsy material. Clinicopathologic cor-relations using MRI and spectroscopy providehope that advances in our understanding of thepathologic state will allow guided therapeuticinterventions.

The MS plaque appears to begin with the mi-gration of lymphocytes and macrophages acrossthe blood–brain barrier into the perivenularspace (Fig. 11.2). This is followed by diffuseparenchymal infiltration by inflammatory cells,edema, and active stripping of myelin fromaxons by macrophages, leading to multifocalareas of demyelination (Fig. 11.3). Subsequently,astrocytic hyperplasia and the accumulation oflipid-laden macrophages ensue. As plaques enlarge and coalesce, the initial perivenular

FIGURE 11.2 Perivenular infiltrate typical of the early acute inflammatory event in an active lesion.

FIGURE 11.3 Luxol fast blue stain revealing loss of myelin in several irregular geographic lesions.


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distribution of the lesions becomes less apparent.The inflammatory reaction is usually less pro-nounced in grey matter, probably because of thesmaller amount of myelin in these areas. The ex-tent of axonal loss in the demyelinated areas ishighly variable. The sparing of axons is relative,and some axonal loss occurs in almost all lesionsand can become substantial in severe cases. Ax-onal loss can also occur very early and even bepresent during the first clinical attack.

Plaquelike areas of pale myelin staining arecalled shadow plaques and are generally re-garded as evidence of partial remyelination.Several studies have confirmed a remarkablepotential for oligodendrocyte proliferation andpartial remyelination, which seems to be im-peded by as-yet-unknown local factors.

Myelin and Nerve Conduction

Proteolipid protein (PLP), myelin basic protein(MBP), and their isoforms make up 80% to90% of the myelin sheath with 2′,3′-cyclic nu-cleotide 3′-phosphohydrolase (CNPase), myelin-associated glycoprotein (MAG), myelin oligo-dendrocyte protein (MOG), and other minorproteins making up the rest. Both PLP and CN-Pase are restricted to CNS myelin, whereasMBP constitutes about 10% of the protein inPNS myelin. Lipids constitute 80% of the dryweight of myelin. Cultured oligodendroglialcells contain a family of gangliosides of whichGM3 and GM1 are the principal components.

One oligodendrocyte usually forms intern-odal segments of myelin on several differentnerve fibers. This differs from the peripheralnervous system, where one Schwann cell con-tributes myelin to only one internodal segment.This difference may account, in part, for themuch greater efficiency of regeneration in pe-ripheral myelin. The nodes of Ranvier have ahigh concentration of sodium channels concen-trated in the nodal membrane, which are re-quired for saltatory conduction. During anepisode of inflammatory demyelination, conduc-tion may be transiently impaired as a result ofedema, loss of myelin, and some degree of

metabolic dysfunction of the nerve axon. Con-duction can recover acutely on resolution ofedema, subacutely with redistribution of sodiumchannels along the internodal membrane, orchronically after partial remyelination.

Pathologic Correlations withMagnetic Resonance Imaging

■ SPECIAL CLINICAL POINT: The profoundimpact of modern imaging technologies,particularly MRI, is evident from its expandingrole in the diagnosis and prognosis of MS.

High signal (bright) T2-weighted lesions corre-late well with the presence of lesions on grosspathology. However, T2 lesions lack specificityfor microscopic tissue pathology and seem torepresent a composite of factors includingedema, demyelination, remyelination, gliosis,and axonal loss. Therefore, the T2-lesion bur-den does not correlate strongly with clinical dis-ability even in clinically eloquent areas of theCNS (brainstem and spinal cord) because notall T2 lesions purport the destructive axonalpathology. Indeed, this is exactly what the T2-weighted lesion volume studies show—aweak but significant correlation with clinicaldisability (Expanded Disability Status Scale, orEDSS, and cognitive impairment). Because ofthe imprecise specificity of T2 images, moreemphasis is being placed on T1-weighted im-ages in which persistent low signal (black holes)seems to correlate better with axonal dropoutand clinical disability. However, one must becautious because during the acute enhancingphase of a lesion, and perhaps for severalmonths thereafter, low signal T1 lesions mayrepresent extracellular edema that can resolve.

Another misunderstood aspect of imagingis that there is a temporal sequence of lesionpathology such that acute contrast-enhanced le-sions correlate well with the perivenular infil-trate and the likelihood of a clinical exacerbationbut also predict future formation of black holesand brain atrophy. Indeed in a clinical trial of interferon beta (IFNβ), the drug suppressed inflammation on the MRI in the first year of


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treatment but did not slow brain atrophy untilthe second year. This suggests that those axonsthat were already demyelinated prior to treat-ment may follow an inexorable course of de-generation during the first year of treatment,but the axons that were salvaged from demyeli-nation by suppression of the inflammatory attack in the first year are spared degenerationin the second year. This also would explain whyin two recent short-term trials of potent im-munosuppressive drugs used for 12 months orone dose, contrast-enhancing lesions were re-duced, but there was no effect on progression ofdisability or brain atrophy. Newer methods suchas magnetization transfer imaging, diffusiontensor imaging, and proton magnetic resonancespectroscopy (1H-MRS) may be more sensitivemeasures of underlying structural pathology.

ETIOLOGY ANDIMMUNOPATHOGENESIS

Although the cause of MS remains uncertain,our understanding of the underlying mecha-nisms and pathology has grown enormously.

■ SPECIAL CLINICAL POINT: The bestformulation of the pathogenesis of MS is thatthe disease is an autoimmune process thatoccurs in a genetically susceptible individualafter an environmental exposure.

This hypothesis is supported by an extensive anddiverse literature but is based on three seminaldiscoveries. The recognition by Rivers that theacute paralytic encephalitis that occasionally fol-lowed rabies and small pox vaccination was anautoimmune reaction to contaminating self- proteins led him to the discovery of experimentalallergic encephalomyelitis (EAE), which has sincebeen studied extensively as an animal model forMS. The discoveries that genes influence diseasesusceptibility and specifically that the humanleukocyte antigen class II region on the short armof chromosome 6 is associated with the risk ofdeveloping MS have led to a multitude of studiessuggesting that polygenetic influences predisposecertain individuals to acquiring MS. Finally, the

observations made regarding latitudinal gradient,migration, and disease clustering have stronglysuggested an environmental role in the disease.Although no specific microbial agent has stoodthe test of time, modern molecular immunologyhas provided numerous potential mechanismsthrough which numerous infections could medi-ate autoimmunity.

Genetics

Genetic susceptibility to MS has long been sus-pected, based on widely differing prevalence indifferent ethnic populations. Family studies havefound that first-degree relatives of patients are at20-fold increased risk of developing MS. Fur-thermore, monozygotic twins are more likely tobe concordant for MS (20% to 40%) than dizy-gotic twins (3% to 4%). Nonbiologic first- degree (adopted) relatives are no more likely todevelop MS than the population at large, whichfurther supports the notion that familial cluster-ing for MS is largely genetic in origin. However,unless one invokes incomplete penetrance ofgenes, the twin studies also suggest a strong envi-ronmental component because no more than40% of monozygotic twins are concordant forMS. Widely different MS prevalence among similar high-susceptibility genetic groups that inhabit different environments (such as Anglo-Saxons in England versus in South Africa) presumably must be tied to this second, environ-mental element of disease etiology. Studies ofcandidate genes and whole-genome screens sug-gest that multiple weakly acting genes interactepistatically to determine risk toward MS, assuspected from epidemiologic studies. Recently,various single-nucleotide polymorphisms (SNPs)associated with a higher risk of developing MSwere identified on the interleukin-2 receptorα gene, interleukin-7 receptor α gene, and con-firmed in the HLA-DRA locus.

Immunology of Multiple Sclerosis

The inflammatory reaction in MS is of un-known origin. Although no infectious agent has


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been proved to be the cause of MS, it is hypoth-esized that many common viruses can triggerautoimmune-mediated demyelination in suscep-tible individuals through molecular mimicry(cross-reactivity between microbial proteins andmyelin). In addition, there is evidence that quies-cent autoreactive T cells that are present inhealthy individuals may be activated throughbystander activation by cytokine or polyclonalT-cell activation mediated by bacteria or viruses.

■ SPECIAL CLINICAL POINT: It remainsuncertain how tissue injury (to myelin,oligodendroglia, axons, and neurons) occurs inMS, but the inflammatory events surroundingthe vast majority of acute MS lesions seem tosuggest a direct immune-mediated pathology.

The MS lesion resembles a delayed-type hyper-sensitivity (DTH) reaction, containing activatedT cells, B cells, numerous mononuclear phago-cytes, inflammatory cytokines, and adhesionmolecules. Electron microscopy studies suggestthe macrophage may play a major role in the di-rect stripping of myelin from axons, althoughthis could be a secondary phagocytic response

to excitotoxic injury of oligodendrocytes orneurons. There has been more emphasis recentlyon the role of innate immune cells in MS, specif-ically, dendritic cells and microglia. These cellsseem to help facilitate the proinflammatory im-mune response in MS and direct autoreactive T-cell function within the CNS through antigenpresentation. Therapies directed toward thesecells could prove to be very beneficial.

DISEASE COURSE ANDCLINICAL PATTERNS

The clinical course of MS is divided into cate-gories according to neurologic symptoms asthey develop over time. A new classification forMS categories was developed by consensusamong MS experts (Table 11.1).

Relapsing–Remitting Multiple Sclerosis

Relapsing–remitting MS (RR-MS) is the mostcommon form in patients younger than age40 years. Patients may develop focal neurologicsymptoms and signs acutely or over a few days.

Multiple Sclerosis Clinical CategoriesTABLE 11.1

Multiple Sclerosis Clinical Categories and Disease Explanation

Relapsing-remitting(RR-MS)

Primaryprogressive

(PP-MS)

Secondaryprogressive

(SP-MS)

Progressive-relapsing(PR-MS)

Gradual neurologicdeterioration with orwithout superimposedrelapses in a previousRR-MS patient

Episodes of acuteworsening withrecovery and stablecourse betweenrelapses

Gradual, nearlycontinuous neurologicdeterioration fromonset of symptoms

Gradual neurologicdeterioration fromonset of symptomswith subsequentsuperimposed relapses

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907–911.


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These exacerbations or attacks are remarkablyunpredictable and heterogeneous in character,probably because they result from varying de-grees of inflammation that can occur in anypart of the brain or spinal cord.

■ SPECIAL CLINICAL POINT: Commonpresentations of multiple sclerosis includeblurred or double vision, sensory symptoms(numbness, tingling, or pain), weakness, vertigo,or impaired balance.

A new symptom will commonly present over 24to 72 hours, stabilize for a few days or weeks,and then improve spontaneously over 4 to 12weeks. Subsequent new focal symptoms orsigns typically follow the initial attack monthsor years later and again remit partially or com-pletely. It is very common for old symptoms topersist or reoccur, especially in response to peri-ods of stress such as infections or prolonged el-evations of core body temperature. Over time,it becomes difficult to determine whether thesymptom flare represents a new exacerbationor worsening symptoms referable to past dis-ease. Recovery from relapses is often incom-plete, and permanent disability can accumulatein a stepwise fashion at this stage of the disease.

Secondary Progressive Multiple Sclerosis

Secondary progressive MS (SP-MS) refers to thepatient with an initial RR-MS course who thenprogressively worsens over months (at least 6)to years. Natural history studies have shownthat with time most patients with RR-MS con-vert to SP-MS. This usually occurs after 10 to20 years from onset or after the age of 40. Apatient with SP-MS may still experience re-lapses but does not stabilize between relapses.The predominant clinical pattern is one of con-tinued clinical worsening. As time passes, re-lapses become less discrete, and the patternbecomes one of continued worsening withoutrelapses. Conversion to SP-MS is considered apoor prognostic sign because this stage of thedisease is much more refractory to the presentlyavailable immunomodulatory therapies. Some

patients with SP-MS spontaneously stabilize forconsiderable periods, although they only rarelyrecover after deficits have persisted for 6 months.The pathogenic mechanisms underlying conver-sion from RR-MS to SP-MS may relate to failureof remyelination and progressive axonal injury.

Primary Progressive Multiple Sclerosis

Primary progressive MS (PP-MS) accounts forapproximately 10% to 15% of patients and ischaracterized by progressive worsening fromthe onset of symptoms without interposed re-lapses. Patients with PP-MS are more likely tobe men and older than 40 years of age at symp-tom onset. This form of the disease often pres-ents with progressive gait disorder as a result ofleg weakness, spasticity, and impaired coordi-nation. In cases of progressive neurologic dys-function, it is extremely important to rule outstructural pathology, infections, and hereditaryand other neurodegenerative diseases. Patientswith PP-MS have fewer gadolinium-enhancingbrain lesions on MRI, less tissue inflammationon histopathologic assessment, and less cere-brospinal fluid (CSF) inflammation than typicalfor SP-MS; pathologic studies have suggestedthis form of the disease may represent a pri-mary problem with the oligodendrocyte.

Progressive-Relapsing Multiple Sclerosis

According to the new classification, progres-sive- relapsing MS (PR-MS) refers to the rarepatient with progressive disease from symptomonset, who subsequently experiences one ormore relapses. In all likelihood, this is anotherform of SP-MS without clinically apparent re-lapses in the early stages of disease, and if con-sidered separately, this group comprises only6% or fewer of all patients with MS.

Disease patterns change over time, and itmay be difficult at a given time to clearly catego-rize a patient’s disease. The problem is particu-larly difficult when a patient is converting froma purely relapsing–remitting disease course to apurely progressive disease course. This has been


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termed “relapsing progressive MS” by someand “transitional MS” by others, but these dis-ease categories cannot be defined precisely bycurrent methods. Observation for as long as1 year may be required to categorize such a pa-tient with confidence.

Clinically Isolated Syndromesand Prognosis

■ SPECIAL CLINICAL POINT: In the era ofpartially effective prophylactic MS therapies,there has been increased emphasis on making adiagnosis early in the course of the disease toinitiate appropriate preventative treatment.

The use of MRI as a diagnostic tool is dis-cussed later. T2-lesion burden at the time offirst MS symptoms (optic neuritis, transversemyelitis, etc.) not only determines the likeli-hood of converting to clinically definite MSbut is also predictive of future disability. For example, a patient with a single episodeof optic neuritis and an abnormal brain MRIhas a 50% to 80% risk of subsequently beingdiagnosed with MS in 5 to 10 years. The fre-quency of gadolinium-enhancing lesions cor-relates with the likelihood of having a clinicalexacerbation and predicts future brain atrophy.However, because T2-weighted lesions lackspecificity for tissue pathology and gadoliniumenhancement is transient (2 to 8 weeks), T1hypointense lesions (black holes) and brainatrophy may be a better measure of axonalloss and have been shown to correlate morestrongly with both present and future disabil-ity. The presence of mild atrophy or persistentT1 black holes early in the course of MS shouldalert the physician to a potentially aggressiveform of the disease.

OTHER VARIANTS OFMULTIPLE SCLEROSIS ANDIMPORTANT MIMICKERS

Several other variants of MS have been de-scribed and are important to recognize.

Marburg Disease

An acute rapidly progressive form of MS, oftencalled Marburg disease, is characterized by aperson who develops acute or subacute pro-gressive neurologic deterioration, leading to severe disability within days to months. Thedisease may progress steadily to a quadriplegicobtunded state with death as a result of inter-current infection, aspiration, or respiratoryfailure from brainstem involvement. Post-mortem studies have documented inflamma-tion in the optic nerves, optic chiasm, cerebralhemispheres, and spinal cord. The pathologyreveals a pronounced mononuclear cell infil-trate with severe axonal damage and tissuenecrosis.

Neuromyelitis Optica

Neuromyelitis optica (NMO) or Devic diseaserefers to the patient who presents with bothoptic neuritis and transverse myelitis, occur-ring either simultaneously or separated by afew months to years. Several features differen-tiate this disease from classical MS, includingolder age of onset, higher female to male inci-dence (9:1), limited white matter lesions on abrain MRI, multilevel contiguous typically cen-tral spinal cord lesions (three or more vertebrallevels), and severe disability and death as a re-sult of respiratory failure in one third of all pa-tients. NMO also seems to be more commonthan MS in non-Caucasians. Pathologically,the syndrome is variable with some lesionscharacterized by inflammation and demyelina-tion, but it is invariable with severe necrosisand many patients having cavitary lesions inthe spinal cord. Those patients who survive theacute attack commonly follow a course withfeatures indistinguishable from RR-MS buthave a worse prognosis. An NMO serum bio-marker (NMO-IgG) has recently become com-mercially available, which can help differentiatethis disease from MS. This distinction is of utmost importance since the therapeutic inter-ventions are different for NMO and MS. While


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the NMO-IgG blood test is highly specific andthe majority of clinically diagnosed NMO patients will be NMO-IgG positive, a negativeblood test does not exclude the diagnosis.

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM)and its hyperacute form, acute necrotizing hem-orrhagic encephalopathy (ANHE), are thoughtto be forms of immune-mediated inflammatorydemyelination. They differ from MS in that theyare typically monophasic, whereas MS is by def-inition multiphasic or chronically progressive.Patients with ADEM or ANHE usually presentwith fever, headache, meningeal signs, and al-tered consciousness, which are exceedingly rarein MS. Multiple reports of clinical and patho-logic overlap have been published. Some authorshave suggested that the MRI can be used to dif-ferentiate MS from ADEM, but no reliable clini-cal criteria to differentiate the two processesexist.

PRECIPITATING FACTORS

Exposure to viruses and bacteria has been asso-ciated with precipitating disease exacerbations.The risk of an exacerbation decreases duringpregnancy, with the rate being decreased by ap-proximately two thirds in the third trimester.The risk of an acute attack in the first 3 monthspostpartum is increased and has been estimatedthat 20% to 40% of postpartum patients withMS will have an exacerbation. The decreasedrelapse rate during pregnancy is probably re-lated to a family of immunosuppressive hor-mones and Th2. Overall, pregnancy probablyhas little overall effect on the course of the dis-ease, and therefore remains a realistic possibil-ity for woman with MS. There is increasingevidence that vitamin D deficiency may play animportant role in MS. Recent studies have sug-gested that higher serum vitamin D levels corre-spond to a decreased risk of developing MS. Itis well established that vitamin D receptors arepresent within immune cells and may promote

immune regulation. The anti-inflammatory cy-tokine, transforming growth factor-β1 (TGF-β1), is typically decreased in MS and increasesupon vitamin D supplementation. This associa-tion further supports the contributions of envi-ronmental factors, especially since sunlightexposure provides a major source for vitaminD. This could also explain the unusual geo-graphical distribution of MS.

SYMPTOMS AND SIGNS

See Tables 11.2 and 11.3.

Optic Neuritis

Multiple sclerosis commonly affects the opticnerves and chiasm, and approximately 30% ofpatients present with visual symptoms. In acuteoptic neuritis, the patient experiences monocu-lar loss of central vision and often has eye orbrow pain, which worsens on lateral eye move-ment. The symptoms may present over a fewhours to 7 days, with a few cases progressingover several weeks. Loss of visual acuity andcolor perception are often considerable. Mostpatients will recover significantly after 2 to 3 months, although continued improvement

Initial Symptoms in Patients withMultiple Sclerosis

TABLE 11.2

Symptom Percentage

Sensory disturbance in one or more limbs 33

Disturbance of balance and gait 18Vision loss in one eye 17Diplopia 13Progressive weakness 10Acute myelitis 6Lhermitte’s symptom 3Sensory disturbance in face 3Pain 2

Paty DW, Poser CM. Clinical symptoms and signs of multiplesclerosis. In: Poser CM, ed. The Diagnosis of Multiple Sclerosis. New York: Thieme & Stratton; 1984:27.


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Common Symptoms and Signs in Patients with Multiple SclerosisTABLE 11.3

Symptom Sign Comment

Visual blurring (central) Diminished acuity (central) Syndrome of optic neuritis seenusually early in disease

Vision loss/eye pain Scotoma/deafferented pupil

Diplopia Internuclear ophthalmoplegia May be associated with nausea,vertigo, or other brainstem signs

Oscillopsia Rarely other oculomotor weakness, flutter, or dysmetria

Loss of dexterity Upper motor neuron signs often Develops in many MS patientsaffecting legs early and arms later over time

Weakness

Tightness and pain

Shaking Intention tremor, dysmetria, dysarthria, Occurs in 30% of patients; maytruncal or head titubation be the predominant

manifestations in some patients

Imbalance

Paresthesias Decreased vibration and position Sensory symptoms are often sense in legs > hands painful and distressing

Loss of sensation Decreased fine sensation in hands

Bandlike disturbance Sensory level

Falls Wide-based gait Gait disturbances are common inMS and can cause severe disability

Lack of coordination Ataxic and unsteady gait

Inability to concentrate Diminished concentration, processing May be subtle or have severe impact or learn speed, or verbal learning on on patient and family; severe

neuropsychologic testing dementia in <10% of patientsEasily distractible

Emotional lability Episodic crying or laughing Distressing to patient; generally notrelated to patients’ actual emotions

Depression — Commonly underrecognized orunderestimated

Fatigue — Disabling in many patients with MS;does not correlate with severity ofmotor signs

Pain — Numerous etiologies (see text)

Urinary urgency, Requires urodynamic testing to Often complicated by intercurrent hesitancy, frequency, fully characterize type of bladder UTIand incontinence dysfunction

MS, multiple sclerosis; UTI, urinary tract infection.


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can occur as long as a year later; however, somepatients sustain permanent damage and can be-come blind. Acuity is variably diminished in theaffected eye. A central or centrocecal scotoma(marked enlargement of the blind spot to in-volve central vision) can be documented at thebedside with an Amsler grid, and red desatura-tion can be demonstrated with color plates orwith a red-tipped hat pin. Using the swingingflashlight test in a darkened room, one candemonstrate a defect in the afferent pathwaysuch that pupillary constriction in the affectedeye is greater with contralateral than with direct light stimulus. A positive test reveals arelative afferent pupillary defect, sometimescalled a Marcus Gunn pupil. Funduscopic examination is usually normal in acute retrob-ulbar neuritis. When the optic nerve is affectedanteriorly, the disc may be congested andswollen, thus resembling papilledema. Severalmonths after an optic neuritis, the disc often ap-pears pale, especially at the temporal border,and this can provide evidence of a previous at-tack. Occasionally, optic nerve demyelinationand axonal damage can manifest silently and isnoticed only in the setting of other symptomssuggestive of MS.

A novel noninvasive eye scan called opticalcoherence tomography (OCT) is now beingused to assess MS patients. The scan provideshigh-resolution quantifiable images of the reti-nal nerve fiber layer that have been shown inrecent studies to reflect optic nerve damageeven in asymptomatic eyes. OCT scans mayprove to be a very important biomarker for dis-ease monitoring and therapeutic effectiveness;however, since OCT scans are not specific forMS/optic nerve pathology, they are not consid-ered a diagnostic test to the exclusion of a thor-ough eye exam.

Oculomotor Syndromes

Eye movement abnormalities are also extremelycommon in MS and include broken (saccadic)smooth pursuits, nystagmus, ocular dysmetria(overshooting target), isolated extraocular

muscle palsies, and the classical internuclearophthalmoplegia (INO).

■ SPECIAL CLINICAL POINT: An INO resultsfrom damage to the medial longitudinalfasciculus, and its presence in a young adult,particularly when bilateral, is highly suggestiveof MS.

In its complete form, one eye is unable toadduct and the other has abducting nystagmus.More commonly one observes varying degreesof adduction lag with dysconjugate nystagmus.The patient is asked to make a rapid saccadefrom midline to a laterally situated target, andthe examiner focuses on whether the eyes movein a conjugate manner. The condition is fre-quently bilateral, with one eye being more in-volved than the other. Quantitative infraredoculography has demonstrated that the fre-quency of subtle INOs is probably muchgreater than can be clinically appreciated.

Motor Dysfunction

Weakness, spasticity, hyperreflexia, and Babinski’ssign (upgoing toe) are common manifestationsof damage to the pyramidal tracts (corti-cospinal tracts) in patients with MS. This mostcommonly presents in the legs (spastic para-paresis) because of the relative length that thesefibers have to travel, which makes them moresusceptible to numerous areas of demyelina-tion and noticeable conduction delays. It is notuncommon for cervical lesions to manifest firstin the lower extremities. Concomitant symp-toms include stiffness, spasms, and pain. Ex-treme hyperreflexia causes clonus, which isusually described by the patient as a shaking ortremor.

Cerebellar Signs

End-point tremor (dysmetria) on finger tonose testing is most noticeable in the upper ex-tremities, probably because of their importantrole in fine movement tasks. Lower extrem-ity and midline truncal ataxia result in gait


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Cognitive and Memory Symptoms

■ SPECIAL CLINICAL POINT: Approximately50% of patients with MS exhibit significantshort-term memory loss or difficulty withconcentration, attention, and processing speed.

Cortical deficits relating to language and visualspatial function are much less common. In onlya minority of patients is dementia an incapaci-tating aspect of the disease. Correlations be-tween the severity of cognitive impairment andthe extent of MRI changes have been found.

Psychiatric Manifestations

Inappropriate laughing and weeping, often inresponse to minor provocation, occurs in morethan 10% of patients with MS. Approximately50% of patients with MS will have an episodeof major depression during the course of theirillness, and many patients will have chroniclow-level depressive symptoms. MRI studieshave confirmed an association with lesion loador atrophy, especially in the frontal and tem-poral lobes, and depression in MS. The healthcare provider should have a heightened aware-ness of the risk of suicide in patients with MS.Depression may also be part of a bipolar ill-ness, which is more common in patients withMS than in control populations.

Fatigue

Fatigue may be the most common single com-plaint of patients with MS and can be dis-abling. Fatigue usually comes on late in theafternoon or may occur with strenuous activityor with exposure to heat. Short rest periodsusually restore function. A less specific andmore generalized fatigue is also seen and maytake the form of overwhelming lassitude, whichcan be disabling. Episodic fatigue may heraldclinical disease exacerbation. The mechanismsunderlying MS fatigue are unknown.

Bladder, Bowel, and Sexual Dysfunction

Bladder dysfunction is common and can be di-vided into two categories. Patients may fail to

impairment, and some patients with MS aremistaken for being intoxicated. Head or trun-cal titubation or scanning dysarthria (impairedprosody) can become disabling aspects of thedisease.

Sensory Symptoms

Approximately one third of patients with MSpresent initially with sensory disturbance in-volving the limbs, and the majority of patientswill have paresthesias as the disease progresses.Symptoms are usually described as “pins andneedles” and less commonly as a loss of sensa-tion. Paresthesias can be painful burning orelectrical sensations. The sensory symptomsfollow a spinal cord pattern, often with an in-complete loss of sensation to either vibration(posterior columns) or pinprick (spinothalamic)pathways. It is important to distinguish thespinal pattern from peripheral or root lesions,which follow cutaneous or dermatomal pat-terns of sensory loss. Occasionally, patients willdescribe patches of numbness or symptoms inan apparently nonanatomic distribution, whichpresumably could relate to multifocal areas ofdemyelination or may be a manifestation ofpsychiatric disease.

Lhermitte’s phenomenon refers to an elec-tric tingling sensation that is precipitated byneck flexion, usually into the arms or down theback. Lhermitte’s phenomenon suggests cervi-cal spinal cord disease. It is very common inpatients with MS with cervical spinal cord in-volvement but is not specific for MS.

Pain

Pain is very common in MS and may be causeddirectly by abnormal firing of sensory nerves,as a result of severe spasticity, or because ofsecondary orthopedic injuries. Trigeminal neu-ralgia (TN) or atypical facial pain are commoncauses of severe pain in MS. Younger patientswho present with TN should be evaluated forMS as this pain syndrome is more commonabove the age of 50.


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empty urine adequately, causing urinary hesi-tancy, postvoid fullness or dribbling, or frankinability to initiate urination despite a feelingof fullness. Alternatively, patients may fail toproperly store urine, causing urgency, urge in-continence, dysuria, frequency, and nocturia.The correlation between bladder symptomsand the underlying pathophysiology is oftenimperfect; therefore, objective testing by cys-tometrogram is often necessary to characterizethe problem and to guide management.

Constipation is also common in MS andshould be managed aggressively to preventcomplications. Fortunately, fecal incontinenceis relatively rare but when present is sociallydevastating.

Sexual dysfunction is reported by 50% to75% of patients with MS and is exacerbated bya variety of problems, including fatigue, de-creased sensation, decreased libido, erectiledysfunction, spasticity, impaired lubrication,body image disorder, and depression.

Other Manifestations

Paroxysmal disorders in MS include dystonicspasms, tic douloureux, episodic paresthesias,seizures, ataxia, and dysarthria. Sleep disordersand sleep-related movement disorders (restlessleg syndrome) are common in MS and can con-tribute to daytime fatigue. Various other diseasemanifestations occur more rarely, includinghearing loss, spasms, aphasia, homonymoushemianopsia, gait apraxia, movement disorders(myoclonus and chorea), and autonomic dys-function (sweating, feeling hot and cold, edema,and postural hypotension).

DIAGNOSIS OF MULTIPLE SCLEROSIS

■ SPECIAL CLINICAL POINT: MS isdiagnosed clinically through the demonstrationof CNS lesions disseminated in time and spaceand with no better explanation for the diseaseprocess.

There is no single diagnostic test, and severalother diseases can mimic MS. Therefore,

diagnostic criteria based on clinical featuressupplemented by laboratory tests have beenused. The original and recently revised Mc-Donald criteria were developed by a panel ofMS experts and were based on review of ex-tensive supportive scientific studies focusingon the sensitivity and specificity of MRI diag-nostic criteria (Table 11.4). The major changeassociated with the latest criteria is that a di-agnosis of MS can be made early after a clini-cally isolated syndrome if a follow-up MRIperformed 1 month later demonstrates theformation of a new T2 lesion that is of suffi-cient size and location (Tables 11.5 and 11.6).These criteria also define MRI lesion charac-teristics that increase the likelihood of MS:number (>9), abutting the ventricles, juxtacor-tical, infratentorial, spinal, and contrast en-hancing. As with all the criteria, the clausethat “there must be no better explanation” re-mains a critical part of the definition of MS.Critics of these criteria have complained theyare too restrictive, whereas purists remain un-convinced of the utility of MRI for diagnosis.The lack of specificity for MS of white matterlesions seen on MRI must also be remem-bered, and overreliance on imaging to the ex-clusion of the clinical picture can lead todiagnostic errors. Ultimately, how one definesthe clinical syndrome of MS, within the recog-nized spectrum of multifocal demyelinationdiscovered at autopsy to hyperacute demyeli-nating syndromes, remains an ongoing de-bate. The revised McDonald criteria providean important update and have been adoptedfor the incorporation of patients in researchstudies.

Important Radiologic andLaboratory Features

Magnetic Resonance Imaging

■ SPECIAL CLINICAL POINT: MRI is thesingle most useful test in confirming thediagnosis of MS.

A brain MRI performed on a high field (>1.5Tesla) magnet is abnormal in 95% of patients


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with clinically definite MS, and the absence ofhigh signal abnormalities in either the brain orspinal cord is strong evidence against the diag-nosis of MS. MS lesions appear as areas of highsignal usually in the cerebral white matter onT2-weighted images (Figs. 11.4 and 11.5). Theyare typically round or ovoid but may appear asfingerlike projections extending perpendicu-larly from the ventricular wall that is visualized

best on sagittal imaging (Dawson’s fingers).Typical locations include the corpus callosum,abutting the walls of the ventricles, in the juxta-cortical lesions (grey–white junction), in theposterior fossa (pons and cerebellar peduncles),and in the spinal cord (cervical twice as com-monly as thoracic). Fluid-attenuated inversionrecovery (FLAIR) is more sensitive than con-ventional T2-weighted imaging for cerebral lesions but is less useful in the posterior fossa orspinal cord. Short tau inversion recovery (STIR)images have the highest sensitivity for detecting

McDonald Diagnostic CriteriaTABLE 11.4

Paraclinical Tests Needed

Clinical Presentation Space Time

Two attacks; two locations No NoTwo attacks; one location MRI abnormal or No

two MRI lesions + CSFOne attack; two locations No MRI criteria or One attack; one location (CIS) MRI abnormal or second attack

two MRI lesions + CSF MRI criteria or second attack

PP-MS (progression for 1 year) Need two of the following:Nine MRI brain lesions or four to eight brain lesions + VEP

Two MRI cord lesionsPositive CSFa

CSF, cerebrospinal fluid; CIS, clinically isolated syndromes; PP-MS, primary progressive multiple sclerosis; VEP, visual-evoked potential.aEvidence of oligoclonal bands or increased IgG index or both.Modified from Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” AnnNeurol. 2005;58:840–846.

MRI Criteria for Brain AbnormalityTABLE 11.5

Three of the followinga:One Gd-enhancing lesion or nine T2-hyperintense lesions if there is no Gd-enhancing lesion

At least one infratentorial lesionAt least one juxtacortical lesionAt least three periventricular lesions

Gd, gadolinium.aOne spinal cord lesion can be substituted for one infratentorialbrain lesion. An enhancing cord lesion can substitute for anenhancing brain lesion and count twice in the MRI criteria fordiagnosis (one enhancing lesion and one infratentorial lesion).Polman CH, Reingold SC, Edan G, et al. Ann Neurol. 2005;58:840–846.

Dissemination in TimeTABLE 11.6

Two possible ways to demonstrate imagingdissemination in time:(1) Scan 3 months after clinical event showing a Gd-

positive lesion not at same site of original event(2) New T2W lesion at least 30 days after initial

clinical event scan

Gd, gadolinium; T2W, T2-weighted.Polman CH, Reingold SC, Edan G, et al. Ann Neurol. 2005;58:840–846.


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demyelination in the spinal cord. All MRIs per-formed in suspected or definite patients withMS should be done before and after intra-venous (IV) administration of the paramagneticagent gadolinium diethylenetriaminepentaaceticacid (GdDTPA). Lesions that enhance afterGdDTPA have been shown to represent acuteinflammatory lesions and as such increase thelikelihood that a lesion is related to MS as op-posed to a nonspecific small-vessel diseaseprocess. Enhancing lesions are also used as ameasure of disease activity in clinical trials. En-hancing lesions last only for 2 to 8 weeks andtherefore can be missed easily, so FLAIR is amore reliable measure of the total burden ofdisease or for infrequent serial scanning. MRIis also useful for ruling out non-MS–related

structural lesions such as spinal tumors, sy-rinxes, Chiari malformations, and herniateddisc material.

CSF Analysis

CSF studies to rule out infectious and neoplas-tic etiologies and to look for the presence of in-trathecal immunoglobulin (Ig) synthesis are animportant part of laboratory testing in cases inwhich the clinical picture and MRI are not di-agnostic. The presence of more than 50 mononu-clear cells/mm3, any neutrophils, or a CSFprotein of greater than 100 mg/dL should raiseconcern about a diagnosis of MS. Depending onthe laboratory and technique, approximately80% to 90% of patients with clinically definite

FIGURE 11.4 Magnetic resonance imaging scans of the brain of a patient with multiple sclerosis. A: Fluid-attenuated inversion recovery (FLAIR) sequence demonstrating typical periventricular whitematter lesions. B: On T1-weighted image with contrast only two of these lesions appear active. C: In aseparate patient, T2-weighted scan demonstrating two demyelinating lesions of apparent equal intensity.D:The T1-weighted images with contrast reveal one lesion is active and the other is hypointense,suggesting formation of a T1 black hole. Persistence of T1 holes correlates with axonal dropout.

A B

C D


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MS will have two or more IgG bands presenton a CSF gel electrophoresis and not in amatched serum sample (oligoclonal bands).Quantitative increases in the CSF IgG indexprovide similar information but do not alwayscorrelate with the presence of oligoclonal

bands and should therefore also be ordered aspart of CSF analysis. The sensitivity of thesetests in clinically isolated syndromes is lower.In addition, oligoclonal bands are not specificfor MS and have been observed in 50% of pa-tients with infectious diseases of the nervous

A B

C D

E

FIGURE 11.5 Magnetic resonance imaging scans of the brain of apatient with multiple sclerosis demonstrating typical lesion locations. A: Periventricular lesions extending perpendicularly from the ventricles(Dawson’s fingers). B: Juxtacortical lesion. C: Edematous enhancing opticnerve. D: Enhancing lesion on the cerebellar peduncle. E: Lesions in thecorpus callosum and high cervical cord.


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system and in about 15% of patients with non-inflammatory diseases such as tumors and in-farctions. MBP is released after CNS tissueinjury from many processes, and other thandocumenting an organic etiology to the clinicalpresentation, the test is not helpful.

Evoked Potentials

Sensory evoked potentials are used in MS toprovide objective evidence to supplement sub-jective sensory symptoms or occasionally to re-veal clinically silent lesions. This can beparticularly valuable if a psychiatric basis forthe symptoms is being considered or in earlycases in which MRIs are inconclusive. Of thethree types of evoked potentials, brainstem au-ditory evoked response (BAER), somatosen-sory evoked potential (SSEP), and visualevoked potential (VEP), the latter is the mostuseful because remote optic nerve disease iscommon and not well visualized on MRI. VEPscan also be helpful in supporting a diagnosis ofPP-MS based on the McDonald criteria.

Serologic Testing

As part of excluding other disease processes, itis often prudent to obtain peripheral blood totest: vitamin B12, methylmalonic acid, 25-OHvitamin D, thyroid-stimulating hormone, ery-throcyte sedimentation rate, antinuclear anti-bodies, Lyme titer, and rapid plasma reagin. Inunusual cases, more extensive testing may in-clude antineutrophil cytoplasmic antibodies,antiphospholipid antibodies, anti-dsDNA anti-bodies, anti-Smith antibodies, Sjögren syn-drome A and B antibodies, hepatitis profile,copper levels, ceruloplasmin, NMO-IgG, andangiotensin-converting enzyme. Rarely, humanimmunodeficiency virus and opportunistic in-fection can mimic MS. Some risk exists of ob-taining false-positive tests, and some expertshave questioned the cost-effectiveness of exten-sive serologic testing.

Errors in Diagnosing Multiple Sclerosis

Conditions commonly misdiagnosed for MS arelisted in Tables 11.7 and 11.8.

Conditions Commonly Mistaken for Multiple SclerosisTABLE 11.7

AVM, arteriovenous malformation; Deg., degeneration; HSP, hereditary spastic paraparesis; HIV, human immunodeficiency virus; HTLV-1, human T-cell lymphotrophic virus type-1.

Conditions Commonly Mistaken for Multiple Sclerosis

VascularDiseases

StructuralLesions

DegenerativeDiseases

InfectionsOther

Conditions

Small-vesseldiseaseAVMVasculitis

CervicalspondylosisSkull-base anomalyInfratentorial tumorsSpinal cord tumors

Motor system diseaseSpinocerebellar deg.HSP

HIV myelopathyHIV cerebritisHTLV-1Lyme disease

Neuromyelitis OpticaSarcoidosisSjögren syndromeCobalamin deficiency


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■ SPECIAL CLINICAL POINT: The rules ofdissemination in time and space are critical tomaking an accurate diagnosis of MS.

ADEM can appear clinically and radiographi-cally like MS but is usually a monophasic dis-ease process. Similarly, the presence of acervicomedullary lesion such as with a Chiarimalformation can cause multiple symptoms emanating from one location in the nervous system, so careful attention to documenting aclear second location is critical. In both situa-tions, MRI has proved extremely useful; how-ever, T2-weighted lesions are not specific forMS, and therefore vascular, infectious, and neo-plastic etiologies of multifocal disease must beconsidered. The extent of exclusionary testingis usually dictated by the clinical presentation.In a case of RR-MS with typical findings andconfirmatory brain MRI, little other testing isnecessary. In atypical presentations with un-usual historical features (fever, altered level ofconsciousness, exposures, no relapses), strongfamily history, no eye findings, purely progres-sive disease, or very aggressive disease fromonset (NMO), more extensive testing is manda-tory. Finally, psychiatric disease must be consid-ered in the patient with numerous symptomsand little objective evidence for disease. The ex-perienced clinician, however, recognizes thatearly in the course of MS, objective evidence

may be lacking and comorbid psychiatric dis-ease can be the primary symptom. The level ofconfidence in the diagnosis of MS increaseswith time, and the physician should always be alert to alternative or coexistent diseaseprocesses even in patients who carry a diagno-sis of MS.

When to Refer a Patient to a Neurologist

MS is a complicated neurologic disease, andthe approaches to diagnosis and treatment arechanging rapidly.

■ SPECIAL CLINICAL POINT: It isappropriate to refer any patient suspected ofhaving MS to a neurologist with MS experience,even if the patient has had only a single clinicalevent.

Symptoms that are suspicious for MS includeunexplained numbness/tingling, fatigue, uri-nary urgency, loss of vision in one eye, or im-paired coordination. Although many of thesesymptoms occur commonly in healthy people,it is the persistence of a symptom or multiplesymptoms that should provoke further evalua-tion. The non-neurologist should not be dis-suaded by concomitant emotionality orpsychiatric disease because this can be part ofthe presentation of MS. A brain MRI is a goodfirst step in screening for MS. The presence ofany high signal lesions in a young person war-rants neurologic consultation.

THERAPY OF MULTIPLE SCLEROSIS

Disease-Modifying Therapies

Four partially effective disease-modifying thera-pies (DMT) for the initial management of MSare available in the United States: IFNb-1a(Avonex), IFNb-1a (Rebif), IFNb-1b (Be-taseron), and glatiramer acetate (Copaxone).Mitoxantrone (Novantrone) was approved inthe United States for the treatment of worseningforms of RR-MS, PR-MS, and SP-MS. A sixthnovel agent, Natalizumab (Tysabri), was reap-proved for use in the United States for patients

Diseases That Mimic Multiple Sclerosis on MRI

TABLE 11.8

ADEM HistiocytosisHTN/small-vessel disease HTLV-1CADASIL Lyme diseaseSarcoidosis LeukodystrophiesVasculitis Mitochondrial diseaseMigraine LupusAging-related changes Behçet diseaseOrganic aciduria HIV

ADEM, acute disseminated encephalomyelitis; HTN, hypertension;HTLV-1, human T-cell lymphotrophic virus type-1; CADASIL, cerebralautosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy.


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with RR-MS who have either inadequate re-sponse to first-line therapies or are intolerantto them. Table 11.9 lists these immunomodu-lating pharmacologic treatments.

Beta Interferons Beta interferons (IFNα) arenaturally occurring cytokines with a varietyof immunomodulating and antiviral activitiesthat may account for their therapeutic utility.IFNα may act through several mechanismsincluding modulation of major histocompati-bility complex (MHC) expression, suppressorT-cell function, adhesion molecules, and ma-trix metalloproteinases. All three IFNα drugshave been shown to reduce relapses by aboutone third in double-blind placebo-controlledtrials and are recommended either as first-line therapies or for glatiramer acetate intol-erant patients with RR-MS. In addition, ineach of these trials, IFNβ resulted in a 50%to 80% reduction of the inflammatory lesionsvisualized on brain MRI. Evidence also exists

that these drugs improve quality of life andcognitive function.

The major difference between the IFNβdrugs is that Avonex is given weekly intramus-cularly (IM), Rebif is given three times a weeksubcutaneously (SC), and Betaseron is givenevery other day SC. The adequacy of IFNβ-1aweekly dosing has been questioned. Studies ap-pear to support a modest dose–response effectfor IFNβ; however, one study of double dose(60 mg IM) Avonex, once a week, found nobenefit over the single-dose regimen. Whetherthe benefit of more frequent dosing is sustainedfor periods longer than 2 years remains un-clear, and the increased incidence of neutraliz-ing antibodies (NAbs) with the more frequentSC dosing must also be considered.

Flulike symptoms, including fever, chills,malaise, muscle aches, and fatigue, occur in ap-proximately 60% of patients treated with ei-ther IFNβ-1a or IFNβ-1b and usually dissipatewith continued use and premedication with

Pharmacologic Treatments: Immunomodulating and Acute RelapsesTABLE 11.9

Drug Name Indication Starting Dose Stable Dose Comments

Avonex Relapsing MS 30 mcg IM q.d. 30 mcg IM q.d. Flulike side effects(Interferon beta-1a) CISRebif Relapsing MS 22 mcg SC t.i.w. 44 mcg t.i.w. Flulike side effects(Interferon beta-1a) CISBetaseron Relapsing MS 0.0625 mg SC 0.25 mg SC q.o.d. Flulike side effects(Interferon beta-1b) CIS q.o.d.Copaxone Relapsing MS 20 mg SC q.d. 20 mg SC q.d. Idiosyncratic chest (Glatiramer acetate) CIS pain/palpitationsTysabri Relapsing MS 300 mg IV q4 300 mg IV q4 PML and other (Natalizumab) weeks weeks infections reportedMitoxantrone Worsening forms 5–12 mg/m2 IV 5–12 mg/m2 IV Maximum lifetime dose (Novantrone) of relapsing MS q3 months for 140 mg/m2

and SPMS 2–3 years Cardiotoxicity andleukemia reported

Contraindicated inMethylprednisolone Acute relapses 1,000 mg IV q.a.m. 1,000 mg IV avascular necrosis

× 3–5 days q.a.m. × 3–5 days

MS, multiple sclerosis; CIS, clinically isolated syndrome; IM, intramuscularly; SC, subcutaneous; IV, intravenous; SPMS, secondary progressive multiplesclerosis.


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nonsteroidal anti-inflammatory drugs (NSAIDs).Other side effects include injection-site reactions,worsening of preexisting spasticity, depression,mild anemia, thrombocytopenia, and elevationsin transaminases, which are usually not severeand rarely lead to treatment discontinuation.

Development of NAbs can occur with anyof the IFNβ products. Although the results arevariable, IFNβ-1a weekly IM (Avonex) is re-ported to have the lowest incidence. The effectof NAbs on long-term efficacy remains to befully defined. Some experts recommend thatthe results of an NAb assay in patients who ex-hibit insufficient treatment response may guidedecisions for alternative therapy.

Glatiramer Acetate Glatiramer acetate (Copax-one) is a polypeptide mixture that was origi-nally designed to mimic MBP. The mechanismof action of glatiramer acetate is distinct fromthat of IFNβ; therefore, patients may responddifferently to this drug. Glatiramer acetate(20 mg SC q.d.) has also been shown to re-duce the frequency of relapses by approxi-mately one third and therefore is alsorecommended as a first-line treatment for RR-MS or for patients who are IFNβ intolerant.Glatiramer acetate results in a one-third reduc-tion in the inflammatory activity seen on MRI.

Glatiramer acetate is generally well toler-ated and unassociated with flulike symptoms.Immediate postinjection reactions associatedwith administration of glatiramer acetate in-clude a local inflammatory reaction and an un-common idiosyncratic reaction consisting offlushing, chest tightness with palpitations,anxiety, or dyspnea, which resolves sponta-neously without sequelae. Routine laboratorymonitoring is not considered necessary in pa-tients treated with glatiramer acetate, and thedevelopment of binding antibodies does notinterfere with the therapeutic efficacy of glati-ramer acetate.

Mitoxantrone Mitoxantrone (Novantrone) isan anthracenedione antineoplastic agent thatwas shown in a phase III, randomized,

placebo-controlled, multicenter trial to reducethe number of treated relapses by 67% andslowed progression on EDSS, ambulationindex, and MRI measures of disease activity. Itis therefore recommended for worsening formsof MS. Acute side effects of mitoxantrone in-clude nausea and alopecia. The lifetime use ofthis drug is limited to 2 to 3 years (or a cumu-lative dose of 120 to 140 mg/m2) because of itscumulative cardiotoxicity. Since a more rapidcardiotoxicity can occur, a new black boxwarning was added recommending patients tohave their baseline left ventricular ejectionfraction checked prior to the start of therapyand retested before each subsequent dose.There is also increasing awareness and concernabout treatment-related leukemias with thisdrug. More cases have been identified over thelast year suggesting that the risk is higher thanonce suspected. Mitoxantrone is a chemother-apeutic agent that should be prescribed and ad-ministered only by experienced physicians.

Natalizumab Natalizumab (Tysabri) is a novelmonoclonal antibody (mAb) directed againstthe adhesion molecule very late antigen-4(VLA-4) that is expressed on leukocytes (ex-cept neutrophils). This agent is the first andcurrently the only mAb approved for use inMS. Natalizumab prevents leukocytes frombinding to the vascular endothelium, especiallyduring inflammation and ultimately preventstheir transmigration into the CNS. Natal-izumab had promising results in a phase II trialand two phase III clinical trials. In the phase IIItrial, AFFIRM, sustained progression of dis-ability was reduced by 42%, clinical relapserate was reduced by 68%, and MRI activity(enhancing lesions) was reduced by 92% in thenatalizumab-treated group compared toplacebo. Natalizumab was removed from themarket in early 2005 after two MS patientsfrom the second phase III trial (SENTINEL)developed a rare, deadly viral infection of thebrain called progressive multifocal leukoen-cephalopathy (PML). Both patients were oncombination therapy, Avonex plus natalizumab.


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One patient eventually died and the other suf-fered major sustained disability. Natalizumabwas subsequently reintroduced to the marketin 2006 with a restricted indication for use as asecond-line monotherapy treatment in RR-MS.It was initially thought that PML might occuronly in the setting of combination therapy;however, since reapproval, at least four morecases of PML have been confirmed. There arenow a total of seven known cases of PML as of December 2008 (one case was identified post-mortem in a Crohn disease clinical trial afternatalizumab treatment). The absolute risk ofPML associated with natalizumab use is un-known, but an estimated risk of 0.1% isquoted and based on the previous clinical trialdata. Natalizumab is only available in theUnited States through the TOUCH program,which was implemented for careful monitoringof potential drug-related side effects (specifi-cally PML). TYGRIS is a worldwide phase IVsafety study that is monitoring the use of natal-izumab abroad. Natalizumab is given intra-venously every 4 weeks under the care andsupervision of an experienced infusion centerstaff. Serious allergic reactions can occur andtypically happen within 2 hours from the startof infusion. Other more common side effectsinclude infusion-related reactions, rashes, ele-vated transaminases, leucopenia, reactivationof various herpetic infections, sinusitis, andbladder/bowel infections. Two cases ofmelanoma were recently reported after natal-izumab use; however, it is unclear whether atrue association exists. Close neurologic moni-toring is required during natalizumab usealong with frequent blood work monitoring.Natalizumab is a potent monoclonal antibodythat should be prescribed and administeredonly by experienced physicians.

Other Drugs Used in Multiple Sclerosis Severalother drugs are commonly used in MS despitethe lack of U.S. Food and Drug Administra-tion approval and definitive evidence of effi-cacy. Numerous small clinical trials support

the modest effect of intravenous immunoglob-ulin G (IVIg), azathioprine, methotrexate, my-cophenolate mofetil, and cyclophosphamide.

Initiation of Early Therapy

■ SPECIAL CLINICAL POINT: Evidence isaccumulating that the best time to initiatedisease-modifying treatment is early in thecourse of the disease.

Data indicate that irreversible axon damage mayoccur early in the course of RR-MS and thatavailable therapies appear to be most effective at preventing new lesion formation but do not repair old lesions. With disease progression, the autoimmune response of MS may becomemore difficult to suppress. Weekly IM IFNβ-1a(Avonex) has been proved to reduce the cumula-tive probability of developing clinically definiteMS in patients who present with a first clinicaldemyelinating episode and have two or morebrain lesions on MRI (CHAMPS trial). High-dose interferon and glatiramer acetate therapyhave further supported earlier treatment in clini-cal trials (ETOMS, BENEFIT, and PRECISE).Based on these data, the National Multiple Scle-rosis Society (NMSS) recommends initiation ofimmunomodulating treatment at the time of di-agnosis. The clinician must weigh these consider-ations against the practical concerns of youngpatients, for whom the prospect of starting atherapy that requires self-injection may be fright-ening and burdensome. There are also few long-term (more than 10 years) data regarding thesafety and sustained efficacy of disease-modify-ing drugs. Some patients will opt to defer ther-apy, hoping to be among the minority of patientswith benign MS, but certain MRI and clinicalfeatures should prompt the physician and pa-tient to reconsider this approach. An MRI withcontrast-enhancing lesions, large burden ofwhite matter disease, or presence of any T1 lowsignal lesions (black holes) suggests a relativelypoor prognosis. It may be useful to repeat thebrain MRI in 6 months or 1 year to determinehow quickly the disease process is evolving. The


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presence of spinal cord lesions or atrophy alsosuggests a poor prognosis (Figs. 11.6 and 11.7).Clinical features may be less useful for assessingprognosis, and once definite disability develops,it may be too late to treat that component of thedisease.

Combination Therapy

Several trials are studying the addition of oralimmunosuppressive drugs, IVIg, glatiramer ac-etate to IFNβ, and other agents in patients whocontinue to have disease activity. The rationalefor this approach is based on experience with

other diseases, but further testing is requiredboth to ensure its safety and to ensure that themechanism of action of one drug does not inter-fere with that of the other drug. Recently, a lackof clinical efficacy was observed in the AvonexCombination Trial (Avonex and oral methotrex-ate) despite being well tolerated. Combinationtherapies may increase the risk of serious com-plications due to excessive immunosuppressionor decreased immune surveillance, so caution is advised when considering this treatmentparadigm.

Symptomatic Therapy

■ SPECIAL CLINICAL POINT: Appropriaterecognition and treatment of ongoingsymptoms can greatly improve quality of lifein patients with MS (Table 11.10).

Despite the recent advances in immunomodu-lating therapies to decrease new disease activity,many patients continue to suffer from ongoingsymptoms related to preestablished lesions.

■ SPECIAL CLINICAL POINT:Corticosteroids are the mainstay of acuterelapse treatment and are discussed as asymptomatic therapy because at this time noconclusive evidence exists that they have anyeffect on the natural history or long-termoutcome of a disease exacerbation.

FIGURE 11.6 T1-weighted magnetic resonance imaging scans of the brain of a patient with multiplesclerosis demonstrating atrophy. A: Sagittal image revealing thinned corpus callosum and ventriculomegaly.B: Axial image with extensive ventriculomegaly and T1 black hole formation.

A B

FIGURE 11.7 Magnetic resonance imaging scans ofthe spinal cord of a patient with multiple sclerosisrevealing multiple high signal lesions best seen using theshort tau inversion recovery (STIR) sequence.


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Corticosteroids There is evidence that corticos-teroids shorten the duration and severity of anexacerbation. Intravenous methylprednisolone(IVMP), 1,000 mg, is administered daily for 3 to5 days in the office or at home by a visitingnurse. On completion of the IVMP, prednisonemay be started, 60 mg orally in the morning andreduced by 10 mg every other day until taperedoff. The prednisone taper is not necessary buthelps reduce withdrawal symptoms in some pa-tients. An H2 blocker or proton pump inhibitormay be coadministered in patients with a his-tory of ulcer or heartburn. Metoclopramidemay be useful in patients who develop singultus(hiccups). The effects of steroids appear to di-minish with repeated usage, and many patientsreach a stage of unresponsiveness to steroids. Itis unclear whether that stage can be delayed orprevented by restricting the use of steroids, but

this appears to be a wise approach. Patients whobecome refractory to a short course of IVMPmay respond to higher doses (2 g/day), longercourses (10 days), or plasma exchange.

The most common side effects of treatmentare irritability, difficulty sleeping, and fluid re-tention. Additional well-recognized risks in-clude hypokalemia, gastrointestinal side effects,and osteoporosis. Fluid retention can be mini-mized by salt restriction during the therapy, anddiuretic use is discouraged because of the exag-gerated risk of hypokalemia. Ankle edema canbe minimized by wearing elastic stockings andelevating the leg. Hypokalemia is usually not aproblem in the absence of concurrent potas-sium wasting, such as with diuretic therapy, butin the presence of heart disease or with concur-rent diuretic therapy, oral potassium replace-ment should be administered and electrolyte

Pharmacologic Treatments: SymptomaticTABLE 11.10

Drug Indication Starting Dose Stable Dose Comments

Baclofen Spasticity 5 mg t.i.d. 10–40 mg Severe withdrawal t.i.d./q.i.d. reaction

Tizanidine Spasticity 2 mg q.h.s. 4–8 mg t.i.d. —Diazepam Spasticity, anxiety, 2–5 mg q.h.s. 5–10 mg t.i.d. —

insomnia, vertigoMeclizine Vertigo 12.5 mg t.i.d. 25 mg t.i.d. —Oxybutynin Urinary urgency 5 mg q.d. 5–10 mg b.i.d. Anticholinergic effects

may be contraindicated with glaucoma

Tolterodine Urinary urgency 1 mg q.d. 1–2 mg b.i.d. Anticholinergic effects may be contraindicated with glaucoma

Sildenafil Erectile 50 mg 0.5–4 hours 25–100 mg Contraindicated in dysfunction prior to intercourse macular degeneration

and with nitratesModafinil Fatigue 200 mg q.a.m. 100–200 mg Contraindicated with

q.d./b.i.d. certain heart conditionsAmantadine Fatigue 100 mg b.i.d. 100 mg b.i.d. —Gabapentin Pain, dystonic 300 mg q.h.s. 300–900 mg —

spasms t.i.d./q.i.d.Carbamazepine Pain, dystonic 100 mg q.d. 100–600 mg Contraindicated in patients

spasms t.i.d./q.i.d. with preexisting cytopenias


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levels should be monitored during therapy.Anxiety and difficulty sleeping are usuallyminor problems. Patients may on rare occa-sions develop significant depression or maniaduring corticosteroid therapy.

In the Optic Neuritis Treatment Trial(ONTT), the rate of visual recovery was signif-icantly faster in the IVMP group than in pa-tients treated with placebo or oral prednisone,but no significant differences in visual out-come were found between groups at 6 months.Prednisone therapy alone increased the risk ofnew episodes of optic neuritis in either eye;however, the oral dose used was not equivalentto the IV dose. The ONTT results have led towidespread use of IVMP for patients withoptic neuritis and an abnormal brain MRI, al-though equivalent doses of oral prednisonemay be just as efficacious. Hints of a neuro-protective effect of steroids in other studiesawait confirmation.

Spasticity Mild spasticity may be managed bystretching and exercise programs such as aquatherapy and yoga. Drug therapy is indicatedwhen stiffness, spasms, or clonus interfere withfunction or sleep. Baclofen is a good firstchoice for monotherapy. It exerts an antispas-tic effect by stimulating receptors for the in-hibitory neurotransmitter, GABA. The initialdosage is 5 to 10 mg three times a day with in-termittent upward dosage adjustments toachieve a therapeutic response or maximumtolerated dose, which may exceed 100 mg insome patients. Some patients may only requirebedtime dosing to control nocturnal spasms.The principal limiting side effects of baclofenare confusion, sedation, or increased muscleweakness, and careful attention must be givento not overmedicate patients who are depend-ent on their muscle tone to ambulate. Baclofenmay also unpredictably improve or worsenbladder function. Patients should neverabruptly discontinue baclofen from dosesgreater than 30 mg/day because a withdrawalsyndrome can occur consisting of confusion,seizures, or both. Tizanidine is an α-adrenergic

agonist that exerts an antispastic effect by stim-ulating central pathways that provide descend-ing inhibitory input to the spinal cord.Tizanidine is best initiated very slowly, startingwith 2 mg at bedtime, with gradual dosage ad-justment by 2- to 4-mg increments to a maxi-mum of 12 mg three times a day. The principalside effects are sleepiness, orthostatic hypoten-sion, and dry mouth. Tizanidine is said tobe less likely to cause motor weakness than baclofen, but its efficacy is often limited bysomnolence. It can be used alone but is oftensuccessful in low doses combined with ba-clofen. Gabapentin and benzodiazepines alsohave muscle-relaxant properties. In cases of ex-treme spasticity, continuous intrathecal ba-clofen can be delivered through an implantableinfusion pump placed in an abdominal subcu-taneous pocket and connected to a plasticcatheter that is tethered in the lumbar sub-arachnoid space. Occasionally, botulinumtoxin injections can be used for spasticity;however, it is less effective for larger musclegroups (hamstrings) and can be technically dif-ficult with varying success.

Pain and Spasms Patients with disagreeableparesthesias, atypical facial pain, or ticdouloureux often respond to antiepileptic drugssuch as carbamazepine, oxcarbamazepine,phenytoin, gabapentin, or pregabalin. Occa-sionally, amitriptyline can be helpful. Narcoticanalgesics are rarely the solution for chronicpain in MS. For refractory TN, IV phenytoinmay provide rapid relief. Baclofen, mexiletine,misoprostol, valproic acid, topiramate, and lidocaine have also been suggested but haveshown variable success. Surgical procedures torelieve medically intractable pain include rhizo-tomy, injection of anesthetics, and gammaknife. Paroxysmal dystonic spasms can be seenin MS and respond well in most instances tolow doses of some antiepileptic drugs.

Bladder, Bowel, and Sexual Dysfunction The firststep in managing a neurogenic bladder is to de-termine whether the problem is one of failure to


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empty, failure to store, or a combination of bothcalled detrusor external sphincter dyssynergia. Athorough history and urinalysis to rule out infec-tion is appropriate. Immediate treatment of bac-teriuria with antibiotics, even in the absence oftypical dysuria, is necessary in MS because of theknown propensity for infection to cause diseaseexacerbation. A postvoid residual urinary vol-ume is the best means to determine if there is re-tention. Anticholinergic drugs are the initialdrugs of choice for irritative bladder symptomsin the absence of infection. Oxybutynin, 5 mg, isincreased gradually until symptom relief or dis-tressing side effects, such as dry mouth, blurredvision, or worsening constipation, occur. Oxy-butynin is also available in a long-acting formu-lation with reduced peak side effects andenhanced efficacy compared with other agents.Tolterodine, 1 to 2 mg twice a day, is a useful al-ternative with fewer anticholinergic side effects.Solifenacin, 5 to 10 mg daily, and Trospium, 20mg two times a day, are newer overactive blad-der agents. Propantheline bromide andhyoscyamine sulfate are older alternative anti-cholinergic agents. Anticholinergic drugs can beused intermittently if bladder symptoms are dis-tressing at particular times, such as at bedtime orbefore a long automobile ride. The patientshould be made aware of possible urinary reten-tion with anticholinergics. Urinary residual vol-ume should be checked after initiating therapy orshould concerns arise about retention. In cases of concomitant retention and urgency,anticholinergics can be used in combination with intermittent bladder self-catheterization.Patients failing to achieve urinary continencewith anticholinergic pharmacotherapy, with orwithout self-catheterization, need formal uro-logic evaluation for consideration of diversionprocedures.

Drug treatment of urinary retention is usu-ally ineffective, but some patients may benefitfrom attempts at decreasing bladder neck toneusing α1-adrenergic receptor antagonists suchas terazosin, doxazosin, prazosin, and tamsu-losin. Desmopressin, a vasopressin analogue,can be used at a dose of 20 mg by intranasal administration nightly to treat nocturnal

incontinence by temporarily suppressing urineproduction. This approach should be usedwith caution in patients with hypertension orhyponatremia.

Constipation is very common in MS andshould be managed aggressively to avoidlong-term complications. Eating foods rich infiber may help with mild constipation. Stoolsofteners and/or laxatives can be used formoderate constipation. For fecal inconti-nence, the addition of fiber in the form of abulk fiber laxative (e.g., Metamucil) twicea day can provide enough bulk to the stoolto allow a partially incompetent sphincter tohold in the bowel movement long enough toallow the patient to reach a bathroom. Theuse of anticholinergics or antidiarrheal agentsmay be effective for short periods to combatincontinence associated with diarrhea.

A careful sexual history to determine theproblem(s) is a good first step in treating sexualdysfunction. Counseling the patient regardingavoiding the ill effects of elevated body temper-ature can be critical in managing problems thatworsen with sexual intimacy. Erectile dysfunc-tion (ED) in MS can be managed with sildenafileffectively initiated at 50 mg 60 minutes beforeintercourse (higher doses may be necessary).Sildenafil should be used with caution in olderpatients or in those with a history of heart dis-ease. This agent is contraindicated in patientstaking medications with nitrates in them and inpatients with macular degeneration. Neweragents including vardenafil and tadalafil canalso help with ED. Discontinuation of medica-tions known to decrease libido (selective sero-tonin reuptake inhibitors [SSRIs]) or impotence(β-blockers) should be considered if possible.

Neurobehavioral Manifestations The most com-mon neurobehavioral manifestation amenableto drug therapy is depression, which occurs inmore than 50% of patients with MS. Moderateor severe depression should be treated with oneof the SSRIs. For patients with psychomotor retardation and depression, fluoxetine, 20 to 80 mg daily, or sertraline, 50 to 200 mg daily,may be particularly effective. Paroxetine, 100 to


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200 mg daily, is often useful for patients whoare anxious and depressed. These drugs in-crease the levels of tricyclic antidepressants(TCAs), so care should be exercised in com-bining SSRIs with TCAs. Amitriptyline, 50 to200 mg at bedtime, can be useful in depressedpatients who are also having difficulty sleeping,headaches, or other pain. Treatment should beinstituted gradually to minimize anticholinergicor CNS side effects. The patient and familyshould be warned of the delay between initiat-ing therapy and observing a benefit. Thepseudobulbar syndrome of pathologic laughingor weeping may respond to amitriptyline in lowdoses. Several newer antidepressants may beuseful when the anticholinergic side effects ofTCAs or the sexual side effects of SSRIs (de-creased libido and orgasm) become intolerable.Bupropion, citalopram, escitalopram, and ven-lafaxine all may be better tolerated. Bipolar dis-order is also increased in MS and commonlytreated with valproic acid or lithium. SSRIs canaggravate mania complicating treatment ofbipolar disorder, which may warrant psychi-atric consultation.

Alprazolam, a benzodiazepine analogue,has been useful for anxiety in some patients. Adose of 0.25 to 0.50 mg two or three times aday is usually sufficient. Diazepam can be usedas an alternative drug. Infrequently, antipsy-chotic medications are needed in MS. Atypicalantipsychotic agents (risperidone, olanzapine,quetiapine) are preferred over typical agents(Haldol, Thorazine) to minimize the potentialfor extrapyramidal and anticholinergic side effects. As with other symptomatic therapies,the need for pharmacotherapy over time shouldbe assessed intermittently, and the drug shouldbe tapered if appropriate.

Fatigue Some types of MS fatigue may respondto short periods of rest, but if this is not possi-ble, or in cases of severe fatigue, medicationshould be considered. Amantadine, 100 mgtwice a day, may be effective in treating aboutone third of the cases of fatigue. Modafinil, anewer narcolepsy drug that acts as a CNS stim-ulant, was found to be effective in patients with

MS at a dose of 200 mg in the morning. Occa-sionally, treatment with an SSRI (fluoxetineand sertraline) can have a positive effect on fatigue even in the absence of overt depression.4-Aminopyridine (Fampridine or 4-AP) is aninvestigational voltage-gated potassium chan-nel (Kv1.4) blocker, that may help with fatigue,endurance, and ambulation in MS by prolong-ing action potentials. In higher doses, thisagent has been associated with seizures andconfusion limiting its use. A newer sustained-release formulation of 4-AP is under intense in-vestigation. A recent dose comparison studysuggested that walking speed in some patientsmay improve with the sustained-release form;however, two people experienced de novoseizures at the higher dose. Future studies areplanned to further assess the risk–benefit pro-file of this newer formulation.

Special Challenges for Hospitalized Patients Patients with MS may be hospitalized either dur-ing severe exacerbations or for other medicalproblems. In the case of an MS exacerbation,the patient should be screened for sources of in-fection and treated with antibiotics as appropri-ate. Rapid control of fever is also important toprevent worsening of symptoms. Exacerbationsthat warrant hospitalization are usually relatedto acute inability to ambulate or loss of self-care in the more advanced patient, and IV cor-ticosteroids are usually instituted. Plasmaexchange may be useful in steroid-unresponsivecases and requires hospitalization. Physical andoccupational therapy should be initiated imme-diately, and a rehabilitation plan should be putin place with attention to adaptive devices forthe home and orthotics or ambulation aids. Fornon–MS-related hospitalization, it is equallyimportant to be vigilant about infections to pre-vent exacerbation. MS rarely causes respiratorycompromise, and there are no absolute con-traindications to anesthesia. Cosmetic surgeryis discouraged, but necessary operations areusually well tolerated. Patients with MS do nothave any impairment in wound healing. Post-partum exacerbations usually do not occur forseveral weeks after delivery and thus are not


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a major obstetric complication. Counseling, social work, and attention to severe depressionshould be considered during periods of stresssuch as may occur during hospitalization.

Alternative Therapies Used by Patients with MultipleSclerosis Numerous alternative therapies havebeen advocated for MS but they are rarely testedin a placebo-controlled manner and, therefore,they cannot be recommended. Because MS is anunpredictable disease characterized early by re-lapses and spontaneous recovery, patients arevery susceptible to placebo effects and misguidedjudgments about the efficacy of alternative ther-apies. Bee stings have been used for many years,and for those who are not allergic about half ofpatients report a temporary boost in energy per-haps related to endogenous corticosteroid re-lease in response to cutaneous inflammation.Procarin is a patch used by some patients withMS and contains vitamin B12, histamine, caf-feine, and a proprietary substance. Several dietsfor MS, such as the Swank diet, have been popu-lar. Acupuncture is used to relieve pain andsometimes boost energy. Low-dose naltrexone(LDN) has been used off-label for MS and otherdiseases. Naltrexone is an opioid receptor antag-onist approved for the treatment of alcohol andopioid dependence. Its use in MS is controversialand there have been no randomized, double-blinded, placebo-controlled trials to assess LDNtolerability or efficacy. A small, open-label pilotstudy was done suggesting improvements in fa-tigue; however, the NMSS currently does notsupport the use of this agent until further testingis done. None of the above approaches has beentested adequately. Complementary medicine ad-vocates recommend yoga, meditation, aqua ther-apy, body-cooling devices, and stress reduction,all of which are reasonable and safe approachesto dealing with MS.

Physical Therapy Physical therapy has an im-portant role in managing MS. Regular exer-cise and stretching decrease MS symptoms ofstiffness, weakness, and pain and improveoverall well-being. Physical therapy has been

shown to improve disability from MS inde-pendent of drug interventions and should becontinued on a regular basis as part of a main-tenance regimen.

Novel Experimental ImmunomodulatoryApproaches

Several treatments are being tested in prelimi-nary trials, including antibodies to various crit-ical immune molecules (CD25 IL-2α receptor,CD20 B-cell marker, and the CD52 leukocytemarker), phosphodiesterase inhibitors, novelNSAIDs, β-adrenergic agonists, and immuno-suppressive regimens used during organ trans-plantation and malignancies. Of thesetherapies, the monoclonal antibodies (alem-tuzumab, daclizumab, rituximab) and noveloral agents (fingolimod, cladribine) seem tohave the most promise in MS, as shown in re-cent clinical trials. Despite the encouragingtrial data, there have been several serious com-plications associated with many of theseagents, which will potentially limit their futurewidespread use. Immunoablative protocolsusing extremely high doses of chemotherapies,followed by autologous stem-cell rescue, havebeen used in particularly aggressive forms ofMS. This approach has afforded disease stabi-lization, both clinically and by MRI, but has anunacceptably high morbidity and mortality atpresent.

Remyelination and Neuroprotection

Theoretical approaches to remyelination in-clude enhancing existing oligodendrocyte pre-cursors or neural stem cells by using growthfactors or direct transplantation of oligodendro-cytes or autologous stem cells. Growth factorssuch as insulinlike growth factor carry the inher-ent risk of nonspecifically activating the im-mune system. Anti-LINGO antibodies appear tobe a promising means of inducing endogenousremyelination by enhancing oligodendrocyteprogenitor cell differentiation into myelin-form-ing cells in vitro and in animal models.


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QUESTIONS AND DISCUSSION

1. A 24-year-old nursing school studentpresents to her primary care physician(PCP) with complaints of numbness andtingling in her hands for 1 month. Onquestioning, she responds that she has hadrecent fatigue and mild depression, whichshe attributed to stress. She denies anyother past medical history and is onlytaking birth control pills. Her entirephysical examination is normal. The nextappropriate step is to:

A. Recommend EMG/NCS to rule outcarpal tunnel syndrome.

B. Reassure her that she has no abnormalsigns on examination and thereforecannot be diagnosed with multiplesclerosis at this time.

C. Order blood tests and a brain MRI.

D. Treat her for depression and reevaluatein 3 to 6 months for improvement.

The correct answer is C. This woman couldhave early signs of MS, and because there isstrong evidence to support early initiation oftherapy, it is important to make a diagnosis.Blood testing is indicated to exclude thyroiddisease, vitamin B12 deficiency, other inflam-matory neurologic disorders, and infections. Abrain MRI is the single best screening tool forMS. Depression may be a symptom of MS andshould not be considered an adequate expla-nation for ill-defined somatic symptoms.Carpal tunnel syndrome is a common causeof hand numbness but is usually unilateraland would not explain the other reportedsymptoms.

2. A 36-year old woman is diagnosed withoptic neuritis. Her initial brain MRI revealsseveral demyelinating lesions. She isreferred to a neurologist, but she declinesimmunomodulating therapy and prefers to“wait and see.” Three months later, arepeat MRI is obtained and reveals a newgadolinium-enhancing lesion. At this time:

A. She has clinically definite MS accordingto McDonald criteria but treatment isnot indicated because this is probably abenign case.

B. She has clinically definite MS accordingto McDonald criteria and treatment witheither IFNβ or glatiramer acetate wouldbe appropriate.

C. She has PP-MS for which unfortunatelythere is no treatment.

D. In the absence of a second clinical event,she cannot be diagnosed with multiplesclerosis.

The correct answer is B. The demonstrationof a new lesion on MRI more than 3 monthslater provides evidence for dissemination intime and now fulfills criteria for a definite diagnosis of MS. The National Multiple Scle-rosis Society and many MS experts now favorearly initiation of therapy. Benign MS is de-fined as no disability after at least 10 years

Always Remember

• Multiple sclerosis (MS) has features ofinflammation, demyelination, axonal injury,and neurodegeneration.

• Visual dysfunction, sensory disturbances, andgait impairment are very common presentingsymptoms.

• MS is diagnosed clinically through thedemonstration of CNS lesions disseminatedin time and space and with no betterexplanation for the disease process.

• MRI is the single most useful test inconfirming the diagnosis of MS.

• Initiating early disease-modifying treatmentcan influence the clinical course.

• Symptomatic therapy can greatly improve MSpatients’ quality of life.

• MS is a complicated neurologic disease, andthe approaches to diagnosis and treatmentare changing rapidly, therefore, it isappropriate to refer any patient suspected ofhaving MS to a neurologist with MSexperience.


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and can only be diagnosed retrospectively.Progressive MS is defined as 6 months of un-abated worsening without exacerbations, and1 year of disease progression is required tomake a diagnosis of PP-MS.

3. A 40-year-old woman with RR-MSpresents for routine follow-up. She is beingtreated with IFNβ injections, and althoughshe has had no exacerbations since beingon treatment, she complains of increasedstiffness in her legs, and on questioning shealso admits to urinary urgency withoccasional episodes of incontinence. Onexamination, she is more spastic andhyperreflexic in her legs than 6 monthsago, but there is no clear sensory level overher spine or weakness. At this point:

A. She should stop taking the medication asshe now has secondary progressivedisease.

B. She should switch to anotherimmunomodulating drug as she hasfailed IFNβ therapy.

C. A urinalysis should be ordered to ruleout a urinary tract infection.

D. She should stop taking the medicationas these are likely side effects of the IFNβ.

The correct answer is C. Minor changesin neurologic function do not constituteprogressive disease, and it is likely that thereduction in relapses suggests that the IFNβis effective. Although exacerbation of spas-ticity can be a side effect of IFNβ, bladderfrequency is part of underlying MS and isoften a sign of urinary tract infection. An-tibiotic treatment of bacteriuria often allevi-ates the bladder symptoms and sometimesother new symptoms as well.

4. A patient with MS presents to the officewith several days of dizziness, diplopia, andtrouble walking straight. There has been noobvious precipitating factor (infection,heat, stress), and she has been taking hermedications on a regular basis. Onexamination, she is noted to have severalnew findings including bilateral INO,

finger to nose dysmetria, severe gait ataxia,and facial asymmetry. You recommend thefollowing:

A. Treatment with 2 weeks of prednisone(approximately 1 mg/kg).

B. Strict bedrest until the symptoms resolve. C. A brain MRI as soon as possible to

confirm an MS exacerbation. D. Treatment with 3 to 5 days of IV

methylprednisolone (1 g/day).

The correct answer is D. The patient ishaving an acute disabling exacerbation andshould be treated with IV methylpred-nisolone. A brain MRI is a useful means ofassessing disease activity (gadolinium-en-hancing lesions and new T2 lesions) anddetermining the extent of breakthrough dis-ease activity but is not obligatory if theclinical picture is clear.

SUGGESTED READING

Arnold DL, Matthews PM. MRI in the diagnosis andmanagement of multiple sclerosis. Neurology.2002;58:S23–S31.

Brex PA, Miszkiel KA, O’Riordan JI, et al. Assessing the risk of early multiple sclerosis in patients withclinically isolated syndromes: the role of a follow up MRI. J Neurol Neurosurg Psychiatry. 2001;70:390–393.

Brex PA, Ciccarelli O, O’Riordan JI, et al. A longitudinalstudy of abnormalities on MRI and disability frommultiple sclerosis. N Engl J Med. 2002;346:158–164.

Comi G. Why treat early multiple sclerosis patients? CurrOpin Neurol. 2000;13:235–240.

Dhib-Jalbut S. Mechanisms of action of interferons andglatiramer acetate in multiple sclerosis. Neurology.2002;58:S3–S9.

Frohman EM, Zhang H, Kramer PD, et al. MRI charac-teristics of the MLF in MS patients with chronic internuclear ophthalmoparesis. Neurology.2001;57:762–768.

Frohman EM, Racke MK, Raine CS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med.2006;354:942–955.

Grudzinski AN, Hakim Z, Cox ER, et al. The economicsof multiple sclerosis: distribution of costs and relation-ship to disease severity. Pharmacoeconomics.1999;15:229–240.


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Hafler DA, Compston A, Sawcer S, et al. Risk alleles formultiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357:851–862.

Hemmer B, Archelos JJ, Hartung HP. New concepts in theimmunopathogenesis of multiple sclerosis. Nat RevNeurosci. 2002;3:291–301.

Krupp LB, Rizvi SA. Symptomatic therapy for underrec-ognized manifestations of multiple sclerosis. Neurol-ogy. 2002;58:S32–S39.

Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity ofmultiple sclerosis lesions: implications for the pathogen-esis of demyelination. Ann Neurol. 2000;47:707–717.

Lutterotti A, Martin R. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol.2008;7:538–547.

Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the“McDonald Criteria.” Ann Neurol. 2005;58:840–846.

Trapp BD, Peterson J, Ransohoff RM, et al. Axonal tran-section in the lesions of multiple sclerosis. N Engl JMed. 1998;338:278–285.

Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. Thespectrum of neuromyelitis optica. Lancet Neurol.2007;6:805–815.

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Multiple Sclerosis - LiveWiseMS...Chapter 11 Multiple Sclerosis 193 1845. Charcot is generally credited with the first comprehensive account of the clinical and pathologic features