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Relapse Management and Disease Modification

December 2003
Kathleen Costello, MS, RN, MSCN
MS Nursing - Introduction to Multiple Sclerosis Nursing Care
The National Multiple Sclerosis Society


After reading this article, nurses who are new to the care of people with MS will be able to do the


Multiple sclerosis is a complex disease characterized by relapses, remissions, and usually progression of disability over time. Approximately 85% of patients begin the disease with a relapsing-remitting disease course (Coyle, 2000). With each attack or exacerbation, patients have an onset of symptoms over a few days or weeks, and a gradual complete or incomplete recovery over time.

Inflammatory changes in the central nervous system are the hallmark of the relapsing phase of the disease. During the relapsing phase of the disease an MRI will show frequent gadolinium enhancement, which indicates areas of active inflammation. Gadolinium enhancement occurs about 5–10 times more frequently than clinical relapses (Simon, 2000).

Over time, there are often fewer inflammatory changes and more progression of symptoms, often accompanied by more disability. This is classified as secondary-progressive multiples sclerosis. Over time there can also be a decrease in brain volume. Approximately 15% of patients never have relapses; rather their disease is characterized by a progression of symptoms over time. This disease course is known as primary-progressive (Lublin & Reingold, 1996).

Disease management is approached on three fronts; treatment of relapses, disease modification, and symptom management. This module will focus on treatment for acute relapses and disease modification.


A relapse is defined as new or worsening neurological symptoms of greater then 24 hours duration. Usually, relapses evolve over 1–7 days (Johnson, 2000). They will plateau for several weeks and resolve to some degree over weeks to several months. It is important for the nurse to obtain a detailed history of the symptoms to differentiate between a relapse and pseudorelapse. A pseudorelapse is a temporary worsening of symptoms due to concurrent illness, fever, or infection. The nurse should ask the patient to describe the symptoms, including the onset, severity, impact on functional abilities, the effect of activity, and the effect of time of day on the symptoms. General symptoms of infection should be assessed, including fever, chills, achiness, and increased fatigue level. The nurse should also assess for specific infections and investigate the presence of new urinary urgency, frequency, or dysuria as well as the possibility of pharyngitis, cough, or respiratory congestion.

Recent exposure to excessive heat or a recent increase in activity may produce a worsening of symptoms and cause the patient to feel as though a new relapse is occurring. Exposure to heat causing optic symptoms is known as Uhthoff’s phenomenon. Waxman (1988) determined that the demyelinated nerve is sensitive to heat and will conduct messages with less efficiency with heat exposure.

The usual treatment of a relapse is high dose glucocorticoids administered by mouth or intravenous infusion. Although there is little evidence that high dose steroids alter the course of the disease, they are felt to hasten resolution of acute symptoms (Goodkin et al., 1998). The Optic Neuritis Treatment Trial suggested that IV steroids were superior to oral steroids for the treatment of acute optic neuritis (Beck et al., 1993). However, the Multiple Sclerosis Council for Clinical Practice Guidelines has stated that for the treatment of acute exacerbations of MS, there is no really strong evidence to suggest that one type of glucocorticoid is more beneficial than another, nor does the route of administration really influence the clinical outcome (Multiple Sclerosis Council for Clinical Practice Guidelines, 2001). Common dose regimens are IV methylprednisolone 1 gm/day for 3–5 days. Some neurologists will follow the IV steroids with an oral prednisone taper.

Patients receiving steroids need to know the purpose and expectations of the treatment. In addition, patients must be aware of the short- and long-term side effects of the treatments. The short-term side effects of glucocorticoids include a metallic taste in the mouth, weight gain, restlessness, mood swings, insomnia, and stomach upset. A small percentage of patients will experience psychosis secondary to the administration of steroids. Blurred vision can occur and is particularly worrisome to patients as it is felt that a new exacerbation is occurring. Long-term steroid use has a multitude of serious side effects such as cataracts, GI bleeding, diabetes, and osteoporosis. Long-term side effects are best prevented by infrequent and brief courses of steroids. Those who require steroids on a frequent basis should be monitored for long-term side effects (Halper, 2001).


In 1993, the treatment approach for multiple sclerosis changed dramatically. Interferon beta-1b (Betaseron®) was approved for the treatment of ambulatory patients with relapsing-remitting multiple sclerosis, and more recently in 2003, approved for relapsing forms of multiple sclerosis, to include persons with secondary-progressive MS who continue to have relapses (Berlex Laboratories, 2003). In 1996 interferon beta-1a (Avonex®) and glatiramer acetate (Copaxone®) were approved. Avonex is indicated for treatment of relapsing forms of multiple sclerosis, as well as for individuals who have experienced a first clinical episode and have MRI features consistent with MS (Biogen, Inc., 2003). Avonex has also been shown to delay progression of disability, decrease the frequency of clinical exacerbations and reduce the number and size of active lesions in the brain. Copaxone is approved for relapsing-remitting multiple sclerosis (Teva Neuroscience, Inc., 2002). In 2002, Rebif®, another interferon beta-1a, was approved. Rebif is approved for the treatment of relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the onset of progression of physical disability (Serono, Inc., 2003).

In MS, it is thought that inflammatory T-cells are stimulated, migrate into the central nervous system and are reactivated. Upon reactivation, they release damaging cytokines and stimulate cells that injure and/or destroy myelin and axons. Interferons are thought to interfere with the initial stimulation and proliferation of the T-cell in the periphery. In addition, by blocking certain enzyme activity at the blood brain barrier, integrity of the barrier is restored making migration of T-cells into the central nervous system more difficult (Noronha et al., 1993; Stuve et al., 1996). Glatiramer acetate (Copaxone) is thought to work by stimulating T-cells to behave in an anti-inflammatory manner. These glatiramer acetate induced T-cells enter the CNS and reduce the MS inflammatory process (Aharoni, 1997).


Interferon beta-1b (Betaseron), reduced relapses by 31% in the phase III clinical trial. This agent is given by subcutaneous injection, 250 mcg every other day (The IFN Multiple Sclerosis Study Group, 1993). Subsequent trials of this agent in secondary progressive (S-P) MS showed a good effect on S-P patients who were continuing to have relapses, but less of an effect on those who were progressing without relapses (European Study Group on Interferon Beta-1b in Secondary Progressive MS, 1998; Goodkin, 2000). Interferon beta-1b has been shown in various clinical trials to reduce the formation of new MRI lesions and to reduce enhancement on MRI. Interferon beta-1b does not require refrigeration, and can be used with an auto injector. It does, however, need to be reconstituted prior to injection.

In a Phase III clinical trial of Interferon beta-1a 30 mcg weekly (Avonex), relapses were reported to be reduced by 32%; however, the intent-to-treat analysis indicated a reduction in relapses by 18%. The intent-to-treat analysis includes people who had at least one dose of treatment and one assessment, but may have subsequently dropped out of the study for various reasons. It is important to look at the results of an intent-to-treat analysis, because people who drop out of a study may have not had success with the treatment or may have experienced other problems with treatment. Hence, the intent-to-treat analysis shows a smaller reduction of relapses than the analysis of the group that completed the study. Avonex was found to reduce the risk of progression of disability by 37% and also reduced the number of gadolinium enhanced lesions on MRI over the two years of the study (Jacobs et al., 1996). Avonex is given by weekly intramuscular injections of 1 ml volume, using a pre-filled, pre-mixed syringe. This drug requires refrigeration. Interferon beta-1a is also available as a subcutaneously injected medication called Rebif. Rebif is available in two dosages: 22 mcg three times/week and 44 mcg three times/week. In a Phase III trial the 44-mcg dose was found to reduce relapses by 32%. Gadolinium enhancement and burden of disease (total number and size of lesions) were also reduced significantly in this trial (PRISMS Study Group, 1998). Rebif is available in a pre-mixed, pre-filled syringe and can be injected using an auto injector. The medication requires refrigeration.

Both forms of interferon beta-1a were tested in a group of individuals who had experienced one episode of neurological symptoms and who had an MRI highly suggestive of MS. These individuals were thought to be at high risk to develop multiple sclerosis. In two separate trials of weekly interferon beta-1a vs. placebo the treated groups were found to have significantly lower rates of conversion to clinically definite multiple sclerosis. The ETOMS study, sponsored by Serono International SA, showed that treatment with Rebif did not prevent MS, but delayed the conversion to MS, and reduced accumulation of new MRI-detected lesions in the brain (Comi, Fillipi, Barkhof, et al., 2001). The results of the CHAMPS study of Avonex were similar to those of the ETOMS study and led to an approval for use of Avonex in the treatment of people who have a single occurrence of a symptom of demyelinating disease and MRI-detected brain lesions consistent with MS (Jacobs et al., 2000).

Side effects of the interferons are similar. Many individuals are likely to experience flu-like symptoms. These include headache, fever, malaise, muscle achiness, and stiffness. These symptoms seem to dissipate with time; for many patients, the flu symptoms are minimal after the first few months of therapy. Laboratory abnormalities are common with the interferons; however, these rarely require discontinuation of therapy.

Injection site reactions are common with the use of subcutaneous interferons and include erythema, pain, lumps, and itching. Rarely, skin breakdown at the injection site can occur and may lead to injection site necrosis. Intramuscular interferon can produce bruising and discomfort.

Very rarely, a deep infection can result from an IM injection.

Other side effects include menstrual irregularities, nausea, and possibly depression. Menstrual irregularities include cessation of regular periods or excessive bleeding (Berlex Laboratories, 2003; Biogen Inc., 2003; Serono, 2003).

Depression is thought to be a possible side effect with interferons. In the Phase III trial of interferon beta-1b, there were four suicide attempts (Berlex Laboratories, 2003). All individuals were on active drug. However, several additional studies have failed to confirm any relationship between interferon usage and depression. Analyses of data obtained from the PRISMS and SPECTRIMS clinical trials of interferon beta-1a (Rebif) showed that patients on Rebif did not have an increase of depressive symptoms compared with those on placebo (Patten & Metz, 2001; Patten & Metz 2002). Another study of patients treated with interferon beta-1a (Avonex) also failed to show that treatment influenced the depression status of patients (Zephir et al., 2003). Regardless of cause, depression is common in people with MS and it is important to assess the emotional baseline of the individual starting therapy. Follow-up assessments are necessary to identify symptoms of depression, and to initiate treatment.

Although flu symptoms are quite troublesome to patients, the symptoms can be effectively managed. Slow dose escalation at the start of therapy is an effective way to minimize flu symptoms.

In addition, evening dosing and the liberal use of antipyretic medications will help to minimize symptoms. Occasionally, after several months of therapy, flu symptoms may return. The same interventions should be used. In addition, a temporary reduction in dose with subsequent escalation can be tried.

When initial site reactions of erythema, discomfort, lumps and itching occur, injection technique should be reassessed and incorrect procedures should be corrected. Applying ice to the injection site before and after injection may reduce discomfort. The use of a fresh needle just prior to injection is necessary for some individuals, to reduce skin irritation. Although not studied in a controlled trial, over-the-counter hydrocortisone cream has been used for persistent erythema or itching. If skin breakdown and/or necrosis should occur, local wound care is the appropriate intervention. Repeated episodes of skin breakdown, in spite of correct injection technique, may require discontinuation of the medication.

It is unusual for laboratory abnormalities to necessitate discontinuation of interferon. This can occur in a small percentage of individuals, however, and regular monitoring of hematology and chemistry is important for all patients receiving interferons. Because post-marketing cases of severe liver damage have occurred, Dr. Aaron Miller, the Chief Medical Officer of the National Multiple Sclerosis Society, emphasizes the need for periodic liver function testing for all patients taking an interferon medication. He recommends obtaining a baseline evaluation, doing a repeat test after one month on medication, and re-testing every three months thereafter. Abnormalities in lab values can be treated with temporary dose reduction or discontinuation. Rechallenge with the interferon is possible, however, careful monitoring is necessary. A return of the lab abnormality may require permanent discontinuation of the interferon.

Glatiramer Acetate

Glatiramer acetate (Copaxone) for injection is a non-interferon. It is a synthetic mixture of amino acids: L-glutamic acid, L-lysine, L-alanine and L-tyrosine. It was originally developed to assist researchers in the study of the animal model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). When studied in laboratory animals, it was found to improve their disease. Clinical trials demonstrated a positive effect on relapses and MRI. The MRI trial, which was separate from the Phase III pivotal trial, demonstrated a 33% reduction in new MRI lesions.

Comi et al. conducted a separate study that demonstrated fewer permanent black holes in the lesions, and a significant reduction in the number and volume of new enhancing lesions in patients in the Copaxone arm of the MRI study. The relapse rate was reduced by 33% (Johnson et al., 1995; Comi, Fillipi, Wolinsky, et al., 2001).

Recent data of a meta-analysis of three well-controlled clinical trials were reported at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). It was shown that Copaxone significantly reduced the sustained accumulated disability for people with relapsingremitting multiple sclerosis during the first year of treatment and that this effect continued throughout the study follow-up period of nine months to approximately three years (Boneschi et al., 2003).

Copaxone is administered by daily subcutaneous injection. The medication requires refrigeration. It is premixed in a pre-filled syringe. An auto injector is available for administration. The major side effects of glatiramer acetate are injection site reactions and a systemic postinjection reaction. Injection site reactions, which are very common with Copaxone, are rarely serious. They include discomfort, erythema, itching and lumps. Some individuals will experience lipoatrophy from repeated injections. A systemic post injection reaction is thought to occur in about 10% of patients taking Copaxone. It can include one or all of the following symptoms: tachycardia, sweating, anxiety, dyspnea, faint feeling, flushing, and nausea. Although the systemic post-injection reaction has not been found to be dangerous, it can cause anxiety in the patients who experience the symptoms.

Injection site reactions are managed by several interventions. Regular injection site rotation can help to prevent local irritation and lipoatrophy. Discomfort can be managed by applying ice to the injection area. Allowing the solution to come to room temperature may be useful in reducing injection site discomfort.

It is very important to educate the patient about the symptoms of the post injection reaction. Advise the patient to remain calm; the symptoms are likely to subside rapidly. If the symptoms do not begin to resolve within a few minutes, the patient should contact the local emergency services. Should patients experience hives, skin rash with irritation, or dizziness, he or she should make no further injections until consultation with the physician (Bashir & Whitaker, 2002).

Adherence to Disease Modifying Therapy

Although much is said about the importance of early intervention, nonadherence is very high. Based upon data from the North American Research Consortium on MS (NARCOMS), approximately 50% will discontinue therapy. The NARCOMS database was established to facilitate national and international research in multiple sclerosis. When queried as to the reasons for non-adherence, the top four reasons cited were related to expectations of therapy and side effects.

Fraser and Hadjimichael (2001) looked at factors that might predict adherence to Copaxone therapy. They found that self-efficacy, hope, perception that the physician was the most supportive individual and no previous use of immunomodulating therapies were predictors of adherence

Nurses comprise the largest group of health care providers involved with MS care, and have more patient contact then any other group. As such, nurses have the greatest opportunity to enhance adherence. Assessment of readiness to begin a long-term therapy is an important first step. Mutually-established goals between the nurse and the patient are the basis for adherence and are important to long-term treatment success. Frequent contact with a supportive health care professional promotes a trusting relationship and fosters open communication. The nurse in this therapeutic relationship can reinforce realistic expectations of therapy, help manage side effects and help to monitor treatment effects. Nurses must use a hopeful approach, citing the type of success the individual may experience with these therapies.

Education regarding the disease and the disease modifying therapies is a large part of the nurse’s role in multiple sclerosis care. It is very important for patients and families to have a good understanding of what the immunomodulating drugs can and cannot do. These realistic expectations must be reemphasized frequently as patients can become frustrated when the disease symptoms are not improved with the injectable therapy. It is useful to provide resources from a variety of media, as people learn in different ways. Publications from the National Multiple Sclerosis Society, drug companies, and Consortium of MS Centers, as well as reputable websites and teleconferences, will all be useful to patients and their families.

Emotional and spiritual support also influence adherence (Multiple Sclerosis, 1998). Family members are often part of this support; therefore it is important that the nurse include the family in the management plan. When inadequate or no support is available, the nurse can be helpful in investigating possible sources of help, such as the National MS Society, local church groups, and the customer service representatives associated with each pharmaceutical company (Namey, 2001).

In conclusion, relapse management and disease modification are important aspects of overall multiple sclerosis management. The role of the nurse has emerged as vital to the success of therapies. Through a therapeutic relationship that includes education, support and resourcing, nurses can assist patients and their families with long-term adherence to the complex treatment regimens.


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1. Treatment of multiple sclerosis is approached by

a. Treating relapses with disease modifying drugs
b. Treating symptoms and modifying the disease
c. Treating relapses, disease modification and symptom management
d. Treating relapses, disease modification and exclusion of other illnesses
2. A pseudorelapse is best described as
a. New or worsening neurological symptoms that last greater then 24 hours
b. New or worsening neurological symptoms that are brought on by heat
c. New or worsening neurological symptoms that last greater the 48 hours
d. Temporary worsening of symptoms due to concurrent illness, fever or infection
3. Interferon’s are thought to work by
a. Stimulating anti-inflammatory lymphocytes
b. Blocking adhesion of lymphocytes to blood vessel endothelium
c. Interfering with the initial stimulation and proliferation of the T-cell in the periphery
d. Stimulating neutralizing antibodies to form
4. Typical injection site reactions to glatiramer acetate can include
a. Tissue necrosis, itching, and discomfort
b. Erythema, itching, lumps, and discomfort
c. Erythema, necrosis, lumps, and discomfort
d. Erythema, itching, lipoatrophy, and discomfort
5. Interferons should never be prescribed for patients who have depression.
a. True
b. False

Answers: 1 c; 2 d; 3 c; 4 b; 5 b

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