Multiple Sclerosis Treatment & Management

  • Author: Christopher Luzzio, MD; Chief Editor: B Mark Keegan, MD, FRCPC   more...
 
Updated: Feb 16, 2012
 

Approach Considerations

Treatment of multiple sclerosis (MS) has 2 aspects: immunomodulatory therapy (IMT) for the underlying immune disorder and therapies to relieve or modify symptoms. IMT is directed toward reducing the frequency of relapses and slowing progression. Currently, disease-modifying agents have been approved for use only in relapsing forms of MS.

Although therapy for clinically isolated syndrome (a single episode of neurologic symptoms) with immunomodulatory medications has not yet become standard practice throughout the world, trials suggest that early intervention may be appropriate. Decisions regarding early treatment can be guided by using the McDonald diagnostic criteria to help differentiate clinically isolated syndrome from a first episode of relapsing MS.

Given the wide spectrum of clinical manifestations that MS can produce, patients may require consultations with a variety of specialists. Indeed, patients with MS are often best served by a multidisciplinary approach.

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Emergency Department Management

Medical management goals that are sometimes achievable in the emergency department are to relieve symptoms and to ameliorate risk factors associated with an acute exacerbation. In patients with fulminant MS or disseminating acute encephalitis, management involves the following:

  • Stabilize acute life-threatening conditions
  • Initiate supportive care and seizure precautions
  • Monitor for increasing intracranial pressure

Consider intravenous steroids, IV immunoglobulin (IVIG), or emergent plasmapheresis. One study suggested that plasmapheresis may be superior to IV steroids in patients with acute fulminant MS.[59] The 2011 American Academy of Neurology (AAN) plasmapheresis guideline update states that plasmapheresis is possibly effective and may be considered in acute fulminant demyelinating CNS disease.[60]

Identification and control of known precipitants of MS exacerbation include the following:

  • Aggressively treat infections with antibiotics
  • In patients with a fever, normalize the body temperature with antipyretics, as even small increases in temperature can strongly affect conduction through partially demyelinated fibers
  • Provide urinary drainage and skin care, as appropriate

Preoperative considerations for emergency surgery in patients with MS are as follows:

  • Gastric emptying may be delayed secondary to autonomic GI dysfunction
  • Lability of the autonomic nervous system may precipitate hypotension during anesthesia and surgery
  • Spontaneous ventilation may be disrupted
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Treatment of Acute Relapses

Methylprednisolone (Solu-Medrol) can hasten recovery from an acute exacerbation of MS. There is no evidence that it changes the overall disease progression.

Plasma exchange (plasmapheresis) can be used short term for severe attacks if steroids are contraindicated or ineffective. The 2011 AAN guideline for plasmapheresis in neurological diseases categorizes plasmapheresis as “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids.[60]

Texts commonly describe anti-inflammatory treatment as an option for acute transverse myelitis and acute disseminated encephalitis; however, not many supporting data are given. Dexamethasone is commonly used. Anti-inflammatory treatment for ON is very controversial.

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Immunomodulatory Therapy for Relapsing-Remitting MS

Disease-modifying therapies have shown beneficial effects in patients with relapsing MS, including reduced frequency and severity of clinical attacks. These agents appear to slow the progression of disability and the reduce accumulation of lesions within the brain and spinal cord. The disease-modifying agents for MS (DMAMS) currently approved for use by the US Food and Drug Administration (FDA) include the following:

  • Interferon beta-1a (Avonex, Rebif)[61] )
  • Interferon beta-1b (Betaseron, Extavia)[62]
  • Glatiramer (Copaxone)[63]
  • Natalizumab (Tysabri)[64, 65]
  • Mitoxantrone (Novantrone)[66]
  • Fingolimod (Gilenya)[67]

These drugs are currently FDA approved only for relapsing MS. With the exception of fingolimod, which is given orally, all these drugs are administered by intramuscular or subcutaneous injection.

Patient lifestyle, patient tolerance, and adverse effects of injections should be considered in the choice of DMAMS. To a certain extent, health-care-provider preference and experience with the medications also play a role in determining which drug is appropriate in a particular situation.

Interferon beta-1b therapy

The first medication approved by the FDA for MS, in 1993, was interferon beta-1b (Betaseron, Extavia). It is indicated for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode of MS and have MRI features consistent with MS.[62]

In a double-blind, placebo-controlled trial of 372 patients with relapsing-remitting MS, interferon beta-1b (8 million IU every other day) decreased the frequency of relapses by 34% after 2 years. In treated patients, the MRI T2 lesion burden increased 3.6% over 5 years, compared with 30.2% in the placebo group. At 5 year follow-up, the incidence of disease progression was lower in the interferon beta-1b group compared with the placebo group (35% versus 45%).[68]

Interferon beta-1b is administered every other day subcutaneously by self-injection. The most frequently reported adverse reactions include asthenia, depression, flu-like symptoms, hypertonia, increased liver enzymes, injection site reactions, leukopenia, and myasthenia. Interferon beta-1b can be coadministered with analgesics or antipyretics to help with the occurrence of flu-like symptoms.[62]

Interferon beta-1a therapy

In a study of 301 patients with relapsing-remitting disease who were given weekly intramuscular injections (6 million U [30 µg]) of interferon beta-1a (Avonex, Rebif), the annual exacerbation rate decreased 29%.[69] Over 2 years, disease progression occurred in 21.9% of patients in the interferon beta-1a group and 34.9% of those in the placebo group. In addition, MRI data showed a decrease in the mean lesion volume and number of enhancing lesions in the interferon beta-1a group.

In Europe and Canada, higher doses of interferon beta-1a were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study.[70] The dose-comparison study of interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 µg/wk and a 33% reduction in those receiving 132 µg/wk. This study, of 560 patients with relapsing-remitting disease, also demonstrated a significant reduction in accrual of disability and MRI lesion burden with the higher dose.[70]

In 2002, the FDA approved interferon beta-1a in 22 µg and 44 µg formulations given 3 times per week.

In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 µg 3 times weekly (Rebif) than with 30 µg once weekly (25% versus 37%).[71] In addition, the mean number of active unique MRI lesions per patient per scan was lower (0.17 versus 0.33). However, patients treated with the Rebif dosage were much more likely to develop neutralizing antibodies. Freedom from relapse, the primary outcome measure, occurred at significantly lower rates in the patients with neutralizing antibodies.[71]

In a subsequent crossover phase of the EVIDENCE trial, patients who were originally randomized to low-dose weekly treatment were switched to the high-dose 3-times-weekly regimen for an additional 8 months. These patients demonstrated a 50% reduction in mean relapse rates, with significant concomitant reductions in MRI activity.[72]

In patients with a history of depression, interferons should be used with caution. Glatiramer may be an appropriate choice in such cases.

Glatiramer

Glatiramer (Copaxone) is a synthetic polypeptide approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer’s mechanism of action is unknown, but this agent is thought to modify immune processes believed to be responsible for the pathogenesis of MS.[63]

In a double-blind trial that included 251 patients with relapsing-remitting MS (RRMS), treatment with glatiramer resulted in a 29% reduction in the relapse rate over 2 years; accumulation of disability was also slowed.[73] A follow-up open-label study demonstrated continued efficacy of glatiramer over 6 years.[74]

Natalizumab

Natalizumab (Tysabri) is a humanized monoclonal antibody that binds with the adhesion molecule alpha-4 integrin, inhibiting its adherence to its receptors. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is generally used in patients who have not responded to a first-line disease-modifying therapy or who have very active disease.[65]

In a placebo-controlled clinical trial, the use of natalizumab reduced the relapse rate (68%) and progression of disability (42%) over a period of 2 years.[75] Natalizumab is given as a 300 mg IV infusion over 1 hour every 4 weeks.

Natalizumab has been associated with progressive multifocal leukocephalopathy (PML), an opportunistic infection of the brain that can lead to death or severe disability. The risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity.

Three cases of PML associated with natalizumab use prompted its temporary withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as Tysabri Outreach Unified Commitment to Health (TOUCH). Use of natalizumab is limited to patients, physicians, and infusion centers that are registered with the TOUCH program.

Fingolimod

Fingolimod (Gilenya) is the first oral disease modifying treatment for relapsing forms of MS approved by the FDA. Like other disease-modifying agents for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day.[67]

Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate receptors, which are a subset of a larger family of cell-surface, G protein–coupled receptors that mediate the effects of bioactive lipids known as lysophospholipids. Lysophospholipids are membrane-derived bioactive lipid mediators that can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.

The mechanism of action of fingolimod is incompletely understood but appears to be fundamentally different from other MS medications. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Fingolimod promotes sequestration of lymphocytes within the lymph nodes, which may reduce lymphocyte migration into the central nervous system.[76]

Adverse effects of fingolimod include transient, generally asymptomatic bradycardia and infrequent atrioventricular block with the first dose. The reduction of peripheral lymphocyte count can possibly lead to an increased risk of infection. Reversible, asymptomatic elevations of liver enzymes may also occur. Other adverse reactions that have been commonly reported include headache, diarrhea, ALT/AST elevations and back pain.

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Treatment of Aggressive MS

High-dose cyclophosphamide (Cytoxan) has been used for induction therapy to stabilize aggressive MS. In a retrospective study of 32 patients, Harrison et al reported that induction with cyclophosphamide (200 mg/kg IV infusion over 4 days) followed by long-term maintenance therapy with glatiramer was well tolerated and appeared to be effective in reducing the risk of relapse, disability progression, and new MRI lesions.[77] Adverse effects of cyclophosphamide include leukemia, lymphoma, infection, and hemorrhagic cystitis.

Mitoxantrone is an immunosuppressive agent approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS. Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.

Mitoxantrone has a black-box warning for cardiotoxicity. The risk of cardiotoxicity increases with cumulative mitoxantrone dose and can occur whether or not cardiac risk factors are present. Mitoxantrone therapy in MS patients and in patients with cancer increases the risk of developing secondary acute myeloid leukemia (AML). Mitoxantrone also has a black-box warning for secondary leukemia. Mitoxantrone treatment in MS patients and in patients with cancer increases the risk of developing secondary AML.

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Immunomodulatory Therapy for Progressive MS

Currently, no approved treatments are available for primary progressive MS (PPMS). A literature review by Rojas et al indicated that interferon beta could not be linked to reduced disability progression in patients with PPMS.[78] The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

Patients with secondary progressive MS (SPMS) who experience relapses are sometimes started on a DMAMS approved for relapsing-remitting MS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with SPMS.[79] }

In a European study of SPMS, patients receiving interferon beta-1b showed a highly significant delay in time to disease progression. FDA approval has not been granted yet for this indication, however.[80, 81, 82]

Mitoxantrone is another treatment option for progressive MS. It is approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing remitting MS.

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Experimental Agents

Alemtuzumab, a monoclonal antibody that is currently approved by the FDA as monotherapy for B-cell chronic lymphocytic leukemia, has been granted fast-track status for FDA approval for use in relapsing-remitting MS. In a single-arm, open-label study in 45 patients with MS that was refractory to treatment with interferon, alemtuzumab effectively reduced relapse rates and improved clinical scores.[83]

Although fingolimod is the only oral drug currently approved for use in MS, other oral agents are under development, including teriflunomide, laquinimod, and dimethyl fumarate. Most of these agents have completed phase 3 testing.[84]

Teriflunomide has both antiproliferative and anti-inflammatory properties. A proof-of-concept clinical trial in patients with relapsing MS demonstrated that teriflunomide produced significant long-term reductions in MRI activity and improvement in clinical endpoints. Subsequent studies have shown that teriflunomide can be safely added to beta interferon or glatiramer therapy, with some evidence of additional improvements in MRI disease burden and clinical signs. Teriflunomide has an acceptable and manageable safety and tolerability profile.[85]

Other experimental agents under intense investigation for use in MS include daclizumab (anti-CD25 antibody)[86] and ocrelizumab (anti-CD20 antibody).[87] Both of these agents have shown promise in early clinical development trials.

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Treatment of MS in Pregnancy

Confavreux et al found that the frequency of MS relapses decreases during pregnancy, particularly in the third trimester, when it drops by as much as 70%.[88] In the first 3 months post partum, however, the frequency of relapses returns to the prepregnancy rate, probably as a result of postpregnancy hormone loss. Overall, pregnancy does not have a negative effect on the course of MS. Initial data suggested that breast-feeding reduced MS relapses, but the most recent study found no significant benefit.[89]

Use of disease-modifying treatments in women planning to become pregnant should be considered on a case-by-case basis, weighing the risks of drug exposure against risks of relapses. Few negative outcomes have been reported with exposure to interferon beta or glatiramer during pregnancy, which supports the possibility of offering treatment until conception.[89]

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Symptom Management

Treatment of symptoms is an essential part of the management of MS. Pharmacologic and nonpharmacologic measures can be used to address the following:

  • Fatigue
  • Spasticity
  • Bladder problems
  • Bowel problems
  • Cognitive dysfunction
  • Pain
  • Paroxysmal symptoms
  • Sexual dysfunction
  • Tremor
  • Heat intolerance
  • Optic neuritis

Cognitive dysfunction

Cognitive dysfunction is a major problem that affects quality of life, family and social relationships, and employment. Cognitive dysfunction can impact memory, comprehension, problem solving, and speech. Treatment for cognitive dysfunction in patients with MS should include supportive therapy provided by speech pathologists or occupational therapists. In addition, depression may contribute to cognitive dysfunction and should be treated if it is diagnosed.

Pharmacologic therapy has not been shown to be beneficial for cognitive impairment in MS. For example, a multicenter randomized clinical trial in MS patients with memory impairment found that donepezil (Aricept) was no better than placebo for improving memory.[90]

Depression

Selective serotonin reuptake inhibitors are preferred for treating depressive symptoms in patients with MS. Second-line treatment options include the use of tricyclic antidepressants. The anticholinergic side effects of tricyclic antidepressants may be helpful to patients with symptoms of bladder spasticity or chronic pain. For more information, see the Medscape Reference article Depression.

Fatigue

Fatigue is one of the most common and disabling symptom of MS, occurring in approximately 76-92% of MS patients.[91] Fatigue can worsen before and during exacerbations and with increased temperatures. There are no FDA-approved drugs for treatment of MS-related fatigue.

Amantadine is perhaps the first-line drug for treatment of fatigue in MS, although this is an off-label use. The usual dosage is 100 mg orally twice a day. Approximately 40% of MS patients experience some fatigue relief with amantadine. Pemoline was found to be effective in some people, but it was removed from the US market in 2005 after the FDA concluded that the overall risk of liver toxicity from pemoline outweighs the benefits.[92]

Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine (Prozac). A disadvantage of methylphenidate is that it is a controlled substance. Methylphenidate has been recommended at dosages of 10-60 mg/day in 2-3 divided doses, using extreme caution. For patients with concurrent depression, fluoxetine may be tried to manage both problems.

Modafinil (Provigil), a drug approved for the treatment of narcolepsy, has demonstrated some success in MS patients at doses of 200 mg/day. In addition, armodafinil (Nuvigil) has also been suggested as being helpful with fatigue.

Nonpharmacologic treatment of fatigue involves energy conservation, work simplification, scheduled rest periods, and the use of cooling garments (eg, vest, hat, collar). Regular exercise also may help alleviate fatigue.

Medications used in MS management often can contribute to fatigue. These drugs include analgesics, anticonvulsants, antidepressants, muscle relaxants, sedatives, and immune-modulating medications.

Pain

Pain can be a common occurrence in patients with MS, with 30-50% of patients experiencing pain at some time in the course of their illness. Treatment for pain accounts for nearly 30% of the medications used for symptom management in MS patients.[93]

Pain in MS may be primary or secondary, and the two may be experienced at the same time. Primary pain is related to the demyelinating process and is often characterized as having a burning, gnawing, or shooting quality. Tricyclic antidepressants are first-line drugs for primary pain. Anticonvulsants, such as carbamazepine, phenytoin, and gabapentin, can be added as second-line agents.

Secondary pain in MS is primarily musculoskeletal in nature, possibly due to poor posture, poor balance, or the abnormal use of muscles or joints as a result of spasticity. Pharmacologic agents for this type of pain include nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. The use of narcotics is seldom indicated.

Heat intolerance

Steps to manage heat intolerance are as follows:

  • Time outside activities for early morning or evening hours to avoid the heat of the day
  • Spread activities throughout the course of the day to avoid overheating
  • Use air conditioning in homes and cars, cooling garments, light-colored clothes, and wide-brimmed hats
  • Avoid exposure to saunas, hot tubs, or even hot showers or baths
  • Avoid exposure to excessive humidity; dehumidifiers can help indoors
  • Treat fevers aggressively with around-the-clock antipyretics.

Spasticity

Treat spasticity when it interferes with function, mobility, positioning, hygiene, or activities of daily living. Reducing spasticity can give the patient more freedom of movement with less energy expenditure, as well as avoiding complications such as pain, contractures, and decubitus.

Spasticity can be managed through nonpharmacologic means. Pharmacologic treatment of spasticity includes baclofen (Gablofen, Lioresal), which is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity in MS patients with reversible spasticity. Baclofen is effective in most cases, is inexpensive, and is titrated easily from 10-140 mg/day in divided doses. Adverse effects include fatigue and weakness.

Second-line agents include benzodiazepines (eg, diazepam, clonazepam). These agents can be sedating and habit-forming; however, for patients who also have sleep disorders, the sedative effects can be beneficial, allowing the clinician to manage the spasticity and the sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects.

Dantrolene sodium (Dantrium) acts directly on skeletal muscle to decrease spasticity. This agent is used less frequently than baclofen because of its hepatotoxicity at higher doses and numerous drug interactions.

The anticonvulsant drug gabapentin (Neurontin) is particularly useful in patients who experience spasticity and neuropathic pain. It is easily titrated from 300 to 3600 mg/day in divided doses. However, along with being relatively expensive, gabapentin often causes significant sedation, which is effectively dose limiting.

Tizanidine (Zanaflex), a centrally acting alpha-adrenergic agonist, is also used to manage spasticity. Tizanidine has effects similar to those of baclofen, but it produces less weakness and more sedation. This drug is titrated from 2 to 32 mg/day in divided doses.

Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. Because of their greater invasiveness, these treatments are usually reserved for the most difficult cases.

Impaired ambulation

Oral, sustained-release dalfampridine (Ampyra) has been shown to improve walking ability in patients with MS. It is the only medication approved by the FDA for this indication for MS patients.

Fourteen weeks of treatment with dalfampridine was found to improve walking ability in a significant percentage of patients in a randomized, multicenter, double-blind, phase III trial (which was not limited to any specific form of MS).[94] The mechanism of action of dalfampridine appears to be restoration of action potential conduction via blockade of an as-yet uncharacterized subset of potassium channels in demyelinated axons.

An increased risk of seizures has been observed in patients taking dalfampridine; therefore, it is contraindicated in patients with a history of seizures. Urinary tract infections have been reported more frequently in patients receiving dalfampridine 10 mg twice daily (12%) than in those receiving placebo (8%).[95]

Bladder problems

Bladder dysfunction in MS may consist of failure to store, failure to empty, or a combination of the two. Interventions for failure to store include the following[96] :

  • Scheduled voiding
  • Limiting fluid intake in the evening
  • Using anticholinergic medications (eg, oxybutynin)
  • Eliminating diuretics (eg, caffeine)
  • Injecting onabotulinumtoxinA (Botox) into the bladder[97]

Failure to empty is characterized by a large, flaccid bladder and an inability of the urinary sphincter to relax. Symptoms include urgency, frequency, hesitancy, nocturia, incontinence, incomplete emptying, and frequent urinary tract infections. Interventions include intermittent catheterization or the use of alpha-blockers (eg, prazosin) and, possibly, the Crede maneuver.

Combined dysfunction is due to incoordination of the detrusor and sphincter (dyssynergia). Symptoms in combined dysfunction are similar to those of failure to empty. Interventions may include anticholinergic medications or intermittent catheterization.

Bladder problems usually can be managed appropriately after a careful history, physical examination, and urinalysis. If initial attempts at symptom management are not effective, more studies, such as renal ultrasonography, voiding cystourethrography, renal scanning, or urodynamic studies, may be indicated to better characterize the problem.

Bowel problems

Constipation, the most common bowel problem in MS patients, may result from neurogenic bowel, immobility, or restricted fluid intake. The first step in management of constipation is to increase fluid intake to 8-10 cups daily and increase dietary fiber to 15 g.

Next, it is essential to establish a consistent bowel program time. A bowel program is most effective if done at least every other day and preferably after a meal, which takes advantage of the body's gastrocolic reflex. Sitting in an upright position, rather than lying in bed, permits gravity to assist in evacuation. The patient should also be involved in an exercise program, consisting of walking or simply performing chair exercises.

Pharmacologic management of constipation includes stool softeners, bulk formers, or laxatives. Stool softeners, such as docusate sodium, work by decreasing surface tension, allowing water to enter the stool. Bulk formers (eg, Metamucil, Per Diem, Citrucel, FiberCon) work by increasing the bulk and weight of the stool. Laxatives act as an irritant to the bowel, increasing peristalsis; they generally work within 8-12 hours. Examples include milk of magnesia and Peri-Colace.

For patients with a neurogenic bowel or with poor abdominal muscle tone, rectal suppositories may be part of an effective bowel program that can help prevent incontinence episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl and glycerin.

Nonpharmacologic techniques of bowel management include proper positioning, abdominal massage, and digital stimulation. Abdominal massage performed in the direction of bowel peristalsis, from ascending toward the descending colon, can be useful. Finally, digital stimulation, in which a lubricated finger is inserted gently into the rectum and moved side to side along the wall of the rectum, can stimulate a bowel movement.

Diarrhea

Diarrhea, if it occurs, typically is not related to MS per se. Rather, it is more likely from fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners. Diarrhea may also be an adverse effect of medications.

Diarrhea is treated first by eliminating the cause and then, possibly, with bulk formers (eg, psyllium). Drugs that slow the muscles of the bowel, such as Lomotil (diphenoxylate and atropine) are rarely indicated.

Sexual Dysfunction

Sexual dysfunction in patients with MS may be associated with other symptoms of the disease, such as fatigue, spasticity, depression and bowel dysfunction. Erectile dysfunction is common in men with MS and may be treated with oral phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra, Staxyn); for more information, see the Medscape Reference article Erectile Dysfunction. Penile prostheses are an alternative for men with erectile dysfunction who do not respond to medical management.

Tremor

Tremor is difficult to manage in MS patients. Several treatments have been used for tremor, with little success. Treatments have included anticonvulsants, isoniazid, primidone, benzodiazepines, propranolol, and ondansetron.

Optic neuritis

In the Optic Neuritis Treatment Trial (ONTT), patients recovered visual function regardless of whether they were treated with oral prednisone, intravenous methylprednisolone (IVMP), or placebo.[98] However, patients who received IVMP recovered faster. IVMP also seemed to decrease the incidence of the development of MS over a 2-year period, but this effect was not sustained after year 3. Patients treated with oral prednisone demonstrated an increased incidence of recurrent optic neuritis compared with those who were administered IVMP or placebo.

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Rehabilitation

Patients with MS may benefit from referral to physical therapists, occupational therapists, and speech therapists. Speech therapists assess the patient's speech, language, and swallowing abilities and may work with the patient on compensatory techniques to manage cognitive problems.

Physical therapy

Physical therapists provide assessment of gross motor skills (eg, ambulation) and assessment and training in appropriate assistive devices to improve mobility in patients with MS. They evaluate and train the patient in appropriate exercise programs to decrease spasticity, maintain range of motion, strengthen muscles, and improve coordination. They also provide invaluable input into the prescription of appropriate seating systems for the nonambulatory patient.

Physical therapy for spasticity in patients with MS includes the establishment of a stretching program in which joints are moved slowly to positions that stretch the spastic muscles. Each position is held for at least a minute to allow the stretched muscle to slowly relax. Stretching exercises may be performed in a cool (85°F) pool, which provides buoyancy and cooling. Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.

Nonpharmacologic treatments for primary pain in MS, such as the use of imagery or distraction, can be helpful. Transcutaneous electrical nerve stimulation (TENS) is useful in some patients.

Nonpharmacologic treatment for secondary pain includes moist moderate heat, massage, physical therapy, and exercise (eg, stretching). Devices such as the WalkAide and Bioness use functional electrical stimulation to aid walking and may be helpful to some MS patients.

Occupational therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing activities of daily living, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs. They can provide treatment for cognitive dysfunction.

Treatment approaches for cognitive dysfunction include cognitive retraining and the use of compensatory strategies. Cognitive retraining involves the employment of repetitive drills and mentally stimulating exercises designed to strengthen areas of cognition that are weak.

Compensatory strategies emphasize coping methods or organizational skills to help patients use their strengths to compensate for areas of relative weakness. Such strategies can include the following:

  • Maintaining a consistent routine
  • Making lists
  • Keeping a daily planner
  • Organizing the home or work environment

In providing education on MS management to patients with cognitive impairment, it is important to involve family or caregivers in training, provide step-by-step instructions, and present information in a visual and verbal format. New topics should be presented at times when fatigue is less likely to be an issue.

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Surgery for Alleviating Symptoms

Surgical procedures that relate to MS are directed primarily at alleviating symptoms, such as dysphagia, significant limb spasticity or contractures, or severe neuropathic pain. Measures include gastrojejunal tube placement, adductor leg muscle tendon release, and rhizotomy, respectively.

Intrathecal pumps for delivery of antispasticity medications (eg, baclofen) can be implanted surgically. Caution should be used with baclofen pumps due to the risk of malfunction and baclofen overdose.

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Deterrence and Prevention

Preliminary evidence suggests that persons with high circulating levels of vitamin D are at lower risk of MS[11] ; thus, vitamin D supplementation may reduce the risk of developing MS and of conversion from a first clinical event suggestive of MS to clinically definite MS. Vitamin D may also reduce the relapse rate among patients with relapsing-remitting MS.[99]

For healthy individuals, serum vitamin D concentrations of 50-125 nmol/L (20-50 ng/mL) are generally considered adequate for bone and overall health, according to the Institute of Medicine.[100] Serum vitamin D concentrations of 75-100 nmol/L (30-40 ng/mL) have been proposed as optimal for patients with MS.[101]

Achieving these levels may require the use of supplemental vitamin D in doses up to 3000 IU daily; maintaining these levels appears to require doses of 500 to 800 IU daily.[101] The safety and effectiveness of vitamin D supplementation among patients with MS remains unclear, however.[102]

Early treatment with immunomodulatory drugs has been associated with decreased disability and lower secondary relapse rates. Patients with MS must understand, however, that current immunomodulatory drugs are not curative.

The Uhthoff phenomenon is an exacerbation of MS symptoms that is induced by exercise, a hot meal, or a hot bath. The most notable symptoms seen with this phenomenon are transient visual obscurations, dyschromatopsia, and contrast sensitivity changes. The symptoms tend to resolve with restoration of euthermia, typically within 60 minutes to 24 hours. Sunlight by itself is not considered to be deleterious, but excessive exposure may mimic the effects of high temperatures.

On the other hand, the impact of stress on MS exacerbations is thought to be minimal or noncontributory. Likewise, trauma has no demonstrated impact on the disease course.

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Consultations

Patients with MS may require multiple consultations to rule out other causes of their symptoms. A significant number of MS patients will need a multidisciplinary approach to their care. For instance, patients with dysphonia may need an evaluation by an otolaryngologist (ie, ear, nose, and throat specialist) to rule out laryngeal lesions unrelated to MS. In addition, having MS does not exclude the possibility of concomitant peripheral neuropathy or other illnesses that may cause pain.

The following are the most common consultation services involved in referrals from an MS clinic:

  • Physical therapy and rehabilitation specialist
  • Speech therapist
  • Ophthalmologist
  • Urologist: Urologic consultation may be warranted to help in the assessment and treatment of incontinence
  • Gastroenterologist
  • Neuropsychologist: Neuropsychologic consultation is advisable so that a baseline assessment for future reference can be obtained; such consultation is especially important in patients with primary cognitive involvement
  • Psychiatrist
  • Otolaryngologist

It is not unusual for patients with more advanced MS to lose all family support, become separated from their spouse, lose the ability to walk, and require constant psychiatric and nursing assistance. These patients create a challenge for the physician who is not trained in handling the demanding administrative or ancillary aspects of medical care. A social worker specialist can be instrumental in helping to address these issues.

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Long-Term Monitoring

Recommended follow-up is yearly at minimum. Patients receiving therapy with certain agents (eg, natalizumab, fingolimod) require monitoring as often as every 3-4 months. Clinicians who also provide primary care for the patient with MS can perform routine health maintenance at these annual visits. For patients with worsening symptoms, a medical cause, such as infection, should be ruled out first before assuming that the patient is having an exacerbation.

Once a patient/provider relationship is established, a great deal of symptom management can be provided through careful telephone triage. More frequent visits, such as bimonthly or quarterly, may be necessary for patients with difficult symptoms, such as intractable spasticity, or for individuals whose social support system is not as stable as necessary.

Vaccination

MS specialists generally advise against the use of live-attenuated virus vaccines in patients with MS, particularly in patients receiving immunosuppressive therapy. Despite concerns that vaccination may trigger the onset or relapses of MS, almost all killed-virus vaccines studied have been found safe in this regard.[20]

The Vaccine Safety Datalink Research Group of the US Centers for Disease Control and Prevention (CDC) found that vaccination against hepatitis B, influenza, tetanus, measles, or rubella did not increase the risk of developing MS or optic neuritis.[103] The Vaccines in Multiple Sclerosis Study Group reported that vaccination for tetanus, hepatitis B, or influenza does not increase the short-term risk of relapses.[104]

Injectable influenza vaccine has been extensively studied in MS and found to be safe. However, the form of influenza vaccine that is delivered via a nasal spray (FluMist) is a live-virus vaccine and is not recommended for MS patients.

Varicella-zoster vaccine (Zostavax) is also a live-attenuated vaccine. However, in a patient with a definite history of chicken pox or a positive antibody test, this vaccine is likely to be safe and beneficial, although full discussion of the risks and benefits must precede its use. Discussion of risks and benefits is also important before a close family member of an MS patient receives this or any other live-virus vaccine.[20]

A study in 7 patients with relapsing-remitting MS who received yellow fever vaccine found a significantly increased risk of MS relapse during the 6 weeks following the vaccination. For MS patients who must travel to areas where yellow fever is endemic, these researchers advise careful weighing of the risk of relapse with the risk of contracting yellow fever, which is a potentially fatal illness.[105]

No studies have been published addressing the safety of the following vaccines in MS:

  • Pneumonia
  • Meningitis
  • Typhoid
  • Polio
  • Hepatitis A
  • Human papillomavirus (HPV)
  • Pertussis

There are rare reports of demyelination syndromes following administration of the HPV vaccine. Thus, physicians should thoroughly discuss the possible benefits and risks of this vaccine before administering it.[20]

Some special considerations for vaccination in MS patients from the National Multiple Sclerosis Society are as follows[20] :

  • In patients experiencing a serious relapse that affects their ability to carry out activities of daily living, defer vaccination until 4-6 weeks after the onset of the relapse
  • Vaccine response may be blunted in patients who have received immune globulin in the past 3 months or who are taking natalizumab or fingolimod.
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Contributor Information and Disclosures
Author

Christopher Luzzio, MD  Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Fernando Dangond, MD  Senior Director of Medical Affairs, Neurology, EMD Serono, Inc

Fernando Dangond, MD is a member of the following medical societies: American Academy of Neurology and American Medical Association

Disclosure: EMD Serono, Inc. Salary Employment

Chief Editor

B Mark Keegan, MD, FRCPC  Assistant Professor of Neurology, College of Medicine, Mayo Clinic; Master's Faculty, Mayo Graduate School; Consultant, Department of Neurology, Mayo Clinic, Rochester

B Mark Keegan, MD, FRCPC is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Minnesota Medical Association

Disclosure: Novartis Consulting fee Consulting; Bionest Consulting fee Consulting

Additional Contributors

Martin K Childers, DO, PhD Professor, Department of Neurology, Wake Forest University School of Medicine; Professor, Rehabilitation Program, Institute for Regenerative Medicine, Wake Forest Baptist Medical Center

Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Osteopathic Association, Christian Medical & Dental Society, and Federation of American Societies for Experimental Biology

Disclosure: Allergan pharma Consulting fee Consulting

Edmond A Hooker II, MD, DrPH, FAAEM Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine

Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Public Health Association, Society for Academic Emergency Medicine, and Southern Medical Association

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marjorie Lazoff, MD Editor-in-Chief, Medical Computing Review

Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Informatics Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Consuelo T Lorenzo, MD Physiatrist, Department of Physical Medicine and Rehabilitation, Alegent Health, Immanuel Rehabilitation Center

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

William J Nowack, MD Associate Professor, Epilepsy Center, Department of Neurology, University of Kansas Medical Center

William J Nowack, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Electroencephalographic Association, American Medical Informatics Association, and Biomedical Engineering Society

Disclosure: Nothing to disclose.

Richard Salcido, MD Chairman, Erdman Professor of Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine

Richard Salcido, MD is a member of the following medical societies: American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Physician Executives, American Medical Association, and American Paraplegia Society

Disclosure: Nothing to disclose.

Daniel D Scott, MD, MA Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine; Attending Physician, Department of Physical Medicine and Rehabilitation, Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System

Daniel D Scott, MD, MA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, National Multiple Sclerosis Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation

Disclosure: Nothing to disclose.

Fu-Dong Shi, MD, PhD Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Timothy Vollmer, MD Consulting Staff, Department of Emergency Medicine, Geisinger Medical Center

Disclosure: Nothing to disclose.

Sandra F Williamson, MS, ANP-C, CRRN Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center

Sandra F Williamson, MS, ANP-C, CRRN is a member of the following medical societies: Phi Beta Kappa, Phi Kappa Phi, and Sigma Theta Tau International

Disclosure: Nothing to disclose.

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The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. This MRI, performed 3 months after the one in the related image, shows a dramatic decrease in the size of lesions.
Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.
Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.
Gadolinium-enhanced, T1-weighted image showing enhancement of the left optic nerve (arrow).
Corresponding axial images of the spinal cord showing enhancing plaque (arrow). The combination of optic neuritis and longitudinally extensive spinal cord lesions constitutes Devic neuromyelitis optica.
Table 1. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis[35]
Clinical Presentation Additional Data Needed for MS Diagnosis
  • Two or more attacks
  • Objective clinical evidence of 2 or more lesions with reasonable historical evidence of a prior attack
None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,



but must be consistent with MS



  • Two or more attacks
  • Objective clinical evidence of 1 lesion
Dissemination in space demonstrated by MRI or



Await further clinical attack implicating a different site



  • One attack
  • Objective clinical evidence of 2 or more lesions
Dissemination in time demonstrated by



MRI or second clinical attack



  • One attack
  • Objective clinical evidence of 1 lesion (clinically isolated syndrome)
Dissemination in space demonstrated by



MRI or await a second clinical attack implicating a different CNS site



and



Dissemination in time, demonstrated by MRI or second clinical attack



· Insidious neurologic progression suggestive of MSOne year of disease progression and dissemination in space, demonstrated by 2 of the following:
  • One or more T2 lesions in brain, in regions characteristic of MS
  • Two or more T2 focal lesions in spinal cord
  • Positive CSF
Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.
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