Multiple Sclerosis: Hope Through Research, Part II
How is MS Diagnosed?
When faced with a patient whose symptoms, neurological examination, and medical history suggest MS, physicians use a variety of tools to rule out other possible disorders and perform a series of laboratory tests which, if positive, confirm the diagnosis.
Imaging technologies such as MRI--often used in conjunction with the contrast agent gadolinium, which helps distinguish new plaques from old on MRI (see section on "What is the Course of MS?")--can help locate central nervous system lesions resulting from myelin loss. However, since these lesions can also occur in several other neurological disorders, they are not absolute evidence of MS. Magnetic resonance spectroscopy (MRS) is a new tool being used to investigate MS. Unlike MRI, which provides an anatomical picture of lesions, MRS yields information about the biochemistry of the brain in MS.
Evoked potential tests, which measure the speed of the brain's response to visual, auditory, and sensory stimuli, can sometimes detect lesions the scanners miss. Like imaging technologies, evoked potentials are helpful but not conclusive because they cannot identify the cause of lesions.
The physician may also study the patient's cerebrospinal fluid (the colorless liquid that circulates through the brain and spinal cord) for cellular and chemical abnormalities often associated with MS. These abnormalities include increased numbers of white blood cells and higher-than-average amounts of protein, especially myelin basic protein and an antibody called immunoglobulin G. Physicians can use several different laboratory techniques to separate and graph the various proteins in MS patients' cerebrospinal fluid. This process often identifies the presence of a characteristic pattern called oligoclonal bands.
Because there is no single test that unequivocally detects MS, it is often difficult for the physician to differentiate between an MS attack and symptoms that can follow a viral infection or even an immunization. Many doctors will tell their patients they have "possible MS." If, as time goes by, the patient's symptoms show the characteristic relapsing-remitting pattern, or continue in a chronic and progressive fashion, and if laboratory tests rule out other likely causes, or specific tests become positive, the diagnosis may eventually be changed to "probable MS."
A number of other diseases may produce symptoms similar to those seen in MS. Other conditions with an intermittent course and MS-like lesions of the brain's white matter include polyarteritis, lupus erythematosus, syringomyelia, tropical spastic paraparesis, some cancers, and certain tumors that compress the brainstem or spinal cord. Progressive multifocal leukoencephalopathy can mimic the acute stage of an MS attack. The physician will also need to rule out stroke, neurosyphilis, spinocerebellar ataxias, pernicious anemia, diabetes, Sjogren's disease, and vitamin B12 deficiency. Acute transverse myelitis may signal the first attack of MS, or it may indicate other problems such as infection with the Epstein-Barr or herpes simplex B viruses. Recent reports suggest that the neurological problems associated with Lyme disease may present a clinical picture much like MS.
Investigators are continuing their search for a definitive test for MS. Until one is developed, however, evidence of both multiple attacks and central nervous system lesions must be found--a process that can take months or even years--before a physician can make a definitive diagnosis of MS.
Diagnostic Categories for Multiple Sclerosis Definite MS Consistent course (relapsing-remitting course with at least 2 bouts separated by at least 1 month, or slow or stepwise progressive course for at least 6 months) Documented neurologic signs of lesions in more than one site of brain or spinal cord white matter Onset of symptoms between 10 and 50 years of age Absence of other more likely neurologic explanation Probable MS History of relapsing-remitting symptoms Signs not documented and only one current sign commonly associated with MS Documented single bout of symptoms with signs of more than one white matter lesion; good recovery, then variable symptoms and signs Absence of other more likely neurologic explanation Possible MS History of relapsing-remitting symptoms No documentation of signs establishing more than one white matter lesion Absence of other more likely neurologic explanation
Can MS be Treated?
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 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.
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.
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 paresthesias (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.
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.
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.
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.
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 (ACTH) Prednisone Prednisolone Methylprednisolone Betamethasone Dexamethasone Interferons Beta interferons (Avonex, 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 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, 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 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 relax the nerves used for urine retention or contract those needed to empty the bladder.
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.
Drugs Used to Treat Symptoms of Multiple Sclerosis Symptom Drug Drugs currently available Spasticity Baclofen (Lioresal) Tizanidine (Zanaflex) Diazepam (Valium) Clonazepam (Klonopin) Dantrolene (Dantrium) Optic neuritis Methylprednisolone (Solu-Medrol) Oral steroids Fatigue Antidepressants Amantadine (Symmetrel) Pemoline (Cylert) Pain Aspirin or acetaminiphen Antidepressants Codeine Trigeminal neuralgia Carbamazapine, other anticonvulsant drugs Sexual dysfunction Papaverine, injections (in men)
Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health