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Immunomodulating Treatments |
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| Executive Editor.....Anne-Merete Robbs CEO..............Stan Swartz | ||||||||||||||||||||||
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| "Dr. Vollmer is close to a MS cure..but..he needs you to help by joining a trial!" | ||||||||||||||||||||||
Stan Swartz, CEO, The MD Health Channel "Plus...You'll receive all medication and study based procedures at NO CHARGE" . |
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| "MY EDUCATIONAL VIDEO ON MS" | ||||||||||||||||||||||
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| "THE VOLUNTARY SUSPENSION OF TYSABRI BY BIOGEN IDEC AND ELAN" | ||||||||||||||||||||||
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| Timothy L. Vollmer M.D. Director, Barrow NeuroImmunology Program Barrow Neurological Institute St. Joseph's Hospital and Medical Center |
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Sunday
UNIVERSITY OF CALIFORNIA - SAN FRANCISCO MEDICAL CENTER
UNIVERSITY OF CALIFORNIA - SAN FRANCISCO MEDICAL CENTER: CLICK TO READ MORE"Immunomodulating Treatments for Relapsing-Remitting MS
Interferon beta (IFNb) In 1993, based on the results of a large multi-center placebo-controlled trial, IFNb-1b (Betaseron) was approved by the Food and Drug Administration (FDA) for the treatment of relapsing/remitting (RR)MS in the United States (US). Subsequently, based on an independent multi-center placebo-controlled trial, IFNb-1a (Avonex) has also been approved for use in the US. Another brand of IFNb-1a (Rebif) is available in Europe and Canada and is currently under consideration by the FDA for use in the US.
The Betaseron trial demonstrated that, compared to treatment with placebo, treatment with 28 million international units (MIU) per week of IFNb subcutaneously reduced the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. This trial also showed a reduction in confirmed one-point progression rate on the extended disability status scale (EDSS), however, this change was not statistically significant. Treatment with 8 MIU/wk of Betaseron was also better than placebo on several outcome measures but was, in general, not as beneficial as the higher dose. The results of the Avonex trial published in 1996 were substantially similar to the earlier Betaseron trial. After two years, compared to placebo, treatment with 6 MIU/wk of Avonex intramuscularly produced a reduction in the clinical attack rate, the MRI attack rate, and the confirmed one-point EDSS progression rate. The total volume of white matter disease seen on MRI was also reduced in the treated group but this was not statistically significant.
The recently published European trial of Rebif in RRMS augments these two earlier studies of IFNb and demonstrated a significant benefit on each of the four major outcome measures in current use. Thus, compared to placebo, treatment with 36 MIU/wk of Rebif subcutaneously was associated with a reduction in clinical attack rate, the MRI attack rate, the confirmed one-point EDSS progression rate, and the volume of white matter disease seen on MRI. Moreover, although treatment with 18 MIU/wk of Rebif subcutaneously was also highly effective, the higher dose of Rebif did better than lower dose on each of these outcome measures. In addition, two recently presented head-to-head trials (Rebif vs. Avonex and Betaseron vs. Avonex) have demonstrated a short-term advantage of higher dose (or more frequently administered) IFNb in the management of patients with RRMS.
Two recently published trials (Avonex and Rebif) have demonstrated that the early treatment with IFNb of patients who have had a single attack of suspected MS delays significantly their progression to clinically definite MS. Such findings offer considerable empirical support for the notion that MS patients should be offered treatment early in the course of their illness.
Side effects of IFNb (e.g., flu-like symptoms, fevers, muscle pains, and injection site reactions) are not uncommon although these typically subside with continued therapy. The occurrence of side effects depends, in part, upon the total dose of IFNb administered and, in part, on the route of administration. For example, injection site reactions are considerably less common with the intramuscular route of administration. Also, some patients develop neutralizing antibodies to IFNb. These antibodies may be associated with a loss of therapeutic benefit with any of the IFNb preparations. The actual clinical importance of these antibodies is, however, unclear. Thus, some patients who develop neutralizing antibodies to IFNb seem to continue responding favorably to treatment and many patients who are antibody positive at one point in time will revert to being antibody negative at a future time point.
Glatiramer Acetate A second form of immunomodulatory treatment, glatiramer acetate (Copaxone), has also been approved for use in the US based on the results of a multicenter placebo-controlled trial published in 1995. Thus, 20 mg of Copaxone administered subcutaneously every day was associated with a reduction in clinical attack rate over a two year period. The confirmed one-point EDSS progression rate was also slightly reduced but this was not statistically significant. An earlier small pilot trial of 20 mg Copaxone subcutaneously daily reported a reduction in both the clinical attack rate and the confirmed one-point EDSS progression rate. MRI outcomes were not included either in the multicenter trial or in this earlier pilot trial. In a subsequent short-duration trial of Copaxone looking specifically at MRI outcome measures, both MRI attack rate and the volume of white matter disease seen on MRI have been reported preliminarily to be significantly reduced in the group receiving active drug, although these benefits seem to be delayed until approximately 6 months following the onset of therapy. Importantly, Copaxone is well tolerated and generally produces fewer side effects in comparison to the different IFNb preparations.
Immunomodulating Treatments for Secondary-Progressive MS
Based on the fact that RRMS and secondary progressive (SP) MS seem to represent different stages of the same underlying disease process, one would anticipate that treatments effective in one stage of the illness will also be effective in another. Indeed, the results of the European trial of Betaseron seem to offer support for this notion. Thus, this trial also demonstrated a robust clinical benefit of IFNb on same four outcome measures in SPMS that were shown previously to be benefited in RRMS. Compared to treatment with placebo, treatment with 28 MIU/wk of Betaseron subcutaneously reduced the clinical attack rate, the MRI attack rate, the confirmed one-point EDSS progression rate, and the volume of white matter disease seen on MRI. Indeed, the statistical significance of the reduction in clinical progression found in this trial was the best for any of the IFNb trials yet. This study also demonstrated a significant, and clinically important, prolongation for the time to becoming wheelchair bound during each year of Betaseron treatment.
However, the preliminary results of the American trial of Betaseron, the results of the European trial of Rebif, and the preliminary results of the American trial of Avonex in SPMS all failed to confirm the benefit of IFNb on reducing the confirmed one-point EDSS progression despite benefits seen for the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. These apparently disparate findings between these trials and the earlier European Betaseron trial require clarification and suggest that IFNb therapy may not be as useful later in the course of disease.
Conclusions about immunomodulating treatments
The therapeutic efficacy of IFNb in the treatment of MS is well established. Indeed, several large independent multi-center controlled trials have demonstrated a remarkable consistency in the therapeutic benefits provided by this agent. Moreover, there is possibly also therapeutic efficacy of IFNb in SPMS, although the apparent discrepancies between the different IFNb trials requires clarification. The therapeutic effectiveness of glatiramer acetate (Copaxone) in RRMS also seems well established although the available data is less complete. In addition, there is only limited experience with the use of glatiramer acetate (Copaxone) in SPMS, although it is reasonable to consider this agent in patients who cannot tolerate IFNb or who continue to progress despite optimal IFNb treatment. There is no data on the use of these agents in the treatment of PPMS although several clinical trials are currently underway.
Immunosuppressive Treatments
Over the past several decades there has been considerable interest in the possibility that MS might be successfully treated with immunosuppressive agents. These approaches have included the use of azathioprine (Imuran), methotrexate (Rheumatrex), cyclophosphamide (Cytoxan), cyclosporin (Sandimmune), cladribine (Leustatin), mitoxantrone (Novantrone), total lymphoid radiation, monoclonal antibodies, corticosteroids, intravenous gammaglobulin, plasma exchange and bone marrow transplants.
Considering all of the evidence, and despite the often robust effects of these agents on MRI outcome measures, the clinical success rate for these approaches to the management of MS patients has been disappointing. Often, initially optimistic reports of success with a particular agent or method are followed by larger clinical trials that have failed to confirm the original findings. Some agents (e.g., glucocorticoids, azathioprine) have been studied extensively and with repeatedly equivocal findings or demonstrating minimal benefits. Other approaches (e.g., total lymphoid radiation or bone marrow transplants) may carry either large or unknown short-term risks for patients. Some of the chemotherapeutic agents (e.g., cyclosporin. cyclophosphamide) are both acutely toxic and, if used for prolonged periods, carry uncertain long-term risks to health. As a result of such difficulties, in addition to the lack of unequivocal evidence for efficacy, the clinical use of these agents has remained limited and, indeed, many of the currently available agents should be considered only in very selected circumstances.
Methotrexate Methotrexate (Rheumatrex) is relatively mild immunosuppressant in widespread use for other inflammatory neurological conditions such as myasthenia gravis or demyelinating peripheral neuropathies. In MS, it has been reported to slow the progression of upper extremity dysfunction in patients with SPMS, although a comparable benefit on the progression of lower extremity dysfunction was not demonstrated in this study. It is generally well tolerated by patients at single weekly doses ranging from 7.5 to 20 mg orally. Some patients experience nausea, headache, or diarrhea but these side effects rarely necessitate discontinuation of treatment, particularly at the lower doses used for treating MS. Complete Blood Counts (CBCs), in addition to tests of hepatic and renal function, should be followed in all patients. Some patients will develop irreversible liver damage following prolonged treatment (>2 years) and many experts recommend a blind liver biopsy in that setting so that drug-related hepatic toxicity can be detected early. There also may be an increased long-term risk of developing non-Hodgkin’s lymphoma following therapy.
Azathioprine Azathioprine (Imuran) is another relatively mild immunosuppressant that has been used primarily in SPMS. Meta-analysis of published trials suggests that azathioprine (Imuran) is marginally effective. It is generally administered at a total daily dose of 2-3 mg/kg with the therapeutic goal of lowering the white blood cell count to between 3,500 and 4,000 cells/ml. This treatment is also generally well tolerated although some patients will experience abdominal pain or nausea.
Cyclophosphamide Cyclophosphamide (Cytoxan)is a potent immunosuppressant. It often has prominent short-term side effects such as hair loss, nausea, vomiting, and bleeding into the urine. The published experience using this agent in SPMS is mixed. Initial reports were favorable suggesting a short-term benefit from a single course of the drug administered intravenously. However, a large multi-center trial in Canada failed to confirm any long-term benefit of a single course of treatment. Because of the known toxicity of this agent, however, it is probably best reserved for very highly selected patients (e.g., patients in otherwise in good health, ambulatory, and aged less than 40 years) who are unresponsive to other therapies and who continue to progress.
Cladribine Cladribine (Leustatin)is also a potent immunosuppressive agent that is relatively selective for lymphocytes compared to other cell types. It has been used successfully to treat a variety of lymphoid malignancies but it is especially effective in the treatment of hairy-cell leukemia. The Scripps Clinic, in two small studies, reported fairly modest benefits to treatment in patients with either SPMS or RRMS. These findings, however, were not been replicated in a larger multicenter trial. Therefore, this treatment should be considered experimental at the present time.
Mitoxantrone Mitoxantrone (Novantrone) is the most recent immunosuppressive agent reported to be of value in the treatment of MS. This agent has been studied in both RRMS and SPMS at doses of 12 mg/m2 and 5 mg/m2 administered by IV infusion every 3 months for 2 years. Preliminary results from this trial demonstrate that, compared to placebo, treatment with high dose mitoxantrone resulted in a significant reduction in the clinical attack rate, as well as marginally significant reductions in MRI attack rate, the one-point EDSS progression, and the total lesion load on MRI. The final results of this trial are pending, although the FDA has already approved this agent for use in MS. In general, mitoxantrone was well tolerated, although, because of concerns regarding potential cardiac toxicity, the recommended total life-time dose of mitoxantrone (Novantrone) is limited such that continuous treatment with quarterly 12 mg/m2 mitoxantrone (Novantrone) beyond 2-3 years would not, at present, be possible. Clearly, such a limitation will be problematic for patients expected to require treatment over many years. There are also concerns that the drug can increase the risk of certain cancers developing in the future and can cause permanent sterility in some patients. Nevertheless, this therapy may be a reasonable alternative in selected patients who are continuing to deteriorate despite optimal management with other agents.
Intravenous immunoglobulin G Intravenous immunoglobulin G (IVIg) has also been used of in the treatment of RRMS. Several recent trials have reported a beneficial effect of treatment on reducing the clinical attack rate. The findings, however, have been less consistent for other MRI measures and for effects on clinical disability. Moreover, the available trials have often studied only small numbers of patients, lacked complete clinical and MRI outcome data, or have used methods, the validity of which has been challenged. In addition, the treatment regimens used have been so variable between reports that the optimal manner in which to administer IVIg is impossible to determine. At present, therefore, the use of IVIg in MS should be reserved for only selected patients or for research settings.
Selected Experimental Treatments
Bone Marrow Transplant Bone Marrow Transplant (BMT) is a strategy to rid the body of cells capable of orchestrating an immune-mediated attack against myelin. Autologous BMT (using stem cells from the same individual to reconstitute the person’s immune system) has been attempted in only a small number of patients with progressive forms of MS. Although preliminary results have been encouraging, this procedure may produce life threatening infections and some MS patients have died following such BMT. Hetertologous BMT (using stem cells from a different individual to reconstitute the person’s immune system) use less intensive immunosuppression and, therefore, carry less risk to the health of patients. Moreover, this technique may actually prove to be superior to autologous BMT because the reconstituted immune system is less likely to have the propensity to produce further bouts of MS. Additional studies of BMT are currently underway and are clearly necessary to define the clinical value of this experimental approach.
Monoclonal antibodies Monoclonal antibodies (MAB's) are a newer strategy for modulating the body's immune system by interfering with specific steps in the development of the immune response against myelin. This approach differs from traditional immunosuppression by virtue of its selectivity. Preliminary studies have included only a small numbers of MS patients. Some of these studies suggest that monoclonal antibodies are promising treatments for MS. Other studies have shown no benefit or unacceptable toxicity. The role of monoclonal antibodies in the treatment of MS is, therefore, still unclear.
Stem Cells Stem Cells are being considered as a possible means of inducing repair of the myelin sheath that has been injured during the course of MS. One approach would be for stem cells (cells that have the potential to become oligodendrocytes) to be transplanted into an individual. A second approach would be to induce stem cells already present in a person’s body to develop into oligodendrocytes. Both approaches are being explored.
Symptomatic Treatments for MS
Depression
Depression is a very common symptom in MS. Depression is characterized by feelings of hopelessness, the inability to enjoy things that once were pleasurable, feelings of worthlessness, disruption of sleep, crying, feelings of sadness or irritability, social isolation, decreased sexuality, and in some cases, suicidal thoughts. If these symptoms persist occur every day for two weeks or more, or include suicidal thoughts, medical attention is required immediately. Regardless of whether the depression is reactive (i.e., as a result of having a serious illness), genetic (endogenous depression), or a manifestation of the illness itself, medications can be helpful. Individual psychotherapy can also be helpful, either by itself or in combination with medication. However, studies suggest that in MS patients, depression usually requires some form of treatment - it is unlikely to spontaneously remit. In addition to an alteration of mood, depression may contribute to the fatigue experienced by patients with MS and this also may respond favorably to antidepressant medications. Useful agents in the treatment of depression include the selective serotonin reuptake inhibitors (e.g., fluoxitine [Prozac], 20-80 mg/day or sertraline [Zoloft], 50-200 mg/day), the tricyclic antidepressants (e.g., amitriptyline [Elavil], 25-150 mg/day; nortryptiline [Pamelor], 25-150 mg/day; or desipramine [Norpramin],100-300 mg/day), and the non-tricyclic antidepressants (e.g., venlafaxine [Effexor], 75-225 mg/day).
Fatigue
Fatigue is characterized by diminished energy and endurance. Many patients with MS also experience an overwhelming sense of exhaustion that requires them to sit, recline, or fall asleep. This symptom is often aggravated by elevated temperature and can be reversed by cooling. Fatigue in MS can be severe and disabling. It affects almost 90% of patients to some degree and is characterized as moderate to severe in over half. It accounts (in part or in whole) for the disability in approximately 65% of patients unable to work. It is also multifactorial. Thus, depression can often contribute to a patient’s fatigue and may be managed successfully with anti-depressant medications. Patients who expend exceptional effort to accomplish basic ADLs may experience substantial fatigue and may benefit from assistive devices, from help in the home, or from successful management of their spasticity. Not infrequently, patients with MS have nighttime sleep disturbances that translate into day time fatigue. As one example, patients with frequent nocturia (and, thus, frequent nocturnal awakenings) may benefit from an anticholinergic medication at bedtime to prevent these night time arousals and improve the quality of their night time rest. In addition to these other sources of fatigue in MS, however, there is also an extreme lassitude that is more specifically related to the disease. This fatigue can be the sole manifestation of an attack and is often difficult to treat. Several effective medications are now available for the treatment of fatigue. These medications include amantadine (Symmetrel) 200 mg/day; pemoline (Cylert) 37.5-75 mg/day; methylphenidate (Ritalin) 5-25 mg q day, and modafinil (Provigil) 200-400 mg/day. A cooling vest or cap may be helpful when symptoms are provoked by exposure to elevated temperatures.
Spasticity
Spasticity (muscle stiffness) is usually accompanied by weakness, slowness of movement, poor coordination, and spontaneous spasms. Spasticity poses a considerable problem for the management of MS patients. Over 40% of patients describe their spasticity as moderate to severe. Typically it is most severe in the lower extremities and often interferes substantially with a patient’s ability to ambulate, to work, and to perform even the most basic activities of daily living. It is often painful and frequently associated with painful extensor (occasionally flexor) spasms. At times, however, the increased stiffness of the muscles may be helpful to patients by providing non-volitional support during ambulation. In such a circumstance, overly aggressive treatment may actually do more harm than good. Non-pharmacological approaches to the management of spasticity include physical therapy, regular exercise, and stretching, which can provide substantial relief. The avoidance of nociceptive inputs from a variety of sources (e.g., infections, fecal impactions, bed sores, etc.) is an extremely important first principal in patient management because such inputs are known to increase markedly the severity and extent of spasticity. Effective pharmacological agents for reducing both spasticity and spasms include lioresal (Baclofen) 20-120 mg/day; diazepam (Valium) 2-40 mg/day, and tizanidine (Zanaflex) 8-32 mg/day. Several other medications have also been reported to provide occasional benefit for patients with spasticity including clonazepam, carbamazepine, phenytoin, gabapentin, tetrahydrocanabinol, barbiturates, and alcohol. However, the efficacy of these agents is not well established.
When the spasticity is particularly severe and the patient already has limited use of their lower extremities, a surgically implanted lioresal (Baclofen) pump (delivering the medication directly into the spinal fluid that bathes the spinal cord) can often provide substantial relief. This may also allow for improved hygiene and, thereby, reduce the frequency of urinary infections and bed sores. Destructive procedures such as selective rhyzotomy, tenotomy, myotomy, and phenol injections should be reserved for only the most extreme cases that are unresponsive to other measures.
Pain
Pain is an under appreciated symptom of MS. Over half of MS patients complain of pain and, in a substantial fraction, the pain is described as severe, at least at times. MS-related pain can be experienced as jolts of electricity, continuous dull burning, disagreeable tingling, or raw sensations. An improved understanding of the mechanisms that produce pain of central origin has produced several successful approaches to its management, including the anticonvulsant drugs (e.g., carbamazepine [Tegretol], 100-1000 mg/day or phenytoin [Dilantin], 300-600 mg/day or gabapentin [Neurontin], 300-3600 mg/day), or the antidepressant drugs (e.g., amitriptyline [Elavil], 25-150 mg/day or nortryptiline [Pamelor], 25-150 mg/day or desipramine [Norpramin],100-300 mg/day or venlafaxine [Effexor], 75-225 mg/day), or the anti-arrhythmic drugs (e.g., Mexiletine [Mexitil], 300-900 mg/day). If these treatments are unsuccessful, some patients may respond to a comprehensive pain management program. Such persons may be referred to the UCSF Clinical Pain Research Center.
Ataxia/Tremor
Ataxia/Tremor is a common and often intractable symptom in MS that is difficult to treat effectively. Tremor may involve the hand, arm, leg, head, or voice. These movements may be barely noticeable or they can be severely incapacitating. Some medications are occasionally helpful including clonazepam (Klonopin), 1.5-20 mg /day, mysoline (Primadone) 50-250 mg/day, propranalol (Inderal) 40-200 mg/day, or ondansetron (Zofran) 8-16 mg/day. The use of weights on the wrists may occasionally reduce tremor in the arm or hand. Unfortunately, however, the success of most attempts at therapy is limited. Recently, there has been interest in the use thalamotomy and/or the placement of deep brain stimulators to control tremor. However, even in the best of hands the response to this intervention is often partial, the response rate is limited (~50%), the duration of any therapeutic benefit is unknown. Moreover, the surgical procedure itself carries risk.
Bladder Dysfunction
Several different types of bladder dysfunction occur in MS. Not infrequently, different types of dysfunction co-exist in the same patient and, as a result, urodynamic testing can often provide useful clinical information. During normal reflex voiding there is a coordinated relaxation of the bladder sphincter that is precisely timed to the detrusor muscle (bladder wall) contraction. The urinary stream is stopped by a reversal of the above mechanisms with bladder wall relaxation coordinated with sphincter contraction. The bladder reflex is activated by stretch of the bladder wall during filling and it can be voluntarily inhibited. Symptoms of bladder dysfunction are present in over 90% of patients with MS. Many of these symptoms occur only occasionally and are quite mild. In this circumstance, they do not require specific intervention. Nevertheless, over 30% of MS patients experience bladder symptoms of sufficient severity to result in episodes of incontinence weekly or more often. Fortunately, bladder symptoms are among the easiest MS symptoms to treat. These symptoms include (1) urinary frequency the need to go to the bathroom frequently; (2) urgency the need to go to the bathroom immediately; (3) hesitancy difficulty initiating the urine stream; and (4) retention the inability to completely empty the bladder. Most patients can regain continence or experience significant improvement in these symptoms.
The first type of bladder dysfunction, results from decreased inhibition of the bladder reflex. Symptomatically, this decrease causes urinary frequency (having to urinate more often than usual), urinary urgency (having to get to the bathroom right away when you feel the urge), and uncontrolled bladder emptying (incontinence). When these symptoms are mild they can sometimes be treated with fluid management techniques such as evening fluid restriction to prevent night time incontinence or the use of frequent voluntary voiding to prevent day time incontinence. If these simple approaches fail to control the problem, however, there are several medications available that can inhibit bladder wall contraction and thereby lessen the bladder reflex. These medications include propantheline bromide (ProBanthine) 10-15 mg/day; oxybutinin (Ditropan) 5-15 mg/day, hycosamine sulfate (Levsin) 0.5-0.75 mg/day and tolteridine tartrate (Detrol) 2-4 mg/day. Often the co-administration of an over-the-counter medication such as pseudoephedrine (Sudafed, 30-60 mg) which cause contraction of the bladder sphincter can help maintain continence.
The second type of bladder dysfunction, results from the loss of coordination and synchronization between the bladder wall and sphincter muscles (dyssynergia). This results in a difficulty initiating or stopping the urinary stream (hesitancy) and leads to the retention of residual urine in the bladder following voiding. Occasionally, this condition will respond to medications such as phenoxybenzamine (Dibenzyline, 10-20 mg/day) but more often this condition requires the use of intermittent or continuous catheterization. A third type of dysfunction, loss of reflex bladder wall contraction, generally results from a chronically over-filled bladder, which, itself, is often due to long-standing dyssynergia. This condition can occasionally respond to medications such as bethanecol (Urecholine), 30-150 mg/day, but often this condition also often requires intermittent or continuous catheterization.
It is also important to monitor patients for urinary tract infections and treat them promptly when they are identified. Patients who have large volumes of post-void residual urine in their bladders are predisposed to bladder infections and patients at risk for such complications may be identified by measuring a post-void residual volume. It is also often helpful to take steps to prevent infections. Acidification of the urine with cranberry juice or Vitamin C inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to bladder colonization by resistant organisms and can result in infections that are more difficult to treat. Intermittent catheterization may be necessary to allow complete bladder emptying and to prevent recurrent infections.
Bowel Dysfunction
Constipation is a common symptom in MS, occurring in over 30% of patients. High fiber diets (often with supplemental fiber) in addition to plenty of fluids is usually the best approach. Natural or other laxatives can also help. Fecal incontinence is much less common than constipation although 17% of patients (more so in men) report at least some episodes. If it is severe enough to warrant treatment, fecal incontinence may respond to a reduction in total dietary fiber.
Paroxysmal Symptoms
Several different paroxysmal syndromes occur in MS. These syndromes are distinguished by brief duration (30 seconds to 2 minutes); high frequency of occurrence (5-40 paroxysms/day); lack of any alteration of consciousness or change in background EEG during the events; a self-limited nature (generally lasting only months and then subsiding). They may be precipitated by hyperventilation or movement. These syndromes include the familiar L’hermittes sign (electric shock like sensations induced by neck flexion), tonic seizures, paroxysmal dysarthria/ataxia, paroxysmal sensory disturbances, and several other less well characterized syndromes. These syndromes are also distinguished by their marked responsiveness to very low dosages of anticonvulsant medications such as carbamazepine (Tegretol), 50-400 mg/day, phenytoin (Dilantin), 50-300 mg/day, or acetazolamide (Diamox) 200-600 mg/day. Patients with MS may also suffer from trigeminal neuralgia (tic douloureux) which often responds to similar medications.
Heat Sensitivity
Many symptoms are aggravated by exposure to heat or with fever. Keeping away from the direct heat of the sun and the use of air conditioning are often necessary to prevent these symptoms. Cooling vests or caps may be useful in select patients.
Weakness
The potassium channel blockers (e.g., 4-amino pyridine, 10-40 mg/day; and 3,4-di-amino pyridine, 40-80 mg/day) may help some MS symptoms (especially heat sensitive symptoms) and anecdotally some patients experience improved function. These drugs presumably work by prolonging the duration of the nerve action potential and, thereby, facilitating conduction through demyelinated fibers. At high enough doses they may also cause seizures for similar reasons. These agents are not FDA-approved but are currently available from one of several compounding pharmacies around the US. More definitive clinical trials, however, are needed to establish any therapeutic benefit.
Sexual Dysfunction
Sexual dysfunction was reported by over 60% of the women and over 75% of the men in a recent survey of MS patients in northern California. The greater dysfunction in men resulted not only from impotence (61%) but also from less sexual desire and less demonstrated interest by their partners. Nevertheless, sexual dysfunction can be a considerable problem for either gender. Women experiencing sexual dysfunction often experience numbness in the genital area, diminished orgasmic response, unpleasant sensations, and diminished vaginal lubrication. Men commonly report impaired genital sensation, delayed ejaculation, decreased force of ejaculation, and/or inability to achieve and maintain an erection. Approaches such as couples or psychological therapy may help in selected cases. Communication between partners is essential. Teaching your partner how you need to be touched or positioned can result in a return of pleasure and excitement instead of discomfort or pain. The use of water soluble lubricants may be an essential aid in genital stimulation and sexual arousal. The use of vibrators may provide pleasurable and sexually stimulating sensations. Spasms, pain, spasticity, fatigue, and bladder/bowel dysfunction may contribute to sexual dysfunction, and medications to alleviate these symptoms may help. Thus, the effective management of adductor spasticity, the use of devices (e.g., vibrators) to make up for loss of deep sensation, penile injections of papaverine or prostaglandin, or prosthetic devices to assist with maintaining erection may also be helpful in some circumstances. The biggest advance in treatment of impotence, however, has been the introduction of sildenafil (Viagra) 50-100 mg orally 1-2 hours prior to sex.
Memory Problems
Cognitive problems, including problems with memory, are common in MS. Between 45% and 65% of people with MS will have some problems with cognitive functioning. Donepezil HCl (Aricept) is a cholinesterase inhibiting medication used to treat patients with early Alzheimer’s disease. Two small, non-randomized, uncontrolled studies have shown benefit for MS patients with memory problems taking 10 mg/day. Similar small, uncontrolled studies have also shown benefits for patients with memory problems due to traumatic brain injury. Larger, placebo-controlled studies are underway with both these populations. While this medication is not currently approved by the FDA for the treatment of memory problems in patients with MS, it may be of some benefit in some cases."
Interferon beta (IFNb) In 1993, based on the results of a large multi-center placebo-controlled trial, IFNb-1b (Betaseron) was approved by the Food and Drug Administration (FDA) for the treatment of relapsing/remitting (RR)MS in the United States (US). Subsequently, based on an independent multi-center placebo-controlled trial, IFNb-1a (Avonex) has also been approved for use in the US. Another brand of IFNb-1a (Rebif) is available in Europe and Canada and is currently under consideration by the FDA for use in the US.
The Betaseron trial demonstrated that, compared to treatment with placebo, treatment with 28 million international units (MIU) per week of IFNb subcutaneously reduced the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. This trial also showed a reduction in confirmed one-point progression rate on the extended disability status scale (EDSS), however, this change was not statistically significant. Treatment with 8 MIU/wk of Betaseron was also better than placebo on several outcome measures but was, in general, not as beneficial as the higher dose. The results of the Avonex trial published in 1996 were substantially similar to the earlier Betaseron trial. After two years, compared to placebo, treatment with 6 MIU/wk of Avonex intramuscularly produced a reduction in the clinical attack rate, the MRI attack rate, and the confirmed one-point EDSS progression rate. The total volume of white matter disease seen on MRI was also reduced in the treated group but this was not statistically significant.
The recently published European trial of Rebif in RRMS augments these two earlier studies of IFNb and demonstrated a significant benefit on each of the four major outcome measures in current use. Thus, compared to placebo, treatment with 36 MIU/wk of Rebif subcutaneously was associated with a reduction in clinical attack rate, the MRI attack rate, the confirmed one-point EDSS progression rate, and the volume of white matter disease seen on MRI. Moreover, although treatment with 18 MIU/wk of Rebif subcutaneously was also highly effective, the higher dose of Rebif did better than lower dose on each of these outcome measures. In addition, two recently presented head-to-head trials (Rebif vs. Avonex and Betaseron vs. Avonex) have demonstrated a short-term advantage of higher dose (or more frequently administered) IFNb in the management of patients with RRMS.
Two recently published trials (Avonex and Rebif) have demonstrated that the early treatment with IFNb of patients who have had a single attack of suspected MS delays significantly their progression to clinically definite MS. Such findings offer considerable empirical support for the notion that MS patients should be offered treatment early in the course of their illness.
Side effects of IFNb (e.g., flu-like symptoms, fevers, muscle pains, and injection site reactions) are not uncommon although these typically subside with continued therapy. The occurrence of side effects depends, in part, upon the total dose of IFNb administered and, in part, on the route of administration. For example, injection site reactions are considerably less common with the intramuscular route of administration. Also, some patients develop neutralizing antibodies to IFNb. These antibodies may be associated with a loss of therapeutic benefit with any of the IFNb preparations. The actual clinical importance of these antibodies is, however, unclear. Thus, some patients who develop neutralizing antibodies to IFNb seem to continue responding favorably to treatment and many patients who are antibody positive at one point in time will revert to being antibody negative at a future time point.
Glatiramer Acetate A second form of immunomodulatory treatment, glatiramer acetate (Copaxone), has also been approved for use in the US based on the results of a multicenter placebo-controlled trial published in 1995. Thus, 20 mg of Copaxone administered subcutaneously every day was associated with a reduction in clinical attack rate over a two year period. The confirmed one-point EDSS progression rate was also slightly reduced but this was not statistically significant. An earlier small pilot trial of 20 mg Copaxone subcutaneously daily reported a reduction in both the clinical attack rate and the confirmed one-point EDSS progression rate. MRI outcomes were not included either in the multicenter trial or in this earlier pilot trial. In a subsequent short-duration trial of Copaxone looking specifically at MRI outcome measures, both MRI attack rate and the volume of white matter disease seen on MRI have been reported preliminarily to be significantly reduced in the group receiving active drug, although these benefits seem to be delayed until approximately 6 months following the onset of therapy. Importantly, Copaxone is well tolerated and generally produces fewer side effects in comparison to the different IFNb preparations.
Immunomodulating Treatments for Secondary-Progressive MS
Based on the fact that RRMS and secondary progressive (SP) MS seem to represent different stages of the same underlying disease process, one would anticipate that treatments effective in one stage of the illness will also be effective in another. Indeed, the results of the European trial of Betaseron seem to offer support for this notion. Thus, this trial also demonstrated a robust clinical benefit of IFNb on same four outcome measures in SPMS that were shown previously to be benefited in RRMS. Compared to treatment with placebo, treatment with 28 MIU/wk of Betaseron subcutaneously reduced the clinical attack rate, the MRI attack rate, the confirmed one-point EDSS progression rate, and the volume of white matter disease seen on MRI. Indeed, the statistical significance of the reduction in clinical progression found in this trial was the best for any of the IFNb trials yet. This study also demonstrated a significant, and clinically important, prolongation for the time to becoming wheelchair bound during each year of Betaseron treatment.
However, the preliminary results of the American trial of Betaseron, the results of the European trial of Rebif, and the preliminary results of the American trial of Avonex in SPMS all failed to confirm the benefit of IFNb on reducing the confirmed one-point EDSS progression despite benefits seen for the clinical attack rate, the MRI attack rate, and the volume of white matter disease seen on MRI. These apparently disparate findings between these trials and the earlier European Betaseron trial require clarification and suggest that IFNb therapy may not be as useful later in the course of disease.
Conclusions about immunomodulating treatments
The therapeutic efficacy of IFNb in the treatment of MS is well established. Indeed, several large independent multi-center controlled trials have demonstrated a remarkable consistency in the therapeutic benefits provided by this agent. Moreover, there is possibly also therapeutic efficacy of IFNb in SPMS, although the apparent discrepancies between the different IFNb trials requires clarification. The therapeutic effectiveness of glatiramer acetate (Copaxone) in RRMS also seems well established although the available data is less complete. In addition, there is only limited experience with the use of glatiramer acetate (Copaxone) in SPMS, although it is reasonable to consider this agent in patients who cannot tolerate IFNb or who continue to progress despite optimal IFNb treatment. There is no data on the use of these agents in the treatment of PPMS although several clinical trials are currently underway.
Immunosuppressive Treatments
Over the past several decades there has been considerable interest in the possibility that MS might be successfully treated with immunosuppressive agents. These approaches have included the use of azathioprine (Imuran), methotrexate (Rheumatrex), cyclophosphamide (Cytoxan), cyclosporin (Sandimmune), cladribine (Leustatin), mitoxantrone (Novantrone), total lymphoid radiation, monoclonal antibodies, corticosteroids, intravenous gammaglobulin, plasma exchange and bone marrow transplants.
Considering all of the evidence, and despite the often robust effects of these agents on MRI outcome measures, the clinical success rate for these approaches to the management of MS patients has been disappointing. Often, initially optimistic reports of success with a particular agent or method are followed by larger clinical trials that have failed to confirm the original findings. Some agents (e.g., glucocorticoids, azathioprine) have been studied extensively and with repeatedly equivocal findings or demonstrating minimal benefits. Other approaches (e.g., total lymphoid radiation or bone marrow transplants) may carry either large or unknown short-term risks for patients. Some of the chemotherapeutic agents (e.g., cyclosporin. cyclophosphamide) are both acutely toxic and, if used for prolonged periods, carry uncertain long-term risks to health. As a result of such difficulties, in addition to the lack of unequivocal evidence for efficacy, the clinical use of these agents has remained limited and, indeed, many of the currently available agents should be considered only in very selected circumstances.
Methotrexate Methotrexate (Rheumatrex) is relatively mild immunosuppressant in widespread use for other inflammatory neurological conditions such as myasthenia gravis or demyelinating peripheral neuropathies. In MS, it has been reported to slow the progression of upper extremity dysfunction in patients with SPMS, although a comparable benefit on the progression of lower extremity dysfunction was not demonstrated in this study. It is generally well tolerated by patients at single weekly doses ranging from 7.5 to 20 mg orally. Some patients experience nausea, headache, or diarrhea but these side effects rarely necessitate discontinuation of treatment, particularly at the lower doses used for treating MS. Complete Blood Counts (CBCs), in addition to tests of hepatic and renal function, should be followed in all patients. Some patients will develop irreversible liver damage following prolonged treatment (>2 years) and many experts recommend a blind liver biopsy in that setting so that drug-related hepatic toxicity can be detected early. There also may be an increased long-term risk of developing non-Hodgkin’s lymphoma following therapy.
Azathioprine Azathioprine (Imuran) is another relatively mild immunosuppressant that has been used primarily in SPMS. Meta-analysis of published trials suggests that azathioprine (Imuran) is marginally effective. It is generally administered at a total daily dose of 2-3 mg/kg with the therapeutic goal of lowering the white blood cell count to between 3,500 and 4,000 cells/ml. This treatment is also generally well tolerated although some patients will experience abdominal pain or nausea.
Cyclophosphamide Cyclophosphamide (Cytoxan)is a potent immunosuppressant. It often has prominent short-term side effects such as hair loss, nausea, vomiting, and bleeding into the urine. The published experience using this agent in SPMS is mixed. Initial reports were favorable suggesting a short-term benefit from a single course of the drug administered intravenously. However, a large multi-center trial in Canada failed to confirm any long-term benefit of a single course of treatment. Because of the known toxicity of this agent, however, it is probably best reserved for very highly selected patients (e.g., patients in otherwise in good health, ambulatory, and aged less than 40 years) who are unresponsive to other therapies and who continue to progress.
Cladribine Cladribine (Leustatin)is also a potent immunosuppressive agent that is relatively selective for lymphocytes compared to other cell types. It has been used successfully to treat a variety of lymphoid malignancies but it is especially effective in the treatment of hairy-cell leukemia. The Scripps Clinic, in two small studies, reported fairly modest benefits to treatment in patients with either SPMS or RRMS. These findings, however, were not been replicated in a larger multicenter trial. Therefore, this treatment should be considered experimental at the present time.
Mitoxantrone Mitoxantrone (Novantrone) is the most recent immunosuppressive agent reported to be of value in the treatment of MS. This agent has been studied in both RRMS and SPMS at doses of 12 mg/m2 and 5 mg/m2 administered by IV infusion every 3 months for 2 years. Preliminary results from this trial demonstrate that, compared to placebo, treatment with high dose mitoxantrone resulted in a significant reduction in the clinical attack rate, as well as marginally significant reductions in MRI attack rate, the one-point EDSS progression, and the total lesion load on MRI. The final results of this trial are pending, although the FDA has already approved this agent for use in MS. In general, mitoxantrone was well tolerated, although, because of concerns regarding potential cardiac toxicity, the recommended total life-time dose of mitoxantrone (Novantrone) is limited such that continuous treatment with quarterly 12 mg/m2 mitoxantrone (Novantrone) beyond 2-3 years would not, at present, be possible. Clearly, such a limitation will be problematic for patients expected to require treatment over many years. There are also concerns that the drug can increase the risk of certain cancers developing in the future and can cause permanent sterility in some patients. Nevertheless, this therapy may be a reasonable alternative in selected patients who are continuing to deteriorate despite optimal management with other agents.
Intravenous immunoglobulin G Intravenous immunoglobulin G (IVIg) has also been used of in the treatment of RRMS. Several recent trials have reported a beneficial effect of treatment on reducing the clinical attack rate. The findings, however, have been less consistent for other MRI measures and for effects on clinical disability. Moreover, the available trials have often studied only small numbers of patients, lacked complete clinical and MRI outcome data, or have used methods, the validity of which has been challenged. In addition, the treatment regimens used have been so variable between reports that the optimal manner in which to administer IVIg is impossible to determine. At present, therefore, the use of IVIg in MS should be reserved for only selected patients or for research settings.
Selected Experimental Treatments
Bone Marrow Transplant Bone Marrow Transplant (BMT) is a strategy to rid the body of cells capable of orchestrating an immune-mediated attack against myelin. Autologous BMT (using stem cells from the same individual to reconstitute the person’s immune system) has been attempted in only a small number of patients with progressive forms of MS. Although preliminary results have been encouraging, this procedure may produce life threatening infections and some MS patients have died following such BMT. Hetertologous BMT (using stem cells from a different individual to reconstitute the person’s immune system) use less intensive immunosuppression and, therefore, carry less risk to the health of patients. Moreover, this technique may actually prove to be superior to autologous BMT because the reconstituted immune system is less likely to have the propensity to produce further bouts of MS. Additional studies of BMT are currently underway and are clearly necessary to define the clinical value of this experimental approach.
Monoclonal antibodies Monoclonal antibodies (MAB's) are a newer strategy for modulating the body's immune system by interfering with specific steps in the development of the immune response against myelin. This approach differs from traditional immunosuppression by virtue of its selectivity. Preliminary studies have included only a small numbers of MS patients. Some of these studies suggest that monoclonal antibodies are promising treatments for MS. Other studies have shown no benefit or unacceptable toxicity. The role of monoclonal antibodies in the treatment of MS is, therefore, still unclear.
Stem Cells Stem Cells are being considered as a possible means of inducing repair of the myelin sheath that has been injured during the course of MS. One approach would be for stem cells (cells that have the potential to become oligodendrocytes) to be transplanted into an individual. A second approach would be to induce stem cells already present in a person’s body to develop into oligodendrocytes. Both approaches are being explored.
Symptomatic Treatments for MS
Depression
Depression is a very common symptom in MS. Depression is characterized by feelings of hopelessness, the inability to enjoy things that once were pleasurable, feelings of worthlessness, disruption of sleep, crying, feelings of sadness or irritability, social isolation, decreased sexuality, and in some cases, suicidal thoughts. If these symptoms persist occur every day for two weeks or more, or include suicidal thoughts, medical attention is required immediately. Regardless of whether the depression is reactive (i.e., as a result of having a serious illness), genetic (endogenous depression), or a manifestation of the illness itself, medications can be helpful. Individual psychotherapy can also be helpful, either by itself or in combination with medication. However, studies suggest that in MS patients, depression usually requires some form of treatment - it is unlikely to spontaneously remit. In addition to an alteration of mood, depression may contribute to the fatigue experienced by patients with MS and this also may respond favorably to antidepressant medications. Useful agents in the treatment of depression include the selective serotonin reuptake inhibitors (e.g., fluoxitine [Prozac], 20-80 mg/day or sertraline [Zoloft], 50-200 mg/day), the tricyclic antidepressants (e.g., amitriptyline [Elavil], 25-150 mg/day; nortryptiline [Pamelor], 25-150 mg/day; or desipramine [Norpramin],100-300 mg/day), and the non-tricyclic antidepressants (e.g., venlafaxine [Effexor], 75-225 mg/day).
Fatigue
Fatigue is characterized by diminished energy and endurance. Many patients with MS also experience an overwhelming sense of exhaustion that requires them to sit, recline, or fall asleep. This symptom is often aggravated by elevated temperature and can be reversed by cooling. Fatigue in MS can be severe and disabling. It affects almost 90% of patients to some degree and is characterized as moderate to severe in over half. It accounts (in part or in whole) for the disability in approximately 65% of patients unable to work. It is also multifactorial. Thus, depression can often contribute to a patient’s fatigue and may be managed successfully with anti-depressant medications. Patients who expend exceptional effort to accomplish basic ADLs may experience substantial fatigue and may benefit from assistive devices, from help in the home, or from successful management of their spasticity. Not infrequently, patients with MS have nighttime sleep disturbances that translate into day time fatigue. As one example, patients with frequent nocturia (and, thus, frequent nocturnal awakenings) may benefit from an anticholinergic medication at bedtime to prevent these night time arousals and improve the quality of their night time rest. In addition to these other sources of fatigue in MS, however, there is also an extreme lassitude that is more specifically related to the disease. This fatigue can be the sole manifestation of an attack and is often difficult to treat. Several effective medications are now available for the treatment of fatigue. These medications include amantadine (Symmetrel) 200 mg/day; pemoline (Cylert) 37.5-75 mg/day; methylphenidate (Ritalin) 5-25 mg q day, and modafinil (Provigil) 200-400 mg/day. A cooling vest or cap may be helpful when symptoms are provoked by exposure to elevated temperatures.
Spasticity
Spasticity (muscle stiffness) is usually accompanied by weakness, slowness of movement, poor coordination, and spontaneous spasms. Spasticity poses a considerable problem for the management of MS patients. Over 40% of patients describe their spasticity as moderate to severe. Typically it is most severe in the lower extremities and often interferes substantially with a patient’s ability to ambulate, to work, and to perform even the most basic activities of daily living. It is often painful and frequently associated with painful extensor (occasionally flexor) spasms. At times, however, the increased stiffness of the muscles may be helpful to patients by providing non-volitional support during ambulation. In such a circumstance, overly aggressive treatment may actually do more harm than good. Non-pharmacological approaches to the management of spasticity include physical therapy, regular exercise, and stretching, which can provide substantial relief. The avoidance of nociceptive inputs from a variety of sources (e.g., infections, fecal impactions, bed sores, etc.) is an extremely important first principal in patient management because such inputs are known to increase markedly the severity and extent of spasticity. Effective pharmacological agents for reducing both spasticity and spasms include lioresal (Baclofen) 20-120 mg/day; diazepam (Valium) 2-40 mg/day, and tizanidine (Zanaflex) 8-32 mg/day. Several other medications have also been reported to provide occasional benefit for patients with spasticity including clonazepam, carbamazepine, phenytoin, gabapentin, tetrahydrocanabinol, barbiturates, and alcohol. However, the efficacy of these agents is not well established.
When the spasticity is particularly severe and the patient already has limited use of their lower extremities, a surgically implanted lioresal (Baclofen) pump (delivering the medication directly into the spinal fluid that bathes the spinal cord) can often provide substantial relief. This may also allow for improved hygiene and, thereby, reduce the frequency of urinary infections and bed sores. Destructive procedures such as selective rhyzotomy, tenotomy, myotomy, and phenol injections should be reserved for only the most extreme cases that are unresponsive to other measures.
Pain
Pain is an under appreciated symptom of MS. Over half of MS patients complain of pain and, in a substantial fraction, the pain is described as severe, at least at times. MS-related pain can be experienced as jolts of electricity, continuous dull burning, disagreeable tingling, or raw sensations. An improved understanding of the mechanisms that produce pain of central origin has produced several successful approaches to its management, including the anticonvulsant drugs (e.g., carbamazepine [Tegretol], 100-1000 mg/day or phenytoin [Dilantin], 300-600 mg/day or gabapentin [Neurontin], 300-3600 mg/day), or the antidepressant drugs (e.g., amitriptyline [Elavil], 25-150 mg/day or nortryptiline [Pamelor], 25-150 mg/day or desipramine [Norpramin],100-300 mg/day or venlafaxine [Effexor], 75-225 mg/day), or the anti-arrhythmic drugs (e.g., Mexiletine [Mexitil], 300-900 mg/day). If these treatments are unsuccessful, some patients may respond to a comprehensive pain management program. Such persons may be referred to the UCSF Clinical Pain Research Center.
Ataxia/Tremor
Ataxia/Tremor is a common and often intractable symptom in MS that is difficult to treat effectively. Tremor may involve the hand, arm, leg, head, or voice. These movements may be barely noticeable or they can be severely incapacitating. Some medications are occasionally helpful including clonazepam (Klonopin), 1.5-20 mg /day, mysoline (Primadone) 50-250 mg/day, propranalol (Inderal) 40-200 mg/day, or ondansetron (Zofran) 8-16 mg/day. The use of weights on the wrists may occasionally reduce tremor in the arm or hand. Unfortunately, however, the success of most attempts at therapy is limited. Recently, there has been interest in the use thalamotomy and/or the placement of deep brain stimulators to control tremor. However, even in the best of hands the response to this intervention is often partial, the response rate is limited (~50%), the duration of any therapeutic benefit is unknown. Moreover, the surgical procedure itself carries risk.
Bladder Dysfunction
Several different types of bladder dysfunction occur in MS. Not infrequently, different types of dysfunction co-exist in the same patient and, as a result, urodynamic testing can often provide useful clinical information. During normal reflex voiding there is a coordinated relaxation of the bladder sphincter that is precisely timed to the detrusor muscle (bladder wall) contraction. The urinary stream is stopped by a reversal of the above mechanisms with bladder wall relaxation coordinated with sphincter contraction. The bladder reflex is activated by stretch of the bladder wall during filling and it can be voluntarily inhibited. Symptoms of bladder dysfunction are present in over 90% of patients with MS. Many of these symptoms occur only occasionally and are quite mild. In this circumstance, they do not require specific intervention. Nevertheless, over 30% of MS patients experience bladder symptoms of sufficient severity to result in episodes of incontinence weekly or more often. Fortunately, bladder symptoms are among the easiest MS symptoms to treat. These symptoms include (1) urinary frequency the need to go to the bathroom frequently; (2) urgency the need to go to the bathroom immediately; (3) hesitancy difficulty initiating the urine stream; and (4) retention the inability to completely empty the bladder. Most patients can regain continence or experience significant improvement in these symptoms.
The first type of bladder dysfunction, results from decreased inhibition of the bladder reflex. Symptomatically, this decrease causes urinary frequency (having to urinate more often than usual), urinary urgency (having to get to the bathroom right away when you feel the urge), and uncontrolled bladder emptying (incontinence). When these symptoms are mild they can sometimes be treated with fluid management techniques such as evening fluid restriction to prevent night time incontinence or the use of frequent voluntary voiding to prevent day time incontinence. If these simple approaches fail to control the problem, however, there are several medications available that can inhibit bladder wall contraction and thereby lessen the bladder reflex. These medications include propantheline bromide (ProBanthine) 10-15 mg/day; oxybutinin (Ditropan) 5-15 mg/day, hycosamine sulfate (Levsin) 0.5-0.75 mg/day and tolteridine tartrate (Detrol) 2-4 mg/day. Often the co-administration of an over-the-counter medication such as pseudoephedrine (Sudafed, 30-60 mg) which cause contraction of the bladder sphincter can help maintain continence.
The second type of bladder dysfunction, results from the loss of coordination and synchronization between the bladder wall and sphincter muscles (dyssynergia). This results in a difficulty initiating or stopping the urinary stream (hesitancy) and leads to the retention of residual urine in the bladder following voiding. Occasionally, this condition will respond to medications such as phenoxybenzamine (Dibenzyline, 10-20 mg/day) but more often this condition requires the use of intermittent or continuous catheterization. A third type of dysfunction, loss of reflex bladder wall contraction, generally results from a chronically over-filled bladder, which, itself, is often due to long-standing dyssynergia. This condition can occasionally respond to medications such as bethanecol (Urecholine), 30-150 mg/day, but often this condition also often requires intermittent or continuous catheterization.
It is also important to monitor patients for urinary tract infections and treat them promptly when they are identified. Patients who have large volumes of post-void residual urine in their bladders are predisposed to bladder infections and patients at risk for such complications may be identified by measuring a post-void residual volume. It is also often helpful to take steps to prevent infections. Acidification of the urine with cranberry juice or Vitamin C inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to bladder colonization by resistant organisms and can result in infections that are more difficult to treat. Intermittent catheterization may be necessary to allow complete bladder emptying and to prevent recurrent infections.
Bowel Dysfunction
Constipation is a common symptom in MS, occurring in over 30% of patients. High fiber diets (often with supplemental fiber) in addition to plenty of fluids is usually the best approach. Natural or other laxatives can also help. Fecal incontinence is much less common than constipation although 17% of patients (more so in men) report at least some episodes. If it is severe enough to warrant treatment, fecal incontinence may respond to a reduction in total dietary fiber.
Paroxysmal Symptoms
Several different paroxysmal syndromes occur in MS. These syndromes are distinguished by brief duration (30 seconds to 2 minutes); high frequency of occurrence (5-40 paroxysms/day); lack of any alteration of consciousness or change in background EEG during the events; a self-limited nature (generally lasting only months and then subsiding). They may be precipitated by hyperventilation or movement. These syndromes include the familiar L’hermittes sign (electric shock like sensations induced by neck flexion), tonic seizures, paroxysmal dysarthria/ataxia, paroxysmal sensory disturbances, and several other less well characterized syndromes. These syndromes are also distinguished by their marked responsiveness to very low dosages of anticonvulsant medications such as carbamazepine (Tegretol), 50-400 mg/day, phenytoin (Dilantin), 50-300 mg/day, or acetazolamide (Diamox) 200-600 mg/day. Patients with MS may also suffer from trigeminal neuralgia (tic douloureux) which often responds to similar medications.
Heat Sensitivity
Many symptoms are aggravated by exposure to heat or with fever. Keeping away from the direct heat of the sun and the use of air conditioning are often necessary to prevent these symptoms. Cooling vests or caps may be useful in select patients.
Weakness
The potassium channel blockers (e.g., 4-amino pyridine, 10-40 mg/day; and 3,4-di-amino pyridine, 40-80 mg/day) may help some MS symptoms (especially heat sensitive symptoms) and anecdotally some patients experience improved function. These drugs presumably work by prolonging the duration of the nerve action potential and, thereby, facilitating conduction through demyelinated fibers. At high enough doses they may also cause seizures for similar reasons. These agents are not FDA-approved but are currently available from one of several compounding pharmacies around the US. More definitive clinical trials, however, are needed to establish any therapeutic benefit.
Sexual Dysfunction
Sexual dysfunction was reported by over 60% of the women and over 75% of the men in a recent survey of MS patients in northern California. The greater dysfunction in men resulted not only from impotence (61%) but also from less sexual desire and less demonstrated interest by their partners. Nevertheless, sexual dysfunction can be a considerable problem for either gender. Women experiencing sexual dysfunction often experience numbness in the genital area, diminished orgasmic response, unpleasant sensations, and diminished vaginal lubrication. Men commonly report impaired genital sensation, delayed ejaculation, decreased force of ejaculation, and/or inability to achieve and maintain an erection. Approaches such as couples or psychological therapy may help in selected cases. Communication between partners is essential. Teaching your partner how you need to be touched or positioned can result in a return of pleasure and excitement instead of discomfort or pain. The use of water soluble lubricants may be an essential aid in genital stimulation and sexual arousal. The use of vibrators may provide pleasurable and sexually stimulating sensations. Spasms, pain, spasticity, fatigue, and bladder/bowel dysfunction may contribute to sexual dysfunction, and medications to alleviate these symptoms may help. Thus, the effective management of adductor spasticity, the use of devices (e.g., vibrators) to make up for loss of deep sensation, penile injections of papaverine or prostaglandin, or prosthetic devices to assist with maintaining erection may also be helpful in some circumstances. The biggest advance in treatment of impotence, however, has been the introduction of sildenafil (Viagra) 50-100 mg orally 1-2 hours prior to sex.
Memory Problems
Cognitive problems, including problems with memory, are common in MS. Between 45% and 65% of people with MS will have some problems with cognitive functioning. Donepezil HCl (Aricept) is a cholinesterase inhibiting medication used to treat patients with early Alzheimer’s disease. Two small, non-randomized, uncontrolled studies have shown benefit for MS patients with memory problems taking 10 mg/day. Similar small, uncontrolled studies have also shown benefits for patients with memory problems due to traumatic brain injury. Larger, placebo-controlled studies are underway with both these populations. While this medication is not currently approved by the FDA for the treatment of memory problems in patients with MS, it may be of some benefit in some cases."
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS
CLICK TO READ MORE"There is as yet no cure for MS. Many patients do well with no therapy at all, especially since many medications have serious side effects and some carry significant risks. However, three forms of beta interferon (Avonex, Betaseron, and Rebif) have now been approved by the Food and Drug Administration for treatment of relapsing-remitting MS. Beta interferon has been shown to reduce the number of exacerbations and may slow the progression of physical disability. When attacks do occur, they tend to be shorter and less severe. The FDA also has approved a synthetic form of myelin basic protein, called copolymer I (Copaxone), for the treatment of relapsing-remitting MS. Copolymer I has few side effects, and studies indicate that the agent can reduce the relapse rate by almost one third. An immunosuppressant treatment, Novantrone (mitoxantrone ), is approved by the FDA for the treatment of advanced or chronic MS.
While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some patients.
Spasticity, which can occur either as a sustained stiffness caused by increased muscle tone or as spasms that come and go, is usually treated with muscle relaxants and tranquilizers such as baclofen, tizanidine, diazepam, clonazepam, and dantrolene. Physical therapy and exercise can help preserve remaining function, and patients may find that various aids -- such as foot braces, canes, and walkers -- can help them remain independent and mobile. Avoiding excessive activity and avoiding heat are probably the most important measures patients can take to counter physiological fatigue. If psychological symptoms of fatigue such as depression or apathy are evident, antidepressant medications may help. Other drugs that may reduce fatigue in some, but not all, patients include amantadine (Symmetrel), pemoline (Cylert), and the still-experimental drug aminopyridine. Although improvement of optic symptoms usually occurs even without treatment, a short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by treatment with oral steroids is sometimes used."
While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some patients.
Spasticity, which can occur either as a sustained stiffness caused by increased muscle tone or as spasms that come and go, is usually treated with muscle relaxants and tranquilizers such as baclofen, tizanidine, diazepam, clonazepam, and dantrolene. Physical therapy and exercise can help preserve remaining function, and patients may find that various aids -- such as foot braces, canes, and walkers -- can help them remain independent and mobile. Avoiding excessive activity and avoiding heat are probably the most important measures patients can take to counter physiological fatigue. If psychological symptoms of fatigue such as depression or apathy are evident, antidepressant medications may help. Other drugs that may reduce fatigue in some, but not all, patients include amantadine (Symmetrel), pemoline (Cylert), and the still-experimental drug aminopyridine. Although improvement of optic symptoms usually occurs even without treatment, a short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by treatment with oral steroids is sometimes used."
UNIVERSITY OF MARYLAND MEDICAL CENTER
UNIVERSITY OF MARYLAND MEDICAL CENTER: CLICK TO READ MORE"Actions. Interferons (so-called because they "interfere" with viral replication) both suppress important inflammatory factors in the immune system and have anti-viral properties. Interferons specifically block immune factors known as class II MHC molecules, which are associated with the attack on myelin and the breach in the blood-brain barrier that allows the destructive T-cells to pass through.
Specific Interferons Used for MS. Interferon agents used for MS include IFN1b (Betaseron) and IFN1a (Avonex, Rebif). They are now the treatments of choice for relapsing-remitting MS. Expert organizations are urging that they be used early in the course of the disease and continued indefinitely, unless they produce no benefits or have severe side effects. [See Table Comparisons between Major MS Agents, below.]
Successes and Drawbacks. The major interferon preparations reduce flare-ups overall by 30% and have an even greater effect on reducing major relapses. Disease activity, as measured by MRI scanning, is reduced by over 80%. Studies on their effects on quality of life are limited. In one 2000 study, Avonex reduced the risk for mental impairment by nearly half. Evidence to date does not suggest that interferons can slow progression to any appreciable degree, although studies are ongoing using higher doses and comparisons of all interferons. None of the interferons is a cure, in any case, and when the agent is discontinued, disease activity may increase.
Side Effects and Complications. Side effects include the following:
Pain at the injection site. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Experts recommend taking acetaminophen (Tylenol) before the injection and then every 6 hours after each injection for 24 hours during the first six months of treatment.
Skin injury at the injection site. Black dead tissue may form around the site, and many patients taking Betaseron have reported severe skin eruptions. These skin injuries heal after the drug is withdrawn, but scarring can occur. This side effect is least severe with Avonex, followed by Rebif.
Other physical side effects. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, and dizziness. Such side effects usually fade after two or three months.
Depression. Interferon has been associated with depression during the first two to six months following initial therapy. Recent studies have suggested, however, that there is no greater risk for depression in patients taking any of these agents. More work is needed, however, to determine if specific patients may be at higher risk than others for depression with these drugs. MS itself, in any case, is highly associated with depression.
Over time, people taking the interferons develop antibodies to the drugs that neutralize their effects. The risk is highest in Betaseron and lowest in Avonex. Patients who experience this, however, often can be effectively treated with the alternative interferon. In addition, in many cases, the antibody levels decline and the patient may be able to take the same interferon.
Comparisons between Major MS Agents
Comparison Items
Betaseron (IFN1b)
Avonex (IFN1a)
Rebif (IFN1a)
Glatiramer acetate (Copazone)
Injection Timing
Every other day.
Administered weekly by injection.
Three times a week.
Daily injections.
Pain at Injection Site
Severe pain and injury at injection site.
Less pain than Betaseron and very little injury.
Less pain than Betaseron but more than Avonex.
Some pain at injection site. It has less severe side effects than the interferons, however.
Effect on Early MS and Relapsing-Remitting MS
Reduces frequency of relapse by about 30%. Advocates of Betaseron argue that it has demonstrated a more significant effect on reducing lesions and relapse rates than Avonex after two years.
Reduces lesions and relapse rates. Long term use may slow progression. It may delay development of MS in patients with a first MS event, although significance unclear. Has beneficial effects on mental function.
Has impact on all major aspects of relapsing-remitting MS. It was more effective than Avonex in a 2002 study. (The drugs are identical, but Rebif is given more frequently.)
Glatiramer equal to Betaseron in effectiveness.
Significantly reduces relapse rates and lesions and, according to a six-year study, the longer it is taken the better the effects.
Effect on Secondary or Primary Progressive MS
A major 2001 study reported significant reductions in progression in patients with secondary progressive MS.
A 2002 study of secondary progressive MS reported reduction in lesions, fewer relapses, and improved quality of life. (Did not appear to have any effect on disability.)
Not yet known. Early studies reported fewer lesions, fewer relapses, but no affect on disability.
The drug does not appear to stop progression of MS, and, so far, it has little effect on chronic-progressive MS. Studies suggest is has properties that protect nerve cells.
Development of antibodies that neutralize the drug's effect
Within three years, between 25% and 40% of patients develop antibodies to Betaseron. In a 2002 comparative study, Betaseron produced the highest incidences of antibodies, compared to the other beta interferons.
Less risk than in Betaseron and Rebif. Studies report a risk of less than 5%.
Less risk than with Betaseron (18.7% in one study).
No risk.
Glatiramer Acetate
Glatiramer acetate (Copaxone) formerly called Cop-1 or copolymer-1, is a synthetic molecule created to resemble a basic protein found in myelin. It is being used as a decoy to trick white blood cells into attacking it instead of myelin. Studies indicate that relapse rates for patients using glatiramer can be reduced by 30% to 72%. Benefits have persisted for at least six years. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement.
Side Effects. Side effects occur in about 15% of patients, usually right after the injection. They include pain at the injection site, chest pain, rapid heart beat, flushing, anxiety, and shortness of breath. [See Table Comparisons between Major MS Agents.]
Corticosteroids
Actions. Corticosteroids reduce inflammation in the central nervous system (CNS) and may help suppress the immune system's attack on myelin and even improve electrical conduction. Although they are very useful for improving acute symptoms in the relapsing-remitting patient, steroids do not improve the long-term course of the disease and can lose effectiveness if over-used. Physicians generally restrict the use of steroids to severe attacks when the patient's ability to function is severely limited. There is no consensus, however, on the best form, dose, route, or duration of steroid treatment.
Specific Agents. High-dose methylprednisolone given intravenously is typically administered for major relapse, and oral prednisone is given for mild to moderate relapses. In one study, the use of high-dose intravenous methylprednisolone followed by oral prednisone delayed the development of MS in patients with early symptoms (optic neuritis). Studies are underway using pulsed doses of intravenous methylprednisolone on a regular but periodic basis to determine if it will slow progression in patients with secondary progressive multiple sclerosis. A 2001 study on patients with relapsing-remitting disease indicated that it might slow brain changes.
It should be noted that oral prednisone used alone may actually exacerbate optic neuritis, the swelling of the nerves of the eye, so this drug is now rarely prescribed during flare-ups.
Side Effects. Side effects of long-term use of steroids include weight gain and facial fullness, hypertension, diabetes, osteoporosis, cataracts, intestinal bleeding, and increased susceptibility to infections. In addition, side effects of steroids on the central nervous system can be particular problems for MS patients; they include sleeplessness, memory loss, anxiety, and depression. It is extremely important to taper withdrawal very carefully after continuously taking steroids for a prolonged period of time. This gives the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.
Intravenous Immunoglobulin
Intravenous immunoglobulin treatments are monthly infusions of natural antibodies. They appear to have some modest benefits for relapsing-remitting MS. In one two-year study, 31% of treated relapsing-remitting patients improved, 16% had worse symptoms, and 50% were unaffected. Experts are not yet sure why this treatment works. In any case it does appear to slow progression and it is extremely expensive."
Specific Interferons Used for MS. Interferon agents used for MS include IFN1b (Betaseron) and IFN1a (Avonex, Rebif). They are now the treatments of choice for relapsing-remitting MS. Expert organizations are urging that they be used early in the course of the disease and continued indefinitely, unless they produce no benefits or have severe side effects. [See Table Comparisons between Major MS Agents, below.]
Successes and Drawbacks. The major interferon preparations reduce flare-ups overall by 30% and have an even greater effect on reducing major relapses. Disease activity, as measured by MRI scanning, is reduced by over 80%. Studies on their effects on quality of life are limited. In one 2000 study, Avonex reduced the risk for mental impairment by nearly half. Evidence to date does not suggest that interferons can slow progression to any appreciable degree, although studies are ongoing using higher doses and comparisons of all interferons. None of the interferons is a cure, in any case, and when the agent is discontinued, disease activity may increase.
Side Effects and Complications. Side effects include the following:
Pain at the injection site. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Experts recommend taking acetaminophen (Tylenol) before the injection and then every 6 hours after each injection for 24 hours during the first six months of treatment.
Skin injury at the injection site. Black dead tissue may form around the site, and many patients taking Betaseron have reported severe skin eruptions. These skin injuries heal after the drug is withdrawn, but scarring can occur. This side effect is least severe with Avonex, followed by Rebif.
Other physical side effects. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, and dizziness. Such side effects usually fade after two or three months.
Depression. Interferon has been associated with depression during the first two to six months following initial therapy. Recent studies have suggested, however, that there is no greater risk for depression in patients taking any of these agents. More work is needed, however, to determine if specific patients may be at higher risk than others for depression with these drugs. MS itself, in any case, is highly associated with depression.
Over time, people taking the interferons develop antibodies to the drugs that neutralize their effects. The risk is highest in Betaseron and lowest in Avonex. Patients who experience this, however, often can be effectively treated with the alternative interferon. In addition, in many cases, the antibody levels decline and the patient may be able to take the same interferon.
Comparisons between Major MS Agents
Comparison Items
Betaseron (IFN1b)
Avonex (IFN1a)
Rebif (IFN1a)
Glatiramer acetate (Copazone)
Injection Timing
Every other day.
Administered weekly by injection.
Three times a week.
Daily injections.
Pain at Injection Site
Severe pain and injury at injection site.
Less pain than Betaseron and very little injury.
Less pain than Betaseron but more than Avonex.
Some pain at injection site. It has less severe side effects than the interferons, however.
Effect on Early MS and Relapsing-Remitting MS
Reduces frequency of relapse by about 30%. Advocates of Betaseron argue that it has demonstrated a more significant effect on reducing lesions and relapse rates than Avonex after two years.
Reduces lesions and relapse rates. Long term use may slow progression. It may delay development of MS in patients with a first MS event, although significance unclear. Has beneficial effects on mental function.
Has impact on all major aspects of relapsing-remitting MS. It was more effective than Avonex in a 2002 study. (The drugs are identical, but Rebif is given more frequently.)
Glatiramer equal to Betaseron in effectiveness.
Significantly reduces relapse rates and lesions and, according to a six-year study, the longer it is taken the better the effects.
Effect on Secondary or Primary Progressive MS
A major 2001 study reported significant reductions in progression in patients with secondary progressive MS.
A 2002 study of secondary progressive MS reported reduction in lesions, fewer relapses, and improved quality of life. (Did not appear to have any effect on disability.)
Not yet known. Early studies reported fewer lesions, fewer relapses, but no affect on disability.
The drug does not appear to stop progression of MS, and, so far, it has little effect on chronic-progressive MS. Studies suggest is has properties that protect nerve cells.
Development of antibodies that neutralize the drug's effect
Within three years, between 25% and 40% of patients develop antibodies to Betaseron. In a 2002 comparative study, Betaseron produced the highest incidences of antibodies, compared to the other beta interferons.
Less risk than in Betaseron and Rebif. Studies report a risk of less than 5%.
Less risk than with Betaseron (18.7% in one study).
No risk.
Glatiramer Acetate
Glatiramer acetate (Copaxone) formerly called Cop-1 or copolymer-1, is a synthetic molecule created to resemble a basic protein found in myelin. It is being used as a decoy to trick white blood cells into attacking it instead of myelin. Studies indicate that relapse rates for patients using glatiramer can be reduced by 30% to 72%. Benefits have persisted for at least six years. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement.
Side Effects. Side effects occur in about 15% of patients, usually right after the injection. They include pain at the injection site, chest pain, rapid heart beat, flushing, anxiety, and shortness of breath. [See Table Comparisons between Major MS Agents.]
Corticosteroids
Actions. Corticosteroids reduce inflammation in the central nervous system (CNS) and may help suppress the immune system's attack on myelin and even improve electrical conduction. Although they are very useful for improving acute symptoms in the relapsing-remitting patient, steroids do not improve the long-term course of the disease and can lose effectiveness if over-used. Physicians generally restrict the use of steroids to severe attacks when the patient's ability to function is severely limited. There is no consensus, however, on the best form, dose, route, or duration of steroid treatment.
Specific Agents. High-dose methylprednisolone given intravenously is typically administered for major relapse, and oral prednisone is given for mild to moderate relapses. In one study, the use of high-dose intravenous methylprednisolone followed by oral prednisone delayed the development of MS in patients with early symptoms (optic neuritis). Studies are underway using pulsed doses of intravenous methylprednisolone on a regular but periodic basis to determine if it will slow progression in patients with secondary progressive multiple sclerosis. A 2001 study on patients with relapsing-remitting disease indicated that it might slow brain changes.
It should be noted that oral prednisone used alone may actually exacerbate optic neuritis, the swelling of the nerves of the eye, so this drug is now rarely prescribed during flare-ups.
Side Effects. Side effects of long-term use of steroids include weight gain and facial fullness, hypertension, diabetes, osteoporosis, cataracts, intestinal bleeding, and increased susceptibility to infections. In addition, side effects of steroids on the central nervous system can be particular problems for MS patients; they include sleeplessness, memory loss, anxiety, and depression. It is extremely important to taper withdrawal very carefully after continuously taking steroids for a prolonged period of time. This gives the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.
Intravenous Immunoglobulin
Intravenous immunoglobulin treatments are monthly infusions of natural antibodies. They appear to have some modest benefits for relapsing-remitting MS. In one two-year study, 31% of treated relapsing-remitting patients improved, 16% had worse symptoms, and 50% were unaffected. Experts are not yet sure why this treatment works. In any case it does appear to slow progression and it is extremely expensive."
JOHNS HOPKINS HOSPITAL
JOHNS HOPKINS HOSPITAL: CLICK TO READ MORE"Oral corticosteroids, such as prednisone, or intravenous corticosteroids, such as methylprednisolone, may be prescribed to shorten the duration and reduce the severity of attacks.
Your doctor may prescribe interferon beta-1b or interferon beta-1a injections, a form of biological therapy, to treat MS. These medications are synthetically engineered to be identical to a naturally occurring protein and reduce the frequency and severity of attacks by altering many of the body's immune responses. Alternatively, your doctor may prescribe glatiramer acetate injections to modulate the immune dysfunction in MS. The choices among these therapies are complex and usually require the assessment of an MS specialist.
Your doctor may prescribe antispasmodics or tranquilizers, including diazepam or baclofen, to relax spastic muscles and provide pain relief, or antidepressants to treat associated depression.
A variety of medications may be administered to treat incontinence, frequency, hesitancy, and other bladder-control problems.
Try not to become overheated. Avoid excessive sunbathing, heavy exertion, and hot baths, and obtain prompt treatment for fevers; a raised body temperature may trigger or worsen symptoms. Taking a cool shower, swimming, or sitting in an air-conditioned room may relieve the severity of symptoms during an attack.
Pursue a program of moderate exercise to help keep muscles as flexible and strong as possible.
Physical and occupational therapy may help patients adjust to muscular and sensory changes.
Psychological counseling may help patients and their families cope with depression and the lifestyle changes imposed by MS.
Be wary of unproven remedies, such as bee venom."
Your doctor may prescribe interferon beta-1b or interferon beta-1a injections, a form of biological therapy, to treat MS. These medications are synthetically engineered to be identical to a naturally occurring protein and reduce the frequency and severity of attacks by altering many of the body's immune responses. Alternatively, your doctor may prescribe glatiramer acetate injections to modulate the immune dysfunction in MS. The choices among these therapies are complex and usually require the assessment of an MS specialist.
Your doctor may prescribe antispasmodics or tranquilizers, including diazepam or baclofen, to relax spastic muscles and provide pain relief, or antidepressants to treat associated depression.
A variety of medications may be administered to treat incontinence, frequency, hesitancy, and other bladder-control problems.
Try not to become overheated. Avoid excessive sunbathing, heavy exertion, and hot baths, and obtain prompt treatment for fevers; a raised body temperature may trigger or worsen symptoms. Taking a cool shower, swimming, or sitting in an air-conditioned room may relieve the severity of symptoms during an attack.
Pursue a program of moderate exercise to help keep muscles as flexible and strong as possible.
Physical and occupational therapy may help patients adjust to muscular and sensory changes.
Psychological counseling may help patients and their families cope with depression and the lifestyle changes imposed by MS.
Be wary of unproven remedies, such as bee venom."
MAYO CLINIC
MAYO CLINIC: CLICK TO READ MORE"If your attacks are mild or infrequent, your doctor may advise a wait-and-see approach, with counseling and observation. However, if you have a relapsing form of the disease, your doctor may recommend treatment with disease-modifying medications as soon as possible. These medications can't be used if you are pregnant or may become pregnant. They include:
Beta interferons. Interferon beta-1b (Betaseron) and interferon beta-1a (Avonex, Rebif) are genetically engineered copies of proteins that occur naturally in your body. They help fight viral infection and regulate your immune system. If you use Betaseron, you inject yourself under your skin (subcutaneously) every other day. If you use Rebif, you inject yourself subcutaneously three times a week. Avonex is self-injected into your muscle (intramuscularly) once a week. These medications reduce flare-ups of MS. It's uncertain which of their many actions lead to a reduction in disease activity and what their long-term benefits are. Beta interferons should never be used in combination with one another. Only one of these medications should be used at a time.
The Food and Drug Administration (FDA) has approved beta interferons only for people with relapsing forms of MS who can still walk. Beta interferons don't reverse damage and haven't been proved to prevent permanent disability. Some people develop antibodies to beta interferons, which may make them less effective. Other people can't tolerate the side effects, which may include symptoms similar to those of the flu (influenza).
Doctors generally recommend beta interferons for people who have more than one attack of MS a year and for those who don't recover well from flare-ups. The treatment may also be used for people who have a significant buildup of new lesions as seen on an MRI scan, even when there may not be major new symptoms of disease activity.
Glatiramer (Copaxone). This medication is an alternative to beta interferons if you have relapsing remitting MS. Doctors believe that glatiramer works by blocking your immune system's attack on myelin. You must inject glatiramer subcutaneously once daily. Side effects may include flushing and shortness of breath after injection.
Other medications. Mitoxantrone (Novantrone) is a chemotherapy drug used for many cancers. This drug is also FDA-approved for treatment of aggressive forms of relapsing remitting MS, as well as certain forms of progressive MS. It's given intravenously, typically every three months. However, mitoxantrone may cause serious side effects, such as heart damage, after long-term use, so it's typically not used for longer than two years. And it's typically reserved for people with severe attacks or rapidly advancing disease who don't respond to other treatments. Close monitoring is critical for anyone on this medication. Some doctors are also prescribing other chemotherapy drugs, such as cyclophosphamide (Cytoxan), for people with severe, rapidly progressing MS. However, these medications aren't approved for treatment of MS.
Some medications may relieve symptoms of progressive MS. They include:
Corticosteroids. Doctors most often prescribe short courses of oral or intravenous corticosteroids to reduce inflammation in nerve tissue and to shorten the duration of flare-ups. Prolonged use of these medications, however, may cause side effects such as osteoporosis and high blood pressure (hypertension).
Muscle relaxants. Baclofen and tizanidine (Zanaflex) are oral treatments for muscle spasticity. If you have MS, you may experience muscle stiffening or spasms, particularly in your legs, which can be painful and uncontrollable. Baclofen often increases weakness in the legs. Zanaflex appears to control muscle spasms without leaving your legs feeling weak but can be associated with drowsiness or a dry mouth.
Medications to reduce fatigue. To help combat fatigue, your doctor may prescribe an antidepressant medication, the antiviral drug amantadine (Symmetrel) or a medication for narcolepsy called modafinil (Provigil). All appear to work because of their stimulant properties.
Other medications. Many medications are used for the muscle stiffness, depression, pain and bladder control problems often associated with MS. Drugs for arthritis and medications that suppress the immune system may slow MS in some cases.
In addition to medications, these treatments may also be helpful:
Physical and occupational therapy. A physical or occupational therapist can teach you strengthening exercises and show you how to use devices that can ease daily tasks. This can help preserve your independence.
Counseling. Individual or group therapy may help you cope with MS and relieve emotional stress. Your family members or caregivers may also benefit from seeing a counselor.
Plasma exchange (plasmapheresis). Plasma exchange may help restore neurological function in people with sudden severe attacks of MS-related disability who don't respond to high doses of steroid treatment. This procedure involves removing some of your blood and mechanically separating the blood cells from the fluid (plasma). Your blood cells then are mixed with a replacement solution, typically albumin, or a synthetic fluid with properties like plasma. The solution with your blood is then returned to your body.
Replacing your plasma may dilute the activity of the destructive factors in your immune system, including antibodies that attack myelin, and help you to recover. Plasma exchange has no proven benefit beyond three months from the onset of the neurological symptoms."
Beta interferons. Interferon beta-1b (Betaseron) and interferon beta-1a (Avonex, Rebif) are genetically engineered copies of proteins that occur naturally in your body. They help fight viral infection and regulate your immune system. If you use Betaseron, you inject yourself under your skin (subcutaneously) every other day. If you use Rebif, you inject yourself subcutaneously three times a week. Avonex is self-injected into your muscle (intramuscularly) once a week. These medications reduce flare-ups of MS. It's uncertain which of their many actions lead to a reduction in disease activity and what their long-term benefits are. Beta interferons should never be used in combination with one another. Only one of these medications should be used at a time.
The Food and Drug Administration (FDA) has approved beta interferons only for people with relapsing forms of MS who can still walk. Beta interferons don't reverse damage and haven't been proved to prevent permanent disability. Some people develop antibodies to beta interferons, which may make them less effective. Other people can't tolerate the side effects, which may include symptoms similar to those of the flu (influenza).
Doctors generally recommend beta interferons for people who have more than one attack of MS a year and for those who don't recover well from flare-ups. The treatment may also be used for people who have a significant buildup of new lesions as seen on an MRI scan, even when there may not be major new symptoms of disease activity.
Glatiramer (Copaxone). This medication is an alternative to beta interferons if you have relapsing remitting MS. Doctors believe that glatiramer works by blocking your immune system's attack on myelin. You must inject glatiramer subcutaneously once daily. Side effects may include flushing and shortness of breath after injection.
Other medications. Mitoxantrone (Novantrone) is a chemotherapy drug used for many cancers. This drug is also FDA-approved for treatment of aggressive forms of relapsing remitting MS, as well as certain forms of progressive MS. It's given intravenously, typically every three months. However, mitoxantrone may cause serious side effects, such as heart damage, after long-term use, so it's typically not used for longer than two years. And it's typically reserved for people with severe attacks or rapidly advancing disease who don't respond to other treatments. Close monitoring is critical for anyone on this medication. Some doctors are also prescribing other chemotherapy drugs, such as cyclophosphamide (Cytoxan), for people with severe, rapidly progressing MS. However, these medications aren't approved for treatment of MS.
Some medications may relieve symptoms of progressive MS. They include:
Corticosteroids. Doctors most often prescribe short courses of oral or intravenous corticosteroids to reduce inflammation in nerve tissue and to shorten the duration of flare-ups. Prolonged use of these medications, however, may cause side effects such as osteoporosis and high blood pressure (hypertension).
Muscle relaxants. Baclofen and tizanidine (Zanaflex) are oral treatments for muscle spasticity. If you have MS, you may experience muscle stiffening or spasms, particularly in your legs, which can be painful and uncontrollable. Baclofen often increases weakness in the legs. Zanaflex appears to control muscle spasms without leaving your legs feeling weak but can be associated with drowsiness or a dry mouth.
Medications to reduce fatigue. To help combat fatigue, your doctor may prescribe an antidepressant medication, the antiviral drug amantadine (Symmetrel) or a medication for narcolepsy called modafinil (Provigil). All appear to work because of their stimulant properties.
Other medications. Many medications are used for the muscle stiffness, depression, pain and bladder control problems often associated with MS. Drugs for arthritis and medications that suppress the immune system may slow MS in some cases.
In addition to medications, these treatments may also be helpful:
Physical and occupational therapy. A physical or occupational therapist can teach you strengthening exercises and show you how to use devices that can ease daily tasks. This can help preserve your independence.
Counseling. Individual or group therapy may help you cope with MS and relieve emotional stress. Your family members or caregivers may also benefit from seeing a counselor.
Plasma exchange (plasmapheresis). Plasma exchange may help restore neurological function in people with sudden severe attacks of MS-related disability who don't respond to high doses of steroid treatment. This procedure involves removing some of your blood and mechanically separating the blood cells from the fluid (plasma). Your blood cells then are mixed with a replacement solution, typically albumin, or a synthetic fluid with properties like plasma. The solution with your blood is then returned to your body.
Replacing your plasma may dilute the activity of the destructive factors in your immune system, including antibodies that attack myelin, and help you to recover. Plasma exchange has no proven benefit beyond three months from the onset of the neurological symptoms."
CLEVELAND CLINIC: MELLEN MS CENTER
CLEVELAND CLINIC: CLICK TO READ MORE"There is no known cure for multiple sclerosis, but there are many types of treatments. The interventions prescribed by your physician and other health care professionals are not designed to make MS disappear. Instead, the various treatments, including medications, exercises, adaptive aides, and self-care strategies are designed to help manage symptoms, prevent unnecessary complications, control disease progression, and minimize disability. The medical management of your MS involves an ongoing collaboration between you and your health care team. Decisions about treatment must be made on an individual basis.
The treatment of MS can be grouped into three categories: management of acute attacks, disease-modifying treatments, and management of symptoms.
Management of Acute Attacks
The onset of symptoms over several days or weeks, involving either the development of new symptoms or the worsening of old ones, may indicate an attack or exacerbation of the disease. An attack is usually accompanied by inflammation or demyelination in the central nervous system, either in new sites or old ones. Treatment may be recommended if the symptoms are severe or worsen. The swelling and inflammation of demyelination may be reduced by high doses of an intravenous corticosteroids [Solu-Medrol (methylprednisolone)]. Corticosteroids are used in MS for the management of acut attacks or exacerbations because they have the ability to close the blood-brain barrier and reduce inflammation in the central nerouvs system.
Disease-Modifying Treatments
Only recently have there been treatments that hold promise for reducing the course of MS. A number of new drugs have been shown to modify the course of the disease – Betaseron® (interferon beta-1b), Avonex® (interferon beta-1a), Copaxone® (glatiramer acetate), Rebif® (interferon beta-1a) and Novantrone® (mitoxantrone). These drugs do not cure MS, but they have shown a reduction in the frequency and severity of attacks, reduction in brain lesion development, and a slowing of disease progression with reduction in future disability level. Clinical trials have shown that these drugs can improve the quality of life for many people with MS. Therefore it is suggested that treatment with one of these disease-modifying drugs be initiated as soon as possible. Talk with your physician about what treatment may be right for you.
The decision concerning whether or when to begin treatment with one of these drugs is best made by you and your doctor. Factors that should be considered include potential side effects, benefits, frequency, method of drug delivery, and your personal concerns, priorities, and lifestyle. The most important goal is to find a treatment you can use comfortably and consistently.
Each drug company offers customer support and may also provide some financial assistance for qualifying individuals without prescription drug coverage.
>
Berlex (Betaseron®) – MS Pathways 1-800-788-1467
www.betaseron.com
>
Biogen (Avonex®) – The Avonex Alliance 1-800-456-2255
www.avonex.com
>
Teva Neuroscience (Copaxone®) – Shared Solutions 1-800-887-8100
www.copaxone.com
>
Serono (Rebif®) - MS LifLines 1-800-447-3243
www.rebif.com
>
Serono (Novantrone®) - MS LifLines 1-800-447-3243
www.novantrone.com
How do these drugs work?
All of these drugs work by altering or suppressing the activity of the body's immune system. These drugs are based on the theory that MS is possibly a result of an adnormal response of the body's immune system that causes it to attack the myelin surrounding the nerves.
The interferon drugs resemble the interferons the body produces during a response by the immune system. It is thought that the interferons reduce nervous system inflammation by inhibiting inflammatory cells from entering into the system.
Copaxone, the only non-interferon medication, is an artifically made protein that resembles a protein that is part of the myelin that surrounds the nerves. Copaxone is thought to reduce nervous system inflammation by restoring cytokine balance by stimulating anti-inflammatory cells that can enter the nervous system.
Novantrone is an immune suppressing medication. It is used for individuals who are considered to have a worsening of the disease or secondary progressive MS.
Comparing the Disease Modifying Drugs
Name
Avonex
(interferon
beta-1a)
Betaseron
(interferon
beta-1b) Rebif
(interferon
beta-1a) Copaxone
(glatiramer
acetate) Novantrone
(mitoxantrone)
Mode of Delivery Intramuscular
Injection Subcutaneous Injection Subcutaneous
Injection Subcutaneous Injection Intravenous Infusion
Frequency Weekly Every other day 3 times a week Daily Every 3 months
Side Effects
Mild flu-like
symptoms
Mild flu-like
symptoms
Possible injection
site reactions Mild flu-like
symptoms
Possible
injection site reactions Injection site reactions
Chest pain
Flushing
Heart Damage (limit
doses of drug is recommended)
Nausea
Increased risk of infection
Management of Symptoms
There are many effective treatments for the symptoms that develop with MS. Many symptoms can be lessened or even reversed with medical approaches. Drugs can help with many of the chronic symptoms that appear, while modifications in diet or lifestyle may help to eliminate or manage symptoms.
Most of the symptoms of MS can be minimized or corrected with appropriate drug treatment, environmental modifications, or physical therapy. To properly care for your disease, routine follow-up visits with your health care team are essential.
Other Treatments
Physical Therapy can be helpful for MS patients at any stage of the disease. A physical therapist can teach you exercises you can use to strengthen and loosen muscles. The goal of physical therapy is to improve your independence and quality of life by improving movement and function.
Occupational Therapy teaches people new ways to function at their highest level possible. The goals of occupational therapy include: restore or improve physical abilities, adapt patients’ surroundings, promote behavioral changes, and teach new skills.
Counseling is beneficial to patients from as early as the first diagnosis. Being diagnosed with MS and dealing with the changes that accompany all aspects of the disease can be stressful. Counseling can help patients and family members cope with stress, depression and anxiety.
Complementary and Alternative Medicine (CAM)
Alternative medicine includes everything from drugs and diet to supplements and lifestyle changes. CAM therapies come from a variety of disciplines and traditions, each with their own beliefs. Some CAM therapies include yoga, guided imagery, relaxation techniques, massage therapy, herbal therapies and many others. Before starting on any CAM therapy it is important to do your homework. Investigate the background of any CAM provider and talk with others who have usde the treatment. You should talk with your physician before starting any CAM therapy and let your physician know if you are currently on any CAM therapy including vitamin & mineral supplements."
The treatment of MS can be grouped into three categories: management of acute attacks, disease-modifying treatments, and management of symptoms.
Management of Acute Attacks
The onset of symptoms over several days or weeks, involving either the development of new symptoms or the worsening of old ones, may indicate an attack or exacerbation of the disease. An attack is usually accompanied by inflammation or demyelination in the central nervous system, either in new sites or old ones. Treatment may be recommended if the symptoms are severe or worsen. The swelling and inflammation of demyelination may be reduced by high doses of an intravenous corticosteroids [Solu-Medrol (methylprednisolone)]. Corticosteroids are used in MS for the management of acut attacks or exacerbations because they have the ability to close the blood-brain barrier and reduce inflammation in the central nerouvs system.
Disease-Modifying Treatments
Only recently have there been treatments that hold promise for reducing the course of MS. A number of new drugs have been shown to modify the course of the disease – Betaseron® (interferon beta-1b), Avonex® (interferon beta-1a), Copaxone® (glatiramer acetate), Rebif® (interferon beta-1a) and Novantrone® (mitoxantrone). These drugs do not cure MS, but they have shown a reduction in the frequency and severity of attacks, reduction in brain lesion development, and a slowing of disease progression with reduction in future disability level. Clinical trials have shown that these drugs can improve the quality of life for many people with MS. Therefore it is suggested that treatment with one of these disease-modifying drugs be initiated as soon as possible. Talk with your physician about what treatment may be right for you.
The decision concerning whether or when to begin treatment with one of these drugs is best made by you and your doctor. Factors that should be considered include potential side effects, benefits, frequency, method of drug delivery, and your personal concerns, priorities, and lifestyle. The most important goal is to find a treatment you can use comfortably and consistently.
Each drug company offers customer support and may also provide some financial assistance for qualifying individuals without prescription drug coverage.
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Berlex (Betaseron®) – MS Pathways 1-800-788-1467
www.betaseron.com
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Biogen (Avonex®) – The Avonex Alliance 1-800-456-2255
www.avonex.com
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Teva Neuroscience (Copaxone®) – Shared Solutions 1-800-887-8100
www.copaxone.com
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Serono (Rebif®) - MS LifLines 1-800-447-3243
www.rebif.com
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Serono (Novantrone®) - MS LifLines 1-800-447-3243
www.novantrone.com
How do these drugs work?
All of these drugs work by altering or suppressing the activity of the body's immune system. These drugs are based on the theory that MS is possibly a result of an adnormal response of the body's immune system that causes it to attack the myelin surrounding the nerves.
The interferon drugs resemble the interferons the body produces during a response by the immune system. It is thought that the interferons reduce nervous system inflammation by inhibiting inflammatory cells from entering into the system.
Copaxone, the only non-interferon medication, is an artifically made protein that resembles a protein that is part of the myelin that surrounds the nerves. Copaxone is thought to reduce nervous system inflammation by restoring cytokine balance by stimulating anti-inflammatory cells that can enter the nervous system.
Novantrone is an immune suppressing medication. It is used for individuals who are considered to have a worsening of the disease or secondary progressive MS.
Comparing the Disease Modifying Drugs
Name
Avonex
(interferon
beta-1a)
Betaseron
(interferon
beta-1b) Rebif
(interferon
beta-1a) Copaxone
(glatiramer
acetate) Novantrone
(mitoxantrone)
Mode of Delivery Intramuscular
Injection Subcutaneous Injection Subcutaneous
Injection Subcutaneous Injection Intravenous Infusion
Frequency Weekly Every other day 3 times a week Daily Every 3 months
Side Effects
Mild flu-like
symptoms
Mild flu-like
symptoms
Possible injection
site reactions Mild flu-like
symptoms
Possible
injection site reactions Injection site reactions
Chest pain
Flushing
Heart Damage (limit
doses of drug is recommended)
Nausea
Increased risk of infection
Management of Symptoms
There are many effective treatments for the symptoms that develop with MS. Many symptoms can be lessened or even reversed with medical approaches. Drugs can help with many of the chronic symptoms that appear, while modifications in diet or lifestyle may help to eliminate or manage symptoms.
Most of the symptoms of MS can be minimized or corrected with appropriate drug treatment, environmental modifications, or physical therapy. To properly care for your disease, routine follow-up visits with your health care team are essential.
Other Treatments
Physical Therapy can be helpful for MS patients at any stage of the disease. A physical therapist can teach you exercises you can use to strengthen and loosen muscles. The goal of physical therapy is to improve your independence and quality of life by improving movement and function.
Occupational Therapy teaches people new ways to function at their highest level possible. The goals of occupational therapy include: restore or improve physical abilities, adapt patients’ surroundings, promote behavioral changes, and teach new skills.
Counseling is beneficial to patients from as early as the first diagnosis. Being diagnosed with MS and dealing with the changes that accompany all aspects of the disease can be stressful. Counseling can help patients and family members cope with stress, depression and anxiety.
Complementary and Alternative Medicine (CAM)
Alternative medicine includes everything from drugs and diet to supplements and lifestyle changes. CAM therapies come from a variety of disciplines and traditions, each with their own beliefs. Some CAM therapies include yoga, guided imagery, relaxation techniques, massage therapy, herbal therapies and many others. Before starting on any CAM therapy it is important to do your homework. Investigate the background of any CAM provider and talk with others who have usde the treatment. You should talk with your physician before starting any CAM therapy and let your physician know if you are currently on any CAM therapy including vitamin & mineral supplements."
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