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.
How is MS diagnosed?
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.
What are the symptoms of MS?
Symptoms of MS vary among individuals but often include:
- Numbness or tingling in the limbs
- Impaired balance
- Change in vision such as blurred vision in one eye or double vision
- Fatigue that does not seem associated with activity
- Change in bowel, bladder, and sexual function
- Stiffness or tightness in the muscles
- Trouble walking
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.
How is MS managed?
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. Usually, relapses evolve over 1-7 days. They will plateau for several weeks and resolve to some degree over weeks to several months.
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. Infections can also provoke a worsening of symptoms and may provoke a relapse of symptoms.
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– 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.
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. Betaseronâ 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. Copaxoneâ 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.
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.
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.
Natalizumab (Tysabri®) is also a medication FDA approved for the treatment of relapsing multiple sclerosis to reduce the frequency of clinical relapses. It is given by IV infusion in a clinic or doctors office once every 4 weeks. Clinical trial results from the first year of a large Phase III trial of Tysabri® vs. placebo showed a 66% reduction in relapses and a 92 % reduction in new MRI lesions. Tysabri® works by blocking the ability of inflammatory cells from entering the central nervous system.
Fingolimod (Gilenya®) is the newest medication approved for the treatment of relapsing forms of multiple sclerosis. It is the first oral pill that the FDA approved for MS. In phase III clinical trials it was shown to have a 54% reduction in relapse rate over placebo and a 52% reduction in relapse rate over interferon beta 1a. Gilenya® is taken as a once daily pill. It works by sequestering the lymphocytes in the lymph system and not allowing them to circulate and cause inflammation and damage in the CNS.
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.
Natalilzumab (Tysabri®) can cause headache, hypersensitivity (allergic) reactions and may cause some infections. Because it may cause an allergic reaction, a period of one hour of medical supervision following each injection is required.
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.