Diagnosis and management of multiple sclerosis

Diagnosis and management of multiple sclerosis

Peter A. Calabresi

Multiple sclerosis (MS) typically presents in adults who are 20 to 45 years of age. Occasionally, the disease presents in childhood or late middle age. Twice as many women are affected as men, and persons of Northern European descent appear to be at highest risk for the disease.

The onset of MS may be insidious or sudden. Common presenting symptoms include monocular visual impairment with pain (optic neuritis), paresthesias, weakness, and impaired coordination (Table 1). Frequent accompanying signs and symptoms include bladder urgency or retention, constipation, sexual dysfunction, fatigue, depression, diplopia, gait and limb ataxia, and Lhermitte’s sign (electrical sensation down the spine on neck flexion).

MS frequently is overlooked because initial symptoms resolve spontaneously in most patients. Relapses occur within months or years. In some patients, however, MS has a primary progressive course from onset.

Diagnosis

The diagnosis of MS is based on the presence of central nervous system (CNS) lesions that are disseminated in time and space (i.e., occur in different parts of the CNS at least three months apart), with no better explanation for the disease process. Because no single test is totally reliable in identifying MS, and a variety of conditions can mimic the disease (Table 2), diagnosis depends on clinical features supplemented by the findings of certain studies.

Magnetic resonance imaging (MRI) has been shown to be highly sensitive in detecting clinically silent MS plaques. Consequently, findings of this imaging modality are included in diagnostic criteria that have been proposed by one set of investigators. (1) The major advantage of the proposed criteria is that an early diagnosis of MS can be made if an MRI scan performed three months after a clinically isolated attack demonstrates formation of a new lesion. The proposed diagnostic criteria also define MRI lesion characteristics that increase the likelihood of MS, including number of lesions (nine or more), location of lesions (position abutting the ventricles; juxtacortical, infratentorial, or spinal position), and lesion enhancement with the use of contrast medium (Table 3).

CONFIRMATORY STUDIES

CNS Imaging. A brain MRI scan is the most useful test for confirming the diagnosis of MS. (1) MS lesions appear as areas of high signal, predominantly in the cerebral white matter or spinal cord, on weighted images (Figures 1 through 4). MRI scanning is useful for detecting structural pathology in regions that can be difficult to image by computed tomography, such as the posterior fossa, craniocervical junction, and cervical cord. (2) A brain MRI scan performed with a high-field magnet (1.5 tesla or greater) is abnormal in almost all patients who have clinically definite MS.

[FIGURES 1-4 OMITTED]

Sensory Evoked Potential Testing. Evoked potentials (visual, brainstem auditory, and somatosensory) may be useful in demonstrating the presence of subclinical lesions in sensory pathways or in providing objective evidence of lesions suspected on the basis of subjective complaints. (3) Of the sensory evoked potential tests, the visual evoked potential is the most useful because it can provide objective evidence of an optic nerve lesion that may not be evident on an MRI scan. Cerebrospinal Fluid (CSF) Analysis. In approximately 90 percent of patients with definite MS, the CSF IgG concentration is increased relative to other CSF proteins (e.g., albumin), and CSF gel electrophoresis reveals oligoclonal bands that are not present in a matched serum sample. (4) However, an increased CSF IgG index and the presence of oligoclonal bands are not specific for MS and therefore are not diagnostic of the disease. CSF analysis probably is most useful for ruling out infectious or neoplastic conditions that mimic MS.

Serologic Testing. Peripheral blood tests may be helpful in excluding other disease processes. Testing frequently includes determination of the vitamin level, thyroid-stimulating hormone level, erythrocyte sedimentation rate, and anti-nuclear antibody titers, as well as a test for Lyme disease, and a test for syphilis (rapid plasma reagin test).

In unusual cases, a more extensive evaluation may include tests for anti-neutrophil cytoplasmic antibodies, anti-phospholipid antibodies, Sjogren’s syndrome A and B, angiotensin-converting enzyme, human T-lymphotrophic virus type I, and very long chain fatty acids (for adrenoleukodystrophy). Rarely, human immunodeficiency virus infection and opportunistic infections can mimic MS.

DIAGNOSTIC ERROR

Certain clinical or laboratory red flags should alert physicians to a possible diagnostic error. (5) These flags include symptoms that could be explained by localized disease; the presence of steadily progressive disease; the absence of clinical remission; the absence of oculomotor, optic nerve, sensory, or bladder involvement; and normal CSF findings. However, none of these findings excludes the diagnosis of MS.

Management

SYMPTOMATIC THERAPIES

Spasticity. Mild spasticity may be managed by stretching and exercise programs such as water therapy, yoga, and physical therapy. Medication is indicated when stiffness, spasms, or clonus interferes with function or sleep. Baclofen (Lioresal), tizanidine (Zanaflex), gabapentin (Neurontin), and benzo-diazepines are effective antispastic agents (6) (Table 4). Intrathecal baclofen therapy has a major impact on medically intractable spasticity and has largely supplanted chemical rhizotomy or myelotomy. (7)

Paroxysmal Disorders. In most instances, dystonic spasms respond well to carbamazepine (Tegretol). (8) Paroxysmal pain can be treated effectively with anticonvulsants or amitriptyline (Elavil). (9)

Bladder Dysfunction. In patients with new bladder symptoms, urinalysis and culture should be performed to rule out infection, with appropriate treatment provided if needed. The first step in medical management of the neurogenic bladder is to determine whether the problem is a failure to empty urine or a failure to store urine. The history may or may not be helpful. A postvoid residual urinary volume is the best means of determining urinary retention.

The anticholinergic drugs oxybutynin (Ditropan) and tolterodine (Detrol) are effective for symptoms of failure to store urine (in the absence of infection or overflow incontinence). (10)

Drug treatment of urinary retention usually is ineffective, although some patients benefit from attempts to decrease bladder neck tone using an alpha (1)-adren-ergic receptor antagonist such as terazosin (Hytrin), doxazosin (Cardura), or tamsulosin (Flomax). (11) Bethanechol (Urecholine) may be helpful in patients with a flaccid bladder.

Definitive treatment of urinary retention involves teaching the patient to perform intermittent self-catheterization, if possible. In some patients, inhaled desmopressin (DDAVP) can be used to suppress nocturnal urinary production.

Bowel Symptoms. Constipation is common in patients with MS. It should be managed aggressively to avoid long-term complications.

Fecal incontinence is rare; when it occurs, the addition of fiber can provide enough bulk to the stool to allow a partially incompetent sphincter to hold in the bowel movement long enough for the patient to reach a bathroom. Short-term use of anticholinergics or antidiarrheal agents may be effective in combating incontinence associated with diarrhea.

Sexual Symptoms. A careful sexual history may reveal problems such as feelings of sexual inadequacy, impaired libido, or direct sexual dysfunction resulting from erectile dysfunction, impaired lubrication, spasticity, or heat-related sensory dysesthesias. Counseling, a review of the sexual side effects of medications, and medical therapy may be appropriate. In some patients with MS, erectile dysfunction can be managed effectively with sildenafil (Viagra). (12)

Neurobehavioral Manifestations. Depression occurs in more than one half of patients with MS. (13) Patients with mild, transient depression can be cared for with supportive measures. Those with more severe depression should be treated with selective serotonin reuptake inhibitors (SSRIs), which are less sedating than other antidepressants. Bedtime administration of amitriptyline can be useful in depressed patients who also are having difficulty sleeping or have headaches or other pain syndromes.

Fatigue. This symptom often responds to rest or medication. Amantadine (Symmetrel), 100 mg twice daily, may be effective. (14) Modafinil (Provigil), a narcolepsy drug that acts as a CNS stimulant, has been found to be effective in patients with MS; the drug is given in a dosage of 200 mg once daily in the morning. (15) Occasionally, SSRIs can relieve fatigue in patients with MS. Amantadine has the added advantage of having anti-influenza-A properties and may be given from October to March.

RELAPSES

In a patient with an apparent relapse of MS, it is important to rule out a treatable infection such as sinusitis, bronchitis, or urinary tract infection.

Adrenal Corticosteroids. Corticosteroids are the mainstay of symptomatic relief for an acute relapse of MS. These agents work through immunomodulatory and anti-inflammatory effects, restoration of the blood-brain barrier, and reduction of edema. They also may improve axonal conduction. Corticosteroid therapy shortens the duration of acute relapses and accelerates recovery. However, corticosteroids have not been shown to improve the overall degree of recovery or to alter the long-term course of MS. (16)

If a patient is having acute disability from an attack, the physician should consider treatment with a three- to five-day course of intra-venous methylprednisolone (or equivalent corticosteroid) in a dosage of 1 g administered intravenously in 100 mL of normal saline over 60 minutes once daily in the morning.

Other Treatments. In patients with MS, physical therapy always should be considered because it improves function and quality of life independent of drug therapy. (17) Supportive care in the form of counseling, occupational therapy, advice from social workers, input from nurses, and participation in patient support groups are all part of a united health care team approach to the management of MS. Some patients require temporary disability status.

Patients with MS often are tempted to try alternative therapies such as special diets, vitamins, bee stings, a compound “off-label” transdermal medication (i.e., Prokarin), or acupuncture. Although definitive proof of the effectiveness of these treatments in MS is lacking, patients sometimes use them in a complementary fashion. Sole reliance on alternative therapies should be discouraged because patients then may be deprived of therapies that have been shown to be effective in the treatment of MS.

DISEASE-MODIFYING THERAPIES

Four disease-modifying therapies for the initial management of MS are available in the United States: intramuscular interferon beta-1a (Avonex), subcutaneous interferon beta-1a (Rebif), interferon beta-1b (Betaseron), and glatiramer acetate (Copaxone). A fifth agent, mitoxantrone (Novantrone), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of worsening forms of relapsing-remitting MS and secondary progressive MS (Table 5).

Beta Interferons. The beta interferons are naturally occurring cytokines with a variety of immunomodulating and antiviral activities that may account for their therapeutic effects. The three FDA-approved beta interferons that are used for MS have been shown to reduce relapses by about one third and are recommended as first-line therapy or for use in glatiramer-intolerant patients who have relapsing-remitting MS. (18) In randomized, double-blind placebo-controlled trials, (19-21) use of beta interferons resulted in a 50 to 80 percent reduction in inflammatory lesions visualized on brain MRI scans. There also is evidence that these drugs improve quality of life and cognitive function. (22,23)

The major difference in the beta interferon drugs is that intramuscular interferon beta-1a is given once a week and subcutaneous interferon beta-1a and interferon beta-1b are given three times a week, or every other day, respectively. The adequacy of weekly dosing has been questioned. (24,25) There appears to be a modest dose-response effect with the beta interferons. (24) One study (26) of double-dose (60-mcg) intramuscular interferon beta-1a administered once a week found no benefit over the single-dose regimen. Whether the benefit of more frequent dosing is sustained remains unclear. An increased incidence of neutralizing antibodies with the more frequent subcutaneous dosing also must be considered. Influenza-like symptoms, including fever, chills, malaise, muscle aches, and fatigue, occur in approximately 60 percent of patients treated with interferon beta-1a or interferon beta-1b. These symptoms usually dissipate with continued therapy and premedication with a nonsteroidal anti-inflammatory drug. Dose titration at the initiation of beta interferon therapy also is a useful strategy.

Other side effects of the beta interferons include injection-site reactions, worsening of pre-existing spasticity, depression, mild anemia, thrombocytopenia, and elevated transaminase levels. These side effects usually are not severe and rarely lead to discontinuation of treatment.

Treatment with any beta interferon can result in the development of neutralizing antibodies. Although study results are variable, once-weekly intramuscular interferon beta-1a therapy has been reported to have the lowest incidence of neutralizing anti-body development. (27) The effect of neutralizing antibodies on the long-term efficacy of beta interferon therapy remains to be fully defined because titers and durations of antibody positivity (some neutralizing antibodies resolve with time) are variable.

Glatiramer. This drug is a polypeptide mixture that was originally designed to mimic and compete with myelin basic protein. Its mechanism of action is distinct from that of the beta interferons; therefore, patients may respond differently to the drug. Glatiramer in a dosage of 20 mg administered subcutaneously once daily has been shown to reduce the frequency of MS relapses by approximately one third. The drug also is recommended as a first-line treatment in patients with relapsing-remitting MS and in the treatment of patients who cannot tolerate beta interferon therapy. (28) Glatiramer therapy results in a one-third reduction in the inflammatory activity seen on MRI scans. (29)

Glatiramer generally is well tolerated and is not associated with influenza-like symptoms. (30) Immediate postinjection reactions include local inflammation and an uncommon idiosyncratic reaction consisting of flushing, chest tightness with palpitations, anxiety, or dyspnea, which resolves spontaneously without sequelae. Routine laboratory monitoring is not considered necessary in patients treated with glatiramer, and the development of binding anti-bodies does not interfere with therapeutic efficacy. (31)

Mitoxantrone. A phase-III, randomized, placebo-controlled, multicenter trial (32) found that mitoxantrone, an anthra-cenedione antineoplastic agent, reduced the number of treated MS relapses by 67 percent and slowed progression on the Expanded Disability Status Scale, Ambulation Index, and MRI measures of disease activity. Mitoxantrone is recommended for use in patients with worsening forms of MS.

Acute side effects of mitoxantrone include nausea and alopecia. Because of cumulative cardiotoxicity, the drug can be used for only two to three years (or for a cumulative dose of 120 to 140 mg per There also is some concern about treatment-related leukemia. Mitoxantrone is a chemotherapeutic agent that should be prescribed and administered only by experienced health care professionals.

NEW AND OTHER DRUGS

Natalizumab (Antegren) is in the final stages of phase-III clinical trails and is under accelerated review by the FDA. In a phase-II clinical trial, (33) this drug appeared promising in that it reduced active MRI lesions by 90 percent and decreased MS relapses by more than 50 percent. Natalizumab is a monoclonal antibody that is directed against an adhesion molecule called VLA-4. The drug is administered intravenously once a month.

Despite lack of FDA approval and definitive evidence of efficacy, several other drugs commonly are used in patients with MS. A number of small clinical trials (34-38) support the modest effect of intravenous IgG, aza-thioprine, methotrexate, and cyclophosphamide, either alone or in combination with standard therapy.

Initiation of Early Therapy

Accumulating evidence indicates that the best time to initiate disease-modifying treatment is early in the course of MS. (39) Data indicate that irreversible axonal damage may occur early in relapsing-remitting MS, (40) and that drug therapies appear to be more effective in preventing new lesion formation than in repairing old lesions. With disease progression, the autoimmune response of the disease may become more difficult to suppress. Both intramuscular interferon beta-1a therapy and subcutaneous interferon beta-1a therapy have been shown to reduce the cumulative probability of the development of clinically definite MS in patients who present with a first clinical demyelinating episode and have two or more brain lesions on an MRI scan. (41,42) Based on these data, the National Multiple Sclerosis Society (43) supports the initiation of immuno-modulating therapy at the time of diagnosis.

The physician must weigh evidence and recommendations against the practical concerns of young patients for whom the prospect of starting therapy that requires self-injection may be frightening and burdensome. Furthermore, few long-term data (more than 10 years) are available on the safety and sustained efficacy of disease-modifying drugs. A patient may opt to defer therapy, hoping to be among the minority of persons with benign MS; however, certain MRI and clinical features should prompt the physician and patient to reconsider this approach.

An MRI scan with contrast-enhancing lesions, a large burden of white matter disease, or any T1 low-signal lesions (black holes) suggests a relatively poor prognosis. (44) It may be useful to repeat brain MRI scanning in six months or one year to determine how quickly the disease process is evolving. The presence of spinal cord lesions or atrophy also suggests a poor prognosis. Clinical features may be less useful for assessing prognosis. Once definite disability develops, it may be too late to treat that component of the disease.

The ability to diagnose and treat MS has improved considerably in the past 10 years because of the availability of MRI and partially effective immunomodulating therapies. The limited efficacy of immunomodulating drugs in the later, noninflammatory stages of MS highlights the importance of developing remyelinating and neuroprotective strategies for the disease.

TABLE 1

Common Symptoms and Signs

of Multiple Sclerosis

Symptoms

Depression

Dizziness or vertigo

Fatigue

Heat sensitivity

Lhermitte’s sign (electrical sensation down

the spine on neck flexion)

Numbness, tingling, pain

Urinary bladder

dysfunction

Visual impairment (monocular or diplopia)

Weakness

Signs

Action tremor

Decreased perception of pain, vibration,

or position

Decreased strength

Hyperreflexia, spasticity, Babinski’s sign

Impaired coordination and balance

Impaired visual acuity or red color perception

with optic disc pallor and afferent papillary

defect; disconjugate eye movements

Nystagmus

TABLE 2

Conditions That Can Mimic Multiple

Sclerosis

CNS infection (e.g., Lyme disease, syphilis, human immunodeficiency

virus infection, human T-lymphotrophic virus type I)

CNS inflammatory condition (e.g., sarcoidosis, systemic lupus

erythematosus, Sjogren’s syndrome)

CNS microvascular disease (e.g., disease caused by hypertension,

diabetes mellitus, vasculitis, CADASIL)

Genetic disorder (e.g., leukodystrophy, hereditary myelopathy,

mitochondrial disease)

Structural or compressive condition of the brain and spinal cord (e.g.,

cervical spondylosis, tumor, herniated disc, Chiari’s malformation)

Vitamin deficiency

CNS = central nervous system; CADASIL = cerebral autosomal dominant

arteriopathy with subcortical infarcts and leukoencephalopathy.

TABLE 3

MRI Lesion Characteristics

Suggestive of Multiple Sclerosis

Brain lesions

High signal on weighted and FLAIR MRI

sequences (more than nine lesions)

When actively inflamed, often enhanced with

gadolinium contrast

Position abutting ventricles (often perpendicular)

Juxtacortical position (gray-white junction)

Involvement of brainstem, cerebellum, or

corpus callosum

Spinal cord lesions

One or two vertebral segments in length

Incomplete cross-sectional involvement

(dorsolateral common)

Less likely to enhance with gadolinium contrast

No cord swelling

Better seen with STIR MRI sequences

MRI = magnetic resonance imaging; FLAIR = fluid attenuation inversion

recovery; STIR = short tau inversion recovery.

TABLE 4

Symptomatic Therapies for Multiple Sclerosis

Symptom Therapy and possible adverse effects

Spasticity Baclofen (Lioresal), 10 to 40 mg three times daily;

in high doses, can cause weakness and fatigue

Tizanidine (Zanaflex), 2 to 8 mg three times daily;

in high doses, can cause weakness and fatigue

Gabapentin (Neurontin), 300 to 900 mg three or four

times daily; in high doses, causes fatigue

Pain and Gabapentin, 300 to 900 mg three or four times daily;

paroxysmal in high doses, causes fatigue

disorders Carbamazepine (Tegretol), 100 to 600 mg three times

daily; in high doses, causes rash and neurologic side

effects; requires monitoring of complete blood count

and liver function

Other anticonvulsants

Amitriptyline (Elavil), 10 to 150 mg per day at bedtime

Bladder Oxybutynin (Ditropan), 5 mg once daily to 20 mg per day

urgency in divided doses; causes dry mouth and can exacerbate

glaucoma or worsen urinary retention

Tolterodine (Detrol), 2 to 4 mg twice daily; causes dry

mouth and can exacerbate glaucoma or worsen urinary

retention (these side effects occur less often than

with oxybutynin)

Depression SSRIs preferred because of activating properties; can

have sexual side effects

Alternatives to SSRIs when sexual side effects occur:

extended-release venlafaxine (Effexor) 75 to 225 mg

per day, or sustained-release bupropion (Wellbutrin),

150 mg per day to 150 mg twice daily

Third-line drug or for use when a patient has a sleep

disorder or concomitant headaches: amitriptyline,

10 to 150 mg per day at bedtime

Fatigue Amantadine (Symmetrel), 100 mg twice daily; can cause

rash, edema, and anticholinergic effects

Modafinil (Provigil), 100 to 200 mg given in the

morning; can cause jittery sensation and palpitations

SSRIs, can have sexual side effects

SSRI = selective serotonin reuptake inhibitor

TABLE 5

Immunomodulatory Drugs for the Treatment of Multiple Sclerosis

Cost for

Side effects and 1 month of

Drug Dosage monitoring treatment *

Interferon 30 mcg IM Influenza-like symptoms $1,278

beta-1a once weekly Monitoring of CBC and

(Avonex) liver function

Interferon 22 to 44 mcg Influenza-like symptoms 1,517

beta-1a SC three and injection-site

(Rebif) times weekly reactions

Monitoring of CBC and

liver function

Interferon 0.25 mg SC Influenza-like symptoms 1,403

beta-1b every other day and injection-site

(Betaseron) reactions

Monitoring of CBC and

liver function

Glatiramer 20 mg SC Injection-site 1,261

(Copaxone) once daily reactions and,

rarely, a benign

systemic reaction

Requires no blood

monitoring

Mitoxantrone 5 to 12 mg per Mild chemotherapy- 1,453

(Novantrone) [m.sup.2] IV related side effects,

every 3 months cumulative

cardiotoxicity, small

increased risk of

leukemia

IM = intramuscular; CBC = complete blood count SC = subcutaneous;

IV = intravenous.

*–Estimated cost to the pharmacist (rounded to the nearest dollar) for

the lowest given dosage, based on average wholesale prices in Red book.

Montvale, N.J.: Medical Economics Data, 2004. Cost to the patient will

be higher, depending on prescription filling fee.

Strength of Recommendations

Key clinical recommendation Label References

Magnetic resonance imaging should be performed or C 1

repeated three months after a clinically

suspicious episode to facilitate early diagnosis

of MS.

Corticosteroid therapy should be used to shorten A 16

the duration of MS relapses and accelerate

recovery.

Disease-modifying treatment should be started C 35

early in the course of MS to minimize irreversible

axonal damage.

Glatiramer and the beta interferons have different C 23

mechanisms of action. Patients with MS who have an

unsatisfactory response to beta interferons should

be considered for glatiramer therapy.

Patients with worsening forms of MS may be B 26

referred for mitoxantrone therapy; however, this

agent has acute short-term adverse effects, as

well as serious long-term adverse effects that

include cardiotoxicity.

MS = multiple sclerosis.

A = consistent good quality patient-oriented evidence;

B = inconsistent or limited quality patient-oriented evidence;

C = consensus, disease-oriented evidence, usual practice,

opinion, or case series. See page 1845 for more information.

REFERENCES

(1.) McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the Inter-national Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

(2.) Arnold DL, Matthews PM. MRI in the diagnosis and management of multiple sclerosis. Neurology 2002;58(8 suppl 4):S23-31.

(3.) Chiappa KH. Pattern-shift visual, brainstem auditory and short-latency somatosensory evoked potentials in multiple sclerosis. Ann N Y Acad Sci 1984;436:315-27.

(4.) Cole SR, Beck RW, Moke PS, Kaufman DI, Tourtellotte WW. The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Optic Neuritis Study Group. Neurology 1998;51:885-7.

(5.) Rudick RA, Schiffer RB, Schwetz KM, Herndon RM. Multiple sclerosis. The problem of incorrect diagnosis. Arch Neurol 1986;43:578-83.

(6.) Cutter NC, Scott DD, Johnson JC, Whiteneck G. Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000;81:164-9.

(7.) Sampson FC, Hayward A, Evans G, Morton R, Collett B. Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity. J Neurosurg 2002;96:1052-7.

(8.) Bhatia KP. The paroxysmal dyskinesias. J Neurol 1999;246:149-55. 9. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother 2002;3:59-71.

(10.) Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, et al. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc 2001;76:358-63.

(11.) O’Riordan JI, Doherty C, Javed M, Brophy D, Hutchinson M, Quinlan D. Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis? J Urol 1995;153:1114-6.

(12.) Hatzichristou DG. Sildenafil citrate: lessons learned from 3 years of clinical experience. Int J Impot Res 2002;14(suppl 1):S43-52.

(13.) Feinstein A, Feinstein K. Depression associated with multiple sclerosis. Looking beyond diagnosis to symptom expression. J Affect Disord 2001;66:193-8.

(14.) Krupp LB, Rizvi SA. Symptomatic therapy for underrecognized manifestations of multiple sclerosis. Neurology 2002;58(8 suppl 4):S32-9.

(15.) Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-83.

(16.) Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987;50:511-6.

(17.) Patti F, Ciancio MR, Reggio E, Lopes R, Palermo F, Cacopardo M, et al. The impact of outpatient rehabilitation on quality of life in multiple sclerosis. J Neurol 2002;249:1027-33.

(18.) PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS [published correction appears in Neurology 2001;57:1146]. Neurology 2001;56:1628-36.

(19.) Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 1993;43:662-7.

(20.) Simon JH, Jacobs LD, Campion M, Wende K, Simonian N, Cookfair DL, et al. Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 1998;43:79-87.

(21.) Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta-1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis. Ann Neurol 1999;46:197-206.

(22.) Rice GP, Oger J, Duquette P, Francis GS, Belanger M, Laplante S, et al. Treatment with interferon beta-1b improves quality of life in multiple sclerosis. Can J Neurol Sci 1999;26:276-82.

(23.) Fischer JS, Priore RL, Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol 2000;48:885-92.

(24.) Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVI-DENCE Trial. Neurology 2002;59:1496-506.

(25.) Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453-60.

(26.) Double-blind randomized multicenter dose-comparison study of interferon-beta-1a (AVONEX): rationale, design and baseline data. Mult Scler 2001;7:179-83.

(27.) Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, et al. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 2002;73:148-53.

(28.) Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;50:701-8.

(29.) Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001;49:290-7.

(30.) Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45:1268-76.

(31.) Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven-Kreitman R, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 2001;115:152-60.

(32.) Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360:2018-25.

(33.) Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23.

(34.) Achiron A, Gabbay U, Gilad R, Hassin-Baer S, Barak Y, Gornish M, et al. Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 1998;50:398-402.

(35.) Yudkin PL, Ellison GW, Ghezzi A, Goodkin DE, Hughes RA, McPherson K, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991;338:1051-5.

(36.) Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, Schwetz KM, Fischer J, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30-40.

(37.) Calabresi PA, Wilterdink JL, Rogg JM, Mills P, Webb A, Whartenby KA. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. Neurology 2002;58:314-7.

(38.) Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 2002;8:142-54.

(39.) Coyle PK, Hartung HP. Use of interferon beta in multiple sclerosis: rationale for early treatment and evidence for dose- and frequency-dependent effects on clinical response. Mult Scler 2002;8:2-9.

(40.) Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transaction in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-85.

(41.) Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brown-scheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898-904.

(42.) Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandex O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576-82.

(43.) National Multiple Sclerosis Society. Disease management consensus statement. Accessed online September 1, 2004, at http://www.nationalmssociety.org/pdf/forpros/Exp_Consensus.pdf.

(44.) Filippi M, Grossman RI. MRI techniques to monitor MS evolution: the present and the future. Neurology 2002;58:1147-53.

The author indicates that he does not have any conflicts of interest. Sources of funding: Dr. Calabresi has received research support or honoraria as a consultant or speaker for Berlex Laboratories, Biogen, Inc., IDEC Pharmaceuticals, Immunex Corporation, Serono, Inc., and Teva Neuroscience, Inc.

PETER A. CALABRESI, M.D., is associate professor of neurology at Johns Hopkins University School of Medicine, Baltimore. Dr. Calabresi received his medical degree from Brown University School of Medicine, Providence, R.I., and completed a residency in neurology at Strong Memorial Hospital, Rochester, N.Y., where he served as chief resident. He also was a clinical associate and research fellow in the Neuroimmunology Branch of the National Institutes of Health, Bethesda, Md. Dr. Calabresi serves on the fellowship and clinical care committees of the National Multiple Sclerosis Society.

Address correspondence to Peter A. Calabresi, M.D., Johns Hopkins University School of Medicine, Pathology Building 627, 600 N. Wolfe St., Baltimore, MD 21287. Reprints are not available from the author.

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