Multiple sclerosis is a complex disease of the central nervous system (brain, spinal cord, and optic nerves) characterized by relapses (neurologic symptoms which appear rapidly but often improve over weeks or months), remissions and often progression of disability over time. MS is currently not a curable disease. MS is thought to be an “immune-mediated” disease, meaning that errors in the function of the immune system cause damage in the central nervous system. The immune system functions to protect the body from various environmental hazards or pathogens such as viruses, bacteria and fungi. The immune system is very sophisticated and has regulatory mechanisms in place that prevent it from recognizing body tissues as a pathogen. In an immune-mediated disease such as MS, the regulatory mechanisms are disrupted and the ability to ignore “self” is lost. In MS, the immune system is able to recognize tissue within the central nervous system as a pathogen and therefore causes inflammation and damage. Researchers have learned this by looking at the central nervous system tissue and identifying immune system cells in the areas of MS lesions. The disease modifying treatments and treatment for a relapse have some effect on the immune system.
MRI of the Brain following gadolinium demonstrating enhancement of MS lesions
MS is diagnosed based on the history of symptoms (that are referred to the central nervous system) over time, the neurological examination, and imaging tests such as the brain and/or spinal cord MRI. Sometimes other tests are used such as evoked potentials and/or a spinal tap. Many blood tests are also checked to make sure the symptoms are not caused by something other then MS. As there is no single test for MS, the diagnosis is made by putting together the history, neurological exam, MRI findings and the exclusion of other illnesses
There are many symptoms of MS. The symptoms are different for every person. They vary in intensity and problem based on where the nerves are damaged. These symptoms may or may not be transient. Following is a list of many symptoms of MS.
What is the course of MS over time?
Approximately 85% of patients begin the disease with relapsing-remitting MS. Patients have an onset of symptoms over a few days or weeks, and a gradual complete or incomplete recovery over time. Inflammatory changes are the hallmark of the relapsing phase of the disease. During the relapsing phase of the disease there is frequent gadolinium enhancement seen on MRI (areas on the MRI scan that show up as bright spots after injection of the contrast dye), which indicates areas of active inflammation. Gadolinium enhancement occurs about 5-10 times more frequently then clinical relapses. Over time, there are often less inflammatory changes and more progression of symptoms, and often more disability. This is classified as secondary-progressive MS. Over time there can also be a decrease in brain volume. Approximately 15% of patients never have relapses; rather their disease is characterized by a progression of symptoms over time. This disease course is known as primary-progressive MS.
Watch a 30-minute interview with Dr. Walter Royal, in which he discussed the latest in MS diagnosis and treatment options. Requires Real Player.
Management of MS is approached on three fronts; treatment of relapses, disease modification and symptom management.
Relapse Management A relapse is defined as new or worsening neurological symptoms of greater then 24 hours duration, and occurring in the absence of metabolic change such as an untreated infection. Usually, relapses evolve over 1 - 7 days. They will plateau for a period of time and resolve over weeks to several months. Some symptoms may persist and become permanent.
Recent exposure to excessive heat or a recent increase in activity may produce a worsening or return of symptoms and cause one to feel as though they are having a new relapse. Although heat exposure may cause symptoms to worsen, cooling will likely prompt improvement.
Infections can also provoke a temporary worsening of symptoms and symptoms may resolve once the infection clears. Infection do stimulate the immune system and may provoke an exacerbation of MS. If symptoms persist once an infection is treated, treatment for a relapse may be warranted.
The usual treatment of a relapse is high dose glucocorticoids administered by mouth or intravenous infusion. These are not the same type of steroids that many athletes have been accused of using. Rather these are anti-inflammatory steroids. You may have heard of someone getting this type of steroid for an allergic reaction, such as poison ivy. Although there is little evidence that high dose steroids have a long term benefit in MS, they are felt to hasten recovery from relapse symptoms. Commonly steroids are given intravenously (in a vein) for MS relapses. Many physicians give 1 gm of methylprednisolone over 1 – 2 hours for 3 – 5 consecutive days. Some neurologists will follow the IV steroids with a prednisone (a steroid given in pill form) in a tapering dose (reducing the dose every few days).
Disease modifying medications for multiple sclerosis Prior to 1993, there were no approved medications for the treatment of multiple sclerosis that could alter the natural history of the disease. Some medications could alleviate symptoms or hasten recovery from an exacerbation, but none had any long term effect or benefit.
As stated earlier, MS is thought to be an immune-mediated disease. By this it is meant that the body's own immune system is at least in part responsible for the damage seen in the brain and spinal cord of MS patients. It is thought that inflammatory immune cells (types of white blood cells) are activated by exposure to an antigen (i.e. a virus), then migrate into the central nervous system where they are reactivated by exposure to a protein within the CNS – such as a myelin protein. Upon reactivation, they release damaging cytokines (inflammatory substances) and stimulate other types of damaging cells that injure and/or destroy myelin and axons (nerve fibers).
Each of the disease modifying medications have an effect on the inflammatory process seen in MS by affecting the activity of the immune system cells. Interferons are thought to interfere with the initial stimulation and proliferation of T-cell's in the bloodstream. In addition, by blocking certain enzyme activity at the blood brain barrier, interferons make migration of T-cells into the central nervous system more difficult.14,15 Glatiramer acetate (Copaxone) is thought to work by stimulating T-cells to behave in an anti-inflammatory manner. These glatiramer acetate induced T-cells enter the CNS and reduce the MS inflammatory process.16 Natalizumab works by blocking the ability of Tcells to stick to the blood vessels that supply the brain. Thus these Tcells are unable to enter the brain and cause inflammation. Mitoxantrone (Novantrone®) works by suppressing various inflammatory immune system cells including Tcells, Bcells and macrophages.
In July of 1993, the FDA approved interferon beta-1b (Betaseron®) for relapsing-remitting MS to reduce the frequency of clinical relapses. Betaseron? works by reducing the ability of inflammatory cells of the immune system to enter the central nervous system. Betaseron® is given by subcutaneous injection (under the skin) every other day and was found in clinical trials to reduce relapses by about 30% and severe relapses by about 50%. In addition, it reduced new lesion formation within the central nervous system as seen on MRI. In 2004 the FDA approved the drug for use in more progressive patients still having relapses. Although it is not a premixed solution, it can be stored at room temperature and can be given with an auto-injector device.
This approval was followed in 1996 by the FDA approvals of interferon beta-1a (Avonex®) and glatiramer acetate for injection (Copaxone®).
Avonex® is indicated for the treatment of relapsing forms of MS and was found in clinical trials to reduce relapses by 18% and also was found to slow progression of disability over time. In 2004 it was given an indication for use in clinically isolated syndrome (for those who have had one episode of neurological symptoms, but based on symptoms plus abnormal MRI are at high risk to develop MS.) It too had an effect on the formation of new lesions in the central nervous system. It works by the same mechanism as Betaseron? . Avonex® is given by intramuscular (in the muscle) injection once weekly. Avonex must be kept refrigerated. It is premixed and in prepackaged syringes, but because it must be delivered into the muscle, it cannot be used with an auto-injector device
Copaxone® is indicated for relapsing-remitting MS and was found in clinical trials to reduce relapses by approximately 30%. A later trial with this medication found it to reduce new lesions on MRI by about 33%. It was also found to reduce the occurrence of inflammatory lesions in the central nervous system and hypointense lesions, thought to be indicative of more permanent damage. Copaxone works by inducing the immune system cells to behave as anti-inflammatory cells. These cells enter the central nervous system and reduce inflammatory activity. Copaxone® is given by daily subcutaneous injection. It is pre-mixed and packaged in prefilled syringes. It can be given with an auto-injector device. Copaxone® must be refrigerated, however, it may be kept at room temperature for up to 30 days.
In 2002, the FDA approved another interferon for use in relapsing MS. This was interferon beta-1a (Rebif®) Rebif® was found in clinical trials to reduce relapses by about 30%. In addition, it reduced new inflammatory lesions in the central nervous system and the formation of new lesions in the central nervous system. Rebif® works by the same mechanism as Betaseron? and Avonex®. Rebif® is given by subcutaneous injection three times/week. It is pre-mixed and packaged in prefilled syringes. It can be given with an auto-injector device. It too must be kept refrigerated.
Tysabri® was approved by the FDA in 2004 for the treatment of relapsing forms of multiple sclerosis to delay the accumulation of disability and reduce relapses. It was voluntarily removed from the market after several people who had received the drug were diagnosed with PML, a rare, usually fatal infection of the brain. It is back on the market, with numerous safety recommendations and administration protocols that must be adhered to. Tysabri® was tested in a large Phase III clinical trial of patients with relapsing-remitting multiple sclerosis. It was also tested in another large trial in combination with Avonex® in patients who were worsening on Avonex® alone. In the two year trial of Tysabri® monotherapy, Tysabri® given in monthly IV (into a vein) infusions reduced relapses by 67% relative to the placebo group. There was a decrease in the risk of additional disability of 42% in the Tysabri group relative to the placebo group. In addition, gadolinium enhancing lesions were reduced by approximately 90%. Tysabri is thought to work by blocking the ability of activated immune system cells to enter the brain tissue.
The combination trial of Avonex® and Tysabri® was also effective in reducing relapses and delaying disability. However, it was patients who were on combination treatment of Tysabri® with another immunomodulating or immunosuppressant drug that developed PML, so combination therapy with Tysabri® is NOT recommended.
Tysabr® is infused monthly by intravenous (in a vein) infusion in a medical facility. Due to the risk of PML noted above, Tysabri® is generally recommended for patients who do not respond to the interferons and/or glatiramer acetate, or in patients who have intolerable side effects from the other therapies.
Mitoxantrone or Novantrone® is a immunosuppressant medication that is given once every three months and it is indicated for the treatment of worsening MS. Novantrone carries greater toxicity then the other medications for multiple sclerosis, meaning there is somewhat greater risk taken when receiving this drug. This drug works by suppressing the immune system cells. Novantrone® had already been FDA approved for the treatment of certain types of cancer and clinical trials in MS showed that it reduced relapses, delayed worsening and reduced the formation of inflammatory and new lesions as see on the MRI. This drug has a FDA black box warning as it can damage the heart muscle. The risk for damage increases with repeated infusions and cumulative dosage above 140 mg/m2. This drug also increases the risk of certain types of leukemia. Careful cardiac monitoring prior to each dose of medication is required.
What are the possible side effects from these drugs?
Side effects of the interferons (Betaseron®, Avonex® and Rebif®) are all very similar as each of these are preparations of interferon beta. The difference is in how the drugs are manufactured and how they are injected. Betaseron® is made using a bacterial cell while Avonex® and Rebif® are made using mammal cells. Betaseron® and Rebif® are given under the skin and Avonex® is given into the muscle. All the interferons can cause body temperature to become temporarily elevated. This can produce "flu-like" symptoms such as chills, achiness, headache, and fatigue. These symptoms can begin several hours after injection and persist for about 12 hours. These symptoms tend to abate during the first few months of treatment. The subcutaneous injections of interferons can cause redness, discomfort and swelling at the injection sites. The intramuscular interferon can cause discomfort and bruising at the injection site. Interferons may cause symptoms of depression in some individuals. They can alter the menstrual cycle, cause anemia and elevation in liver enzyme activity. They require periodic monitoring for laboratory abnormalities.
Glatiramer acetate for injection (Copaxone®) can cause redness, swelling, itching and discomfort at the injection site. A rare post-injection reaction may occur in 10% of people taking Copaxone. Symptoms of this reaction can include shortness of breath, chest tightness, racing heart and feeling faint. It last for 10-15 minutes and goes away. It has not bee found to cause any long term ill effects.
Side effects from Tysabri® include headache, rash, abdominal discomfort, achiness, allergic reactions including hives, difficulty breathing, dizziness, itching, flushing, infections including the possibility of PML.
Mitoxantrone (Novantrone®) can cause nausea/vomiting, hair thinning, fatigue, and weakness. It will suppress the immune system temporarily and may temporarily increase the risk of infection. In the long term, it may weaken the heart muscle and cause a condition known as heart failure. Because of the risk of heart damage, mitoxantrone may only be given to a life time maximum dose. Once the maximum is reached, at about 2 and ½ years, it may never be used again.
All of these medications have been found to be effective in the treatment of multiple sclerosis. It is important to discuss all treatment options with your neurologist to determine the right therapy for you.
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