Multiple Sclerosis Treatment & Management

Treatment of MS has 2 aspects: immunomodulatory therapy for the underlying immune disorder and management of symptoms. Although therapy for clinically isolated syndrome with immunomodulatory medications has not yet become standard practice throughout the world, trials suggest that early intervention may be appropriate. The McDonald diagnostic criteria are helpful in the decision to treat patients early during the course of relapsing MS.

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 (ICP).
• Consider emergent plasmapheresis. (One study suggested this treatment may be superior to intravenous [IV] steroids in patients with acute fulminant MS.^[33] The 2011 AAN plasmapheresis guideline update stated that plasmapheresis is possibly effective and may be considered in acute fulminant demyelinating CNS disease.^[1] )

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. (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.

Medications used to treat multiple sclerosis (MS) can be classified as immunomodulating or symptom management medications. For acute exacerbations, methylprednisolone (Solu-Medrol) has been shown to hasten recovery from the given attack, but it has uncertain long-term effects. In addition, plasma exchange can be used short term for severe attacks if steroids are contraindicated or ineffective.

The 2011 AAN guideline confirms that plasmapheresis is probably effective in relapsing forms of MS as second-line treatment for exacerbations that resist steroid treatment. However, plasmapheresis is ineffective and should not be used for chronic or secondary progressive MS.^[1]

The disease-modifying agents for MS (DMAMS) currently approved for use in relapsing forms of MS in the United States include the following:

• Interferon beta (Avonex, Betaseron, and Rebif)
• Fingolimod (Gilenya)
• Glatiramer acetate (Copaxone)
• Mitoxantrone (Novantrone)
• Natalizumab (Tysabri)

These drugs, which are available in injectable form, are currently FDA approved only for RRMS. In a European study on SPMS, patients in the interferon beta-1b group showed a highly significant delay in time to disease progression; however, FDA approval has not been granted yet for this indication.

A literature review by Rojas et al indicated that interferon beta could not be linked to reduced disability progression in patients with PPMS.^[34] The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

To a certain extent, health care provider preference and experience with the medications, as well as the patient's preference, play a role in determining which drug is appropriate in a particular situation. Head-to-head comparison studies with the different interferon preparations suggested that higher-dose interferon is more effective in preventing relapses than are lower-dose formulations. In persons with a history of depression, interferons should be used with caution; thus, glatiramer acetate may be an appropriate choice in such cases.

Patient lifestyle and tolerance of injections should be considered in the choice of DMAMS. Adverse effect profiles also must be considered. If the adverse profile of one agent is intolerable in a patient, then a different class of agent may be recommended.

Natalizumab (Tysabri) is indicated as monotherapy for MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Three cases of progressive multifocal leukoencephalopathy (PML) associated with natalizumab use prompted temporary withdrawal from the market in 2005; however, it was later reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as TOUCH. The drug now carries a package insert black box warning about potential risks of opportunistic infections.

Treatment of progressive disease is more controversial. Mitoxantrone is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing-remitting MS. This agent has been shown, however, to have idiosyncratic cardiac toxicities. Cyclophosphamide (Cytoxan) has also been used in MS patients but is associated with risks for leukemia, lymphoma, infection, and hemorrhagic cystitis.

Currently, no approved treatments are available for PPMS. Patients with secondary progressive disease who experience relapses are sometimes started on the currently approved DMAMS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with SPMS.

Oral, sustained-release fampridine (4-aminopyridine) (Ampyra) is now approved by the FDA and has been shown to improve motor function in people with MS. Fourteen weeks of treatment with fampridine 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).^[35]

Anti-inflammatory treatment may shorten an acute exacerbation of MS, but no evidence suggests that it changes the overall disease progression.

Anti-inflammatory treatment may be more effective acutely in patients who have predominantly movement involvement rather than sensory involvement. The most common therapy is high-dose pulsed methylprednisolone. Anti-inflammatory treatment for ON is very controversial (see Optic Neuritis). 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 a common treatment.

Fatigue

Amantadine is perhaps the first-line drug used to treat fatigue. Approximately 40% of patients experience some fatigue relief of fatigue. Pemoline was effective in some people, but it was removed from the market in 2005 after the US Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits.

Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine. A disadvantage of methylphenidate is that it is a controlled substance. For patients with concurrent depression, fluoxetine may be tried to manage both problems. Modafinil (Provigil), a drug approved for treatment of narcolepsy, has demonstrated some success in MS patients. Armodafinil (Nuvigil) has also been suggested as helpful.

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.

Spasticity

With decrease in spasticity, the patient experiences more freedom of movement with less energy expenditure. Treat spasticity when it interferes with function, mobility, positioning, hygiene, or ADL. Spasticity can be managed through nonpharmacologic and pharmacologic means. Complications of inadequately controlled spasticity include pain, contractures, and decubitus. (See Physical Therapy.) Pharmacologic treatment of spasticity includes baclofen (Lioresal) as a first-line drug. Baclofen is effective in most people, is inexpensive, and is titrated easily from 10-140 mg/d in divided doses. Patients may report fatigue or weakness as an adverse effect.

Second-line agents include benzodiazepines, such as diazepam and clonazepam. While these compounds can be useful adjunct medications, they can be sedating and habit-forming. For patients who also experience sleep disorders, the provider may take advantage of the sedating adverse effects of the benzodiazepines to manage the spasticity and 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. It affects all muscles of the body and is used less frequently than baclofen, due to hepatotoxicity at higher doses and numerous drug interactions.

Gabapentin (Neurontin) and tizanidine (Zanaflex) are also used to manage spasticity. Gabapentin is an anticonvulsant drug, which is particularly useful in patients who experience spasticity and neuropathic pain. This drug is titrated easily from 300-3600 mg/d in divided doses. However, along with being relatively expensive, gabapentin may have limited usefulness, because patients often experience significant sedation, which is effectively dose limiting.

Tizanidine has effects similar to baclofen, but it produces less weakness and more sedation. This drug is titrated from 2-32 mg/d in divided doses.

Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. These treatments are more invasive and usually are required in the most difficult cases. Restless legs syndrome has been noted in some patients.

Bladder problems

Interventions for bladder problems include scheduled voiding, limiting fluid intake in the evening, using anticholinergic medications (eg, oxybutynin), and eliminating diuretics (eg, caffeine).^[36] 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 ultrasonogram, voiding cystourethrogram, renal scan, or urodynamic studies, may be indicated.

Bowel problems

The first step in management of constipation is to increase fluid intake to 8-10 cups/d 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 be involved in an exercise program, consisting of walking or simply performing chair exercises.

Diarrhea, if it occurs, typically is not related to MS per se; it is more likely due to fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners, or it is 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), rarely are indicated. 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.

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 to prevent incontinent episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl or glycerin.

Cognitive dysfunction

Cognition-enhancing drugs have met with some success in MS patients. Donepezil (Aricept) is one such medication.

Pain

As previously mentioned, pain is a common occurrence in MS, with 30-50% of patients experiencing pain at some time in the course of their illness.

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, or 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 condition include nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. The use of narcotics seldom is 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 in this regard.
• Treat fevers aggressively with around-the-clock antipyretics.

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.^[37] However, although it did not change the final visual outcome, IVMP hastened the rate of recovery. It 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 ON compared with those who were administered IVMP or placebo.

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.

Spasticity management 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). The WalkAide device uses functional electrical stimulation to aid walking and may helpful for MS patients.

As previously mentioned, a patient with constipation should be involved in an exercise program consisting of walking or of chair exercises.

Occupational therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing ADL, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs.

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 the individual use his or her 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.

Speech therapy

Speech therapists assess the patient's speech, language, and swallowing abilities and may work with the patient on compensatory techniques to manage cognitive problems.

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. Penile prostheses are an alternative for patients with erectile dysfunction who do not respond to medical management.

Preliminary evidence suggests that persons with high circulating levels of vitamin D are at lower risk of MS^[12] ; 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 RRMS.^[38]

Two Cochrane systematic reviews examined the available literature on the use of vitamin D and statin medications in patients with MS.^{[39, 40]} Only one trial with vitamin D was found, and it was judged to be potentially at high risk for bias. The review determined that only “local guidelines for vitamin D supplementation” could be recommended. The safety and effectiveness of vitamin D supplementation, specifically among patients with MS, remains unclear. Two small studies were reviewed that examined combined statins with interferon-beta preparations; the evidence was judged to be insufficient to support use of statins in combination therapy in MS. However, numerous studies are reportedly ongoing to further explore the use of statins in patients with MS.

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 affected by 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, and trauma has no demonstrated impact on the disease course.

A study by Confavreux et al indicated that during pregnancy, especially in the third trimester, a woman’s relapse rate is significantly reduced, dropping by as much as 70%.^[41] Following pregnancy, however, relapses eventually return to their prepregnancy rate, probably as a result of postpregnancy hormone loss.

Patients with MS may require multiple consultations to rule out other causes for their symptoms. 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.

Surgical consultation may be requested for gastric tube placement for feeding in persons with advanced MS.

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

• Otolaryngologist
• 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.
• Ophthalmologist
• Physical therapy and rehabilitation specialist
• Psychiatrist
• Gastroenterologist
• Urologist: Urologic consultation may be warranted to help in the assessment and treatment of incontinence.

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.

Recommended follow-up is yearly at minimum. 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.