Treatment Guidelines in 2013

Multiple Sclerosis: Signs and Symptoms

An immune-mediated inflammatory disease, multiple sclerosis is a disease in which antibodies attack the myelinated axons throughout the central nervous system. Destruction of the myelin and axon produces varying degrees of damage, and results in significant disability in more than 30 percent of patients who are affected.

The signs and symptoms of multiple sclerosis include sensory loss, often an early complaint. Motor dysfunction follows, with muscle cramping as a result of spasticity, and autonomic symptoms occur, including dysfunction of the bowel, bladder, or sexual dysfunction. Cerebellar symptoms may include the Charcot triad of dysarthria, ataxia, and tremor. Other signs and symptoms include trigeminal neuralgia, which manifests as pain or bilateral facial weakness, optic neuritis, facial myokymia, which is irregular twitching of the facial muscles; eye symptoms include diplopia on lateral gaze, which occurs in approximately 33 percent of patients, and heat intolerance. 

Constitutional symptoms that include fatigue and dizziness are common, and pain will occur in 30 to 50 percent of patients during the course of their illness. Seventy-five percent of patients with the disease report overwhelming lassitude or simply a lack of either physical or mental energy that disrupts activities. Other conditions including infections, anemia, vitamin deficiency, or thyroid disease should be ruled out in these patients before determining that the fatigue is a result of multiple sclerosis.  Pain may have a great impact upon quality of life, and it may be related to the demyelinating process. This pain is neuropathic, and is described as burning, gnawing, or shooting. Patients with MS may experience secondary pain that is musculoskeletal, resulting from poor balance, posture, or difficulties with the use of joints and muscles secondary to spasticity.

Patients may notice depression, rarely euphoria, subjective cognitive deficits, and even bipolar disorder or frank dementia. Finally, symptoms associated with partial acute transverse myelitis may be noted.  This may include acute partial loss of sensory, motor, reflex, autonomic, and sphincter function below the level of the lesion. In the presence of symptoms of transverse myelitis, the differential diagnosis should always include spinal cord compression. Urinary symptoms are commonly seen among patients with MS at some point in the course of their disease, and may become a significant cause of functional impairment. Bladder problems may result from failure to store, to empty, or both. Hypercontractility of the detrusor muscle, with a small and spastic bladder, results from impaired storage. Symptoms include frequency, urgency, nocturia, and incontinence. Recurrent urinary tract infections may occur. Constipation is also frequently seen in patients with multiple sclerosis. 

The Disease Course 

The course of multiple sclerosis may be either progressive or relapsing-remitting. The progressive types of multiple sclerosis include primary progressive MS (PPMS), which is notable for the progression of the disease from onset, although patients with PPMS may have temporary periods of remission. Patients with secondary progressive multiple sclerosis (SPMS) demonstrate a relapsing-remitting course initially, which is followed by progression either with or without occasional relapse, minor remission, or plateaus. Finally, progressive-relapsing multiple sclerosis (PRMS) consists of progressive disease from the time of diagnosis, with clear periods of acute relapse, which may or may not be characterized by full recovery. Between the period of distinct relapses, the disease continues to progress.1

Glucocorticoids and ACTH

Acute exacerbations of multiple sclerosis are normally treated with glucocorticoids, specifically a three- to seven-day course of methylprednisolone, often with a prednisone taper. Treatment indications in patients with acute relapse include symptoms that are functionally disabling and accompanied by evidence of neurologic impairment.  Those patients who have relapsing-remitting MS and experience a relapse should be treated with a disease-modifying anti-rheumatic drug. There appears to be no difference in treatment outcomes in patients treated with intravenous glucocorticoids when compared with patients who are treated with oral formulations. 2

Comparisons of methylprednisolone with adrenocorticotropic hormone (ACTH) did not seem to result in significantly different outcomes, as both treatment groups, across several studies, demonstrated a reduction in the risk of worsening or not improving within five weeks of treatment.3 However, some clinicians prefer intravenous glucocorticoids because there is evidence that low-dose oral steroids are associated with an increased risk of optic neuritis. For those patients who can’t tolerate high-dose glucocorticoids, or who have poor venous access, there is a gel form of ACTH available that can be injected subcutaneously or intramuscularly. This is also effective for patients who prefer self-injection. Infection should be rule out before starting either glucocorticoid or ACTH therapy, as the immunosuppression may exacerbate the infection. For those patients with repeated treatment with glucocorticoids, baseline and yearly bone density scans are recommended, as repeated glucocorticoid therapy is associated with an increased incidence of fractures.

Plasma Exchange as a Rescue Strategy

Plasma exchange is sometimes useful in patients who do not respond to treatment with high-dose glucocorticoids. There has been only one formally reported clinical trial, but moderate to great improvement was seen in 42 percent of the patients in the trial. Those patients with antibody and complement-associated CNS demyelination appear more likely to benefit from plasma exchange.4 Patients with relapsing multiple sclerosis may benefit with adjunctive treatment with plasma exchange, and its consideration for use in these patients is a recommendation by the American Academy of Neurology.5

Disease-Modifying Anti-Rheumatic Drugs 

Patients with a history of relapsing-remitting multiple sclerosis with current disease activity should be offered treatment with a DMARD, which may include interferon beta or glatiramer acetate, during an acute exacerbation. Treatment of relapsing-remitting multiple sclerosis with immunomodulatory agents also includes use of natalizumab, fingolimod, and teriflunomide. Use of immunomodulatory agents has been shown to result in a decreased relapse rate and slower accumulation of visible lesions on MRI of the brain. It is not clear if these agents have an affect on brain atrophy. MS is usually less inflammatory and more degenerative in the later stages of the disease.

Interferon beta 

It is for this reason that early treatment should be aggressive. Studies have demonstrated a reduction in the attack rate in patients treated early with interferon. There are several preparations of beta interferon available. These include interferon beta-1b, or Betaseron, which is a cytokine that modulates immune responsiveness. Although the mechanism of action is not understood in multiple sclerosis, it has been demonstrated to be efficacious in a double-blind placebo-controlled trial of MS patients, some of whom were randomized to different doses and some to placebo. The disease progression incidence was lower in patients who received the high-dose interferon beta-1b (250 mcg every other day) at five years, and although the annual exacerbation rate was also decreased by 30 percent in the group receiving high-dose interferon, although that finding did not reach statistical significance. Follow-up of almost 21 years in 98 percent of the original study group revealed lower all-cause mortality for the interferon beta-1b treatment arms when compared to placebo. Patients in this study received interferon beta-1b for the first five years of the study, and received optional disease-modifying therapy as needed. Interferon beta-1b is given as a subcutaneous injection every other day.6,7 

Interferon beta-1a (Avonex) has been demonstrated to result in decreased annual exacerbation rate and decreased volume of MRI lesions when compared to placebo. The effects of Avonex do not appear to be dose-related, and it may have some effectiveness in the decrease of cognitive decline. Another study compared interferon beta-1a with interferon beta-1b, finding that annual relapse rates were almost equal between the groups, although the INCOMIN study found interferon beta-1b to garner better clinical and MRI outcomes than interferon beta-1a. 8 Rebif, another interferon beta-1a, was also associated with a significant reduction in relapse rates and disease burden compared to placebo. An extended study with Rebif suggests that earlier therapy results in more sustained long-term benefits when compared with later therapy. Patients treated with Rebif appeared to have less frequent relapses than those treated with Avonex, but Rebif is associated with a higher rate (25 percent vs. two percent) of development of neutralizing antibodies than patients treated with Avonex. In an extended arm of this same trial, the EVIDENCE trial, those patients who were changed from high-dose to low-dose interferon beta-1a had a 50 percent lower annual relapse rate, although the higher rate seems to be associated with a higher rate of adverse effects.9 

Side effects of interferon include reactions at the injection site, which may progress to necrosis at the injection site. Flu-like symptoms are common and are preferably treated with ibuprofen or glucocorticoids. Because there is a risk of liver dysfunction, usually asymptomatic, associated with use of interferon beta, acetaminophen should be avoided if possible. Serious hepatotoxicity is rare, but use of hepatotoxic drugs or substances like alcohol should be considered when changing drug regimens. Rare side effects or those that may be related to interferon beta treatment include leukopenia, anemia, suicide, and a partially reversible polyneuropathy. Patients should be monitored periodically with a complete blood count, liver function tests, and tests of thyroid function. Current practice includes checking liver function monthly for the first six months after initiation of therapy, decreasing the dose by 50 percent in the case of persistently elevated liver transaminases (or in the case of leukopenia) and continuation of monitoring for another six months in those patients.

Response will vary among patients with multiple sclerosis, and because of patient variability, it has not been possible to classify nonresponders. Older age and longer duration of illness appear to hinder the response rate in patient subgroups, which suggests that the interferon beta treatments are more effective in patients with inflammatory disease than in those with atrophy and neurodegeneration.

Neutralizing antibodies may form, which limit the effectiveness of interferons but do not appear to develop frequently in patients who have been treated with the interferon betas for at least 24 months without antibody formation. Some clinicians recommend treatment for formation of neutralizing antibodies (Nab) at 12 and 24 months, although recommendations regarding the number of tests, cutoff titer, which test to use, and when to test have not been formally made by the American Academy of Neurology.10 

Glatiramer

Glatiramer acetate consists of a mixture of random polymers of four amino acids, which is similar to myelin basic protein. Myelin basic protein is a component of the myelin sheath of nerves. It appears that the mechanism of action occurs when glatiramer binds to major histocompatibility complex molecules and competes with other myelin antigens for presentation to T cells. Glatiramer also induces T helper suppressor cells, which migrate to the brain, suppressing bystander T cells and expressing anti-inflammatory cytokines. Glatiramer is dosed once a day subcutaneously at 20 mg. Evidence shows that the interferons and glatiramer have similar efficacy. Patients followed for two years in one large study showed no difference in relapse risk, disease progression, or volume of MRI lesions.12 Additionally, glatiramer is classified as pregnancy category B, while the interferons are pregnancy category C. Side effects of glatiramer include injections site reaction and transient systemic reactions after injection, but no laboratory monitoring is required with glatiramer. There is some evidence that neutralizing antibodies to glatirimer may form, but their clinical significance has not been determined.13

Dimethyl fumarate

Dimethyl fumarate, and fumarates as a class, may have neuroprotective and immunomodulatory capabilities. In two trials, there was a significant reduction in rate of relapse and formation of new brain lesions on MRI in patients with active MS with dimethyl fumarate.14  Common side effects include flushing and GI symptoms. Complete blood count should be monitored in patients on dimethyl fumarate, as it may decrease lymphocyte counts.

Fingolimod

Fingolimod modulates sphingosine-1-phosphate receptors, altering lymphocyte migration. It may be effective in reducing the relapse rate in patients with RRMS, but because lymphocytes are sequestered in lymph nodes, there is an increased risk of life-threatening infection. There is also an association with tumor development, varicella-zoster infections, and paradoxical worsening of MS disease activity.15 Progressive multifocal leukoencephalopathy was seen in one patient diagnosed with possible MS who was treated with fingolimod, but since that patient was also treated with interferon beta-1a and azathioprine, it is unclear if PML was related to the fingolimod. It should be reserved for treatment of those patients who do not respond adequately to beta interferons or glatiramer.16, 17

Other Therapies

Natalizumab is another drug that is effective in the treatment of RRMS, but is associated with potentially fatal progressive multifocal leukoencephalopathy. It should be reserved for patients resistant to treatment with interferon beta or glatiramer.18 

Teriflunomide inhibits pyrimidine biosynthesis and disrupts interaction of T-cells with antigen-presenting cells. Patients with known liver disease should not be treated with teriflunomide, because of a risk of hepatotoxicity. It is also a pregnancy category X, and because it may remain in the serum for up to two years, patients who wish to conceive should discontinue the drug and receive cholestyramine or activated charcoal for 11 days, avoiding conception until the serum concentration of the drug is less than 0.02 mg/L. Mitoxantrone is approved for use in RRMS and progressive forms of MS, but is cardiotoxic, with limited evidence of benefit. Therefore, the American Academy of Neurology recommends reservation for those patients with rapidly advancing disease who have failed to respond to other treatment.19 

A humanized monoclonal antibody that depletes CD52-expressing T cells, natural killer cells, and monocytes, alemtuzumab appears to be more effective than interferon beta-1a for reduction of relapse rates, but is associated with a small increase in the risk of autoimmune disorders and infections that may be potentially serious.19 This investigational drug may be useful as a second-line therapy for patients with relapsing and remitting multiple sclerosis who do not adequately respond to interferons and glatiramer.

Other drugs that do not have adequate evidence to support their use include azathioprine and cladribine, an immunosuppressive agent. There is no real evidence for the use of IVIG for pain in patients with RRMS. Laquinimod may be modestly effective. There is some observational evidence that supports the use of IV cyclophosphamide in RRMS and the progressive forms of MS, but data are conflicting. There is evidence to suggest that the human monoclonal antibody daclizumab may be effective, but longer-term trials are needed.20