MS Treatment

SOURCE: www.nationalmssociety.org, www.PersonalHealthZone.com,
mscenter.ucsf.edu and some links added by me

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. Naturally occurring or spontaneous remissions make it difficult to determine therapeutic effects of experimental treatments; however, the emerging evidence that MRIs can chart the development of lesions is already helping scientists evaluate new therapies.

Until recently, the principal medications physicians used to treat MS were steroids possessing anti-inflammatory properties; these include Adrenocorticotropic Hormone (better known as ACTH), prednisone, prednisolone, methylprednisolone, betamethasone, and dexamethasone. Studies suggest that intravenous methylprednisolone may be superior to the more traditional intravenous ACTH for patients experiencing acute relapses; no strong evidence exists to support the use of these drugs to treat progressive forms of MS. Also, there is some indication that steroids may be more appropriate for people with movement, rather than sensory, symptoms.

While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some patients. The mechanism behind this effect is not known; one study suggests the medications work by restoring the effectiveness of the blood/brain barrier. Because steroids can produce numerous adverse side effects (acne, weight gain, seizures, psychosis), they are not recommended for long-term use.

One of the most promising MS research areas involves naturally occurring antiviral proteins known as interferons. Two forms of beta interferon (Avonex^® and Betaseron^®) have now been approved by the Food and Drug Administration for treatment of relapsing-remitting MS. A third form (Rebif^®) is marketed in Europe. Beta interferon has been shown to reduce the number of exacerbations/relapses and may slow the progression of physical disability. When attacks do occur, they tend to be shorter and less severe. In addition, MRI scans suggest that beta interferon can decrease myelin destruction.

Modifying the Disease Course

The following agents can reduce disease activity and disease progression for many individuals with relapsing forms of MS, including those with secondary progressive disease who continue to have relapses.

Investigators speculate that the effects of beta interferon may be due to the drug's ability to correct an MS-related deficiency of certain white blood cells that suppress the immune system and/or its ability to inhibit gamma interferon, a substance believed to be involved in MS attacks. Alpha interferon is also being studied as a possible treatment for MS. Common side effects of interferons include fever, chills, sweating, muscle aches, fatigue, depression, and injection site reactions.

Scientists continue their extensive efforts to create new and better therapies for MS. Goals of therapy are threefold: to improve recovery from attacks, to prevent or lessen the number of relapses, and to halt disease progression. Some therapies currently under investigation are discussed below.

Immunotherapy

As evidence of immune system involvement in the development of MS has grown, trials of various new treatments to alter or suppress immune response are being conducted. These therapies are, at this time, still considered experimental.

Results of recent clinical trials have shown that immunosuppressive agents and techniques can positively (if temporarily) affect the course of MS; however, toxic side effects often preclude their widespread use. In addition, generalized immunosuppression leaves the patient open to a variety of viral, bacterial, and fungal infections.

Over the years, MS investigators have studied a number of immunosuppressant treatments. Among the therapies being studied are cyclosporine (Sandimmune), cyclophosphamide (Cytoxan), methotrexate, azathioprine (Imuran), and total lymphoid irradiation (a process whereby the MS patient's lymph nodes are irradiated with x-rays in small doses over a few weeks to destroy lymphoid tissue, which is actively involved in tissue destruction in autoimmune diseases). Inconclusive and/or contradictory results of these trials, combined with the therapies' potentially dangerous side effects, dictate that further research is necessary to determine what, if any, role they should play in the management of MS. Studies are also being conducted with the immune system modulating drugs linomide (Roquinimex), cladribine (Leustatin), and mitoxantrone.

Two other experimental treatments — one involving the use of monoclonal antibodies and the other involving plasma exchange, or plasmapheresis — may have fewer dangerous side effects. Monoclonal antibodies are identical, laboratory-produced antibodies that are highly specific for a single antigen. They are injected into the patient in the hope that they will alter the patient's immune response. Plasmapheresis is a procedure in which blood is removed from the patient, and the plasma is separated from other blood substances, which may contain antibodies and other immmunologically active products. These other blood substances are discarded and the plasma is then transfused back into the patient. Because their worth as treatments for MS has not yet been proven, these experimental treatments remain at the stage of clinical testing.

Bone marrow transplantation (a procedure in which bone marrow from a healthy donor is infused into patients who have undergone drug or radiation therapy to suppress their immune system so they will not reject the donated marrow) and injections of venom from honey bees are also being studied. Each of these therapies carries the risk of potentially severe side effects.

Therapy to Improve Nerve Impulse Conduction

Because the transmission of electrochemical messages between the brain and body is disrupted in MS, medications to improve the conduction of nerve impulses are being investigated. Since demyelinated nerves show abnormalities of potassium activity, scientists are studying drugs that block the channels through which potassium moves, thereby restoring conduction of the nerve impulse. In several small experimental trials, derivatives of a drug called aminopyridine temporarily improved vision, coordination, and strength when given to MS patients who suffered from both visual symptoms and heightened sensitivity to temperature. Possible side effects of these therapies include paraesthesia (tingling sensations), dizziness, and seizures.

Therapies Targeting an Antigen

Trials of a synthetic form of myelin basic protein, called copolymer I (Copaxone^®), have shown promise in treating people in the early stages of relapsing-remitting MS. Copolymer I, unlike so many drugs tested for the treatment of MS, seems to have few side effects. Recent trial data indicate that copolymer I can reduce the relapse rate by almost one third. In addition, patients given copolymer I were more likely to show neurologic improvement than those given a placebo. The Food and Drug Administration has made the drug available to people with early relapsing-remitting MS through its "Treatment IND" program and is currently reviewing data from a large-scale study to determine whether or not to approve the drug for marketing.

Investigators are also looking at the possibility of developing an MS vaccine. Myelin-attacking T cells were removed, inactivated, and injected back into animals with experimental allergic encephalomyelitis (EAE). This procedure results in destruction of the immune system cells that were attacking myelin basic protein. In a couple of small trials scientists have tested a similar vaccine in humans. The product was well-tolerated and had no side effects, but the studies were too small to establish efficacy. Patients with progressive forms of MS did not appear to benefit, although relapsing-remitting patients showed some neurologic improvement and had fewer relapses and reduced numbers of lesions in one study. Unfortunately, the benefits did not last beyond two years.

A similar approach, known as peptide therapy, is based on evidence that the body can mount an immune response against the T cells that destroy myelin, but this response is not strong enough to overcome the disease. To induce this response, the investigator scans the myelin-attacking T cells for the myelin-recognizing receptors on the cells' surface. A fragment, or peptide, of those receptors is then injected into the body. The immune system "sees" the injected peptide as a foreign invader and launches an attack on any myelin-destroying T cells that carry the peptide. The injection of portions of T cell receptors may heighten the immune system reaction against the errant T cells much the same way a booster shot heightens immunity to tetanus. Or, peptide therapy may jam the errant cells' receptors, preventing the cells from attacking myelin.

Despite these promising early results, there are some major obstacles to developing vaccine and peptide therapies. Individual patients' T cells vary so much that it may not be possible to develop a standard vaccine or peptide therapy beneficial to all, or even most, MS patients. At this time, each treatment involves extracting cells from each individual patient, purifying the cells, and then growing them in culture before inactivating and chemically altering them. This makes the production of quantities sufficient for therapy extremely time consuming, labor intensive, and expensive. Further studies are necessary to determine whether universal inoculations can be developed to induce suppression of MS patients' overactive immune systems.

Protein antigen feeding is similar to peptide therapy, but is a potentially simpler means to the same end. Whenever we eat, the digestive system breaks each food or substance into its primary "non-antigenic" building blocks, thereby averting a potentially harmful immune attack. So, strange as it may seem, antigens that trigger an immune response when they are injected can encourage immune system tolerance when taken orally. Furthermore, this reaction is directed solely at the specific antigen being fed; wholesale immunosuppression, which can leave the body open to a variety of infections, does not occur. Studies have shown that when rodents with EAE are fed myelin protein antigens, they experience fewer relapses. Data from a small, preliminary trial of antigen feeding in humans found limited suggestion of improvement, but the results were not statistically significant. A multi-center trial is being conducted to determine whether protein antigen feeding is effective.

Cytokines

As our growing insight into the workings of the immune system gives us new knowledge about the function of cytokines, the powerful chemicals produced by T cells, the possibility of using them to manipulate the immune system becomes more attractive. Scientists are studying a variety of substances that may block harmful cytokines, such as those involved in inflammation, or that encourage the production of protective cytokines.

A drug that has been tested as a depression treatment, rolipram, has been shown to reduce levels of several destructive cytokines in animal models of MS. Its potential as a therapy for MS is not known at this time, but side effects seem modest. Protein antigen feeding, discussed above, may release transforming growth factor beta (TGF), a protective cytokine that inhibits or regulates the activity of certain immune cells. Preliminary tests indicate that it may reduce the number of immune cells commonly found in MS patients' spinal fluid. Side effects include anemia and altered kidney function.

Interleukin 4 (IL-4) is able to diminish demyelination and improve the clinical course of mice with EAE, apparently by influencing developing T cells to become protective rather than harmful. This also appears to be true of a group of chemicals called retinoids. When fed to rodents with EAE, retinoids increase levels of TGF and IL-4, which encourage protective T cells, while decreasing numbers of harmful T cells. This results in improvement of the animals' clinical symptoms.

Remyelination

Some studies focus on strategies to reverse the damage to myelin and oligodendrocytes (the cells that make and maintain myelin in the central nervous system), both of which are destroyed during MS attacks. Scientists now know that oligodendrocytes may proliferate and form new myelin after an attack. Therefore, there is a great deal of interest in agents that may stimulate this reaction. To learn more about the process, investigators are looking at how drugs used in MS trials affect remyelination. Studies of animal models indicate that monoclonal antibodies and two immunosuppressant drugs, cyclophosphamide and azathioprine, may accelerate remyelination, while steroids may inhibit it. The ability of intravenous immunoglobulin (IVIg) to restore visual acuity and/or muscle strength is also being investigated.

Diet

Over the years, many people have tried to implicate diet as a cause of or treatment for MS. Some physicians have advocated a diet low in saturated fats; others have suggested increasing the patient's intake of linoleic acid, a polyunsaturated fat, via supplements of sunflower seed, safflower, or evening primrose oils. Other proposed dietary "remedies" include megavitamin therapy, including increased intake of vitamins B12 or C; various liquid diets; and sucrose-, tobacco-, or gluten-free diets. To date, clinical studies have not been able to confirm benefits from dietary changes; in the absence of any evidence that diet therapy is effective, patients are best advised to eat a balanced, wholesome diet.

Unproven Therapies

MS is a disease with a natural tendency to remit spontaneously, and for which there is no universally effective treatment and no known cause. These factors open the door for an array of unsubstantiated claims of cures. At one time or another, many ineffective and even potentially dangerous therapies have been promoted as treatments for MS. A partial list of these "therapies" includes: injections of snake venom, electrical stimulation of the spinal cord's dorsal column, removal of the thymus gland, breathing pressurized (hyperbaric) oxygen in a special chamber, injections of beef heart and hog pancreas extracts, intravenous or oral calcium orotate (calcium EAP), hysterectomy, removal of dental fillings containing silver or mercury amalgams, and surgical implantation of pig brain into the patient's abdomen. None of these treatments is an effective therapy for MS or any of its symptoms.

Drugs Used to Treat Multiple Sclerosis

Drugs currently available to patients Steroids Adrenocorticotropic Hormone, prednisone,  prednisolone, methylprednisolone, betamethasone, and dexamethasone Interferons Beta interferons (Avonex^® and Betaseron^®) Beta interferon (Rebif^®)—available in Europe only Some experimental therapies Alpha interferon Cyclosporine (Sandimmune) Cyclophosphamide (Cytoxan) Methotrexate Azathioprine (Imuran) Linomide (Roquinimex) Cladribine (Leustatin) Mitoxantrone Aminopyridine, derivatives of Copolymer I (Copaxone) Rolipram Interleukin 4 (IL-4) Retinoids Total lymphoid irradiation Monoclonal antibodies Plasma exchange or plasmapheresis Bone marrow transplantation Peptide therapy Various MS vaccines Protein antigen feeding Transforming growth factor beta (TGF) Intravenous immunoglobulin (IVIg)

Are Any MS Symptoms Treatable?

While some scientists look for therapies that will affect the overall course of the disease, others are searching for new and better medications to control the symptoms of MS without triggering intolerable side effects.

Many people with MS have problems with spasticity, a condition that primarily affects the lower limbs. Spasticity can occur either as a sustained stiffness caused by increased muscle tone or as spasms that come and go, especially at night. It is usually treated with muscle relaxants and tranquilizers. Baclofen (Lioresal), the most commonly prescribed medication for this symptom, may be taken orally or, in severe cases, injected into the spinal cord. Tizanidine (Zanaflex), used for years in Europe and now approved in the United States, appears to function similarly to baclofen. Diazepam (Valium), clonazepam (Klonopin), and dantrolene (Dantrium) can also reduce spasticity. Although its beneficial effect is temporary, physical therapy may also be useful and can help prevent the irreversible shortening of muscles known as contractures. Surgery to reduce spasticity is rarely appropriate in MS.

Weakness and ataxia (incoordination) are also characteristic of MS. When weakness is a problem, some spasticity can actually be beneficial by lending support to weak limbs. In such cases, medication levels that alleviate spasticity completely may be inappropriate. Physical therapy and exercise can also 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. Occasionally, physicians can provide temporary relief from weakness, spasms, and pain by injecting a drug called phenol into the spinal cord, muscles, or nerves in the arms or legs. Further research is needed to find or develop effective treatments for MS-related weakness and ataxia.

Although improvement of optic symptoms (explanation of Optic Neuritis) usually occurs even without treatment, a short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by treatment with oral steroids is sometimes used. A trial of oral prednisone in patients with visual problems suggests that this steroid is not only ineffective in speeding recovery but may also increase patients' risk for future MS attacks. Curiously, prednisone injected directly into the veins—at ten times the oral dose—did seem to produce short-term recovery. Because of the link between optic neuritis and MS, the study's investigators believe these findings may hold true for the treatment of MS as well. A follow-up study of optic neuritis patients will address this and other questions.

Fatigue, especially in the legs (look at symptoms), is a common symptom of MS and may be both physical and psychological. Avoiding excessive activity and heat are probably the most important measures patients can take to counter physiological fatigue. If psychological aspects 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.

People with MS may experience several types of pain. Muscle (Muscle Atrophy, Muscle Cramps, Muscle Spasticity, Loss of Muscle Control or Uncontrolled Movements) and back pain can be helped by aspirin or acetaminophen and physical therapy to correct faulty posture and strengthen and stretch muscles. The sharp, stabbing facial pain known as trigeminal neuralgia is commonly treated with carbamazapine or other anticonvulsant drugs or, occasionally, surgery. Intense tingling and burning sensations are harder to treat. Some people get relief with antidepressant drugs; others may respond to electrical stimulation of the nerves in the affected area. In some cases, the physician may recommend codeine.

As the disease progresses, some patients develop bladder malfunctions. Urinary problems are often the result of infections that can be treated with antibiotics. The physician may recommend that patients take vitamin C supplements or drink cranberry juice, as these measures acidify urine and may reduce the risk of further infections. Several medications are also available. The most common bladder problems encountered by MS patients are urinary frequency, urgency, or incontinence. A small number of patients, however, retain large amounts of urine. In these patients, catheterization may be necessary. In this procedure, a catheter or drainage tube is temporarily inserted (by the patient or a caretaker) into the urethra several times a day to drain urine from the bladder. Surgery may be indicated in severe, intractable cases. Scientists have developed a "bladder pacemaker" that has helped people with urinary incontinence in preliminary trials. The pacemaker, which is surgically implanted, is controlled by a hand-held unit that allows the patient to electrically stimulate the nerves that control bladder function.

MS patients with urinary problems may be reluctant to drink enough fluids, leading to constipation. Drinking more water and adding fiber to the diet usually alleviates this condition. Sexual dysfunction may also occur, especially in patients with urinary problems. Men may experience occasional failure to attain an erection. Penile implants, injection of the drug papaverine, and electrostimulation are techniques used to resolve the problem. Women may experience insufficient lubrication or have difficulty reaching orgasm; in these cases, vaginal gels and vibrating devices may be helpful. Counseling is also beneficial, especially in the absence of urinary problems, since psychological factors can also cause these symptoms. For instance, depression can intensify symptoms of fatigue, pain, and sexual dysfunction. In addition to counseling, the physician may prescribe antidepressant or antianxiety medications. Amitriptyline is used to treat laughing/weeping syndrome.

Tremors are often resistant to therapy, but can sometimes be treated with drugs or, in extreme cases, surgery. Investigators are currently examining a number of experimental treatments for tremor.

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 Multiple Sclerosis (RRMS) in the United States ( see a map of Geographical Prevalence of MS in the 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.

TheBetaseron^®  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 expanded 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 Multiple Sclerosis (SPMS) 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.

List of Symptoms from Multiple Websites

(I researched the symptoms and created this page from many websites.)