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Management of multiple sclerosis

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Although there is no known definitive cure, several therapies for multiple sclerosis (MS) have proven to be helpful. Different therapies are used for patients experiencing acute attacks of multiple sclerosis, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS. Therapy is aimed at returning function after an attack, preventing new attacks, and preventing disability. As any medical treatment, medications used in the management of MS have several adverse effects, and many possible therapies are still under investigation. At the same time different alternative treatments are followed by many patients, despite a paucity of supporting, comparable, replicated scientific study.

This article focuses on therapies for standard MS; borderline forms of MS have particular treatments that are excluded.

Management of acute attacks

Chemical structure of methylprednisolone. Corticoesteroids are used during acute multiple sclerosis relapses

During symptomatic attacks, patients may be hospitalized. Administration of high doses of intravenous corticosteroids, such as methylprednisolone,[1][2] is the routine therapy for acute relapses at present. These are given over a period of three to five days; having a well established efficacy promoting a better recovery of disability as measured by the Expanded Disability Status Scale score (EDSS).[3][4]

The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery: steroids produce a rapid improvement in disability, but this improvement only lasts up to thirty days following the clinical attack, is evident neither six nor thirty-six months after the attack, and does not reduce the number of patients who would subsequently develop a clinical relapse.[5]

Recent studies suggest that oral steroid pills are just as effective at treating MS symptoms as intravenous treatment. However, short term treatment with high-dose intravenous corticosteroids does not seem to be attended by adverse effects; on the contrary, gastrointestinal symptoms and psychiatric disorders are more common with oral corticosteroids.[6]

Management of relapsing-remitting MS

Disease-modifying treatments are expensive and require frequent injections.

As of 2006, six Food and Drug Administration (FDA)-approved treatments for patients with relapsing-remitting MS were available in the United States. Three were interferons: two formulations of interferon beta-1a (trade names Avonex and Rebif; the first given weekly, the latter three times a week),[7][8] or one of interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon).[9] The interferons are medications derived from human cytokines which help regulate the immune system. A fourth medication is glatiramer acetate (Copaxone), [10]a mixture of polypeptides which may protect important myelin proteins by substituting itself as the target of immune system attack.[11] The fifth medication, mitoxantrone, is an immunosuppressant also used in cancer chemotherapy. Finally, the sixth medication is natalizumab (marketed as Tysabri).[12] Natalizumab was finally approved in May 2006 after a long process, due to cases of progressive multifocal leukoencephalopathy (PML) in some patients who had taken it in combination with interferons.[13][14]

All six medications have been proven to be modestly effective at decreasing the number of attacks and slowing progression to disability, although they differ in their efficacy rate. Comparisons between immunomodulators (all but glatiramer) show that the most effective is natalizumab, but studies of its long-term effects are still lacking.[15] Mitoxantrone is probably the most effective of them all;[16] however, its use is limited by severe cardiotoxicity.[17] This is the reason why its mainly used to treat MS patients who have worsening relapsing-remitting or secondary progressive multiple sclerosis despite prior therapy with interferons or glatiramer acetate.

Medications also differ in ease of use, price and side effects. All of these therapies are expensive and require frequent injections, with Tysabri given as intravenous infusions every four weeks, Avonex requiring weekly injections and Copaxone daily injections. Mitoxantrone is intravenously administered every three months as a slow infusion over at least thirty minutes (in order to reduce cardiac toxicity).

Even with appropriate use of medication, most patients with relapsing-remitting MS still suffer from some attacks and subsequent disability.

Management of progressive MS

Chemical structure of mitoxantrone. In 2007 it was the only approved treatment for secondary progressive multiple sclerosis.

Treatment of progressive MS is more difficult than relapsing-remitting MS, and many patients do not respond to any therapy. A wide range of medications have been used to try to slow the progression of disease.

Mitoxantrone has shown positive effects in patients with a secondary progressive and progressive relapsing courses. It is moderately effective in reducing the disease progression and the frequency of relapses in patients in the short-term follow-up.[18] In 2007 it was the only medication approved was for secondary progressive and progressive relapsing multiple sclerosis; but causes dose-dependent cardiac toxicity which limits its long-term use. Interferon-beta-1b slowed progression of the disease in a clinical trials for secondary progressive MS, but not in another. In both studies however interferon recipients had fewer relapses and less MRI-assessed disease activity. Therefore interferons show promise in secondary progressive MS, but more data is needed to support widespread use.[19]

Several trials have been designed specifically for primary progressive multiple sclerosis (PPMS), including trials with interferons and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole.[20] Patients with PPMS have also been included in trials of azathioprine,[21] methotrexate,[22] cladribine,[23] intravenous immunoglobulin, cyclophosphamide,[24] and studies of haematopoietic stem cell transplantation. However, no treatment in these trials has been proven definitively to modify the course of the disease.[25]

Management of demyelination without a diagnosis of MS

The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). In CIS there is a subacute attack suggestive of demyelination but the person doesn't fullfill the criteria for multiple sclerosis.[26] Several studies have shown that starting treatment with interferons during the initial attack can decrease the chance that a patient will develop MS. These results support the use of interferon after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.[27][28][29]

Side effects of disease-modifying treatments

Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause irritation at the injection site.

Interferons are produced in the body during illnesses such as influenza in order to help fight the infection.[30] They are responsible for the fever, muscle aches, fatigue, and headache common during influenza infections. Many patients report influenza-like symptoms when using interferon to fight MS. This reaction often lessens over time and can be treated with over-the-counter fever reducers/pain relievers like paracetamol (known in the U.S. as acetaminophen),[31] ibuprofen,[32] and naproxen.[33] Rare, but potentially serious, liver function abnormalities have also been reported with interferons; requiring that all patients treated regularly be monitored with liver function tests to ensure safe use.[34][35][36] Interferon therapy has also shown that can induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. However the clinical consequences of the presence of antibodies are presently unclear: it has not been proved that these antibodies reduce efficacy of treatment. Therefore any treatment decision should be based only on the clinical response to therapy.[37]

Glatiramer acetate is generally considered to be better tolerated than the interferons although some patients taking glatiramer acetate experience a "post-injection" reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety; which usually lasts less than 30 minutes.[38]

Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; however its most dangerous side effect is its dose-related cardiac toxicity. Therefore careful adherence to the administration and monitoring guidelines is essential; this includes obtaining an echocardiogram and a complete blood count before treatment to decide whether the therapy is suitable for the patient or the risks are too great. It is recommended that mitoxantrone be discontinued at the first signs of heart damage, infection or liver malfunction during therapy.[39]

In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leukoencephalopathy(PML) were identified. PML is a rare and progressive demyelinating disease of the brain that typically causes permanent disability or death. It is caused by infection by the JC virus (JCV), a virus thought to be present in most healthy individuals; and at first its symptoms may be similar to a MS relapse. There are no known treatments for PML; but the sooner the immune system returns to normal the higher the probabilities for recovery will be. Although the analysis of cerebrospinal fluid for JCV DNA is very specific for the diagnosis of PML, in early PML cerebrospinal fluid is usually negative for JCV DNA; therefore clinical vigilance by neurologists is the most important method of monitoring for PML and should allow for early recognition of PML. If there is a worsening and the neurologist has any doubts about the cause of clinical symptoms, natalizumab should be discontinued immediately and a lumbar puncture done; but even if the DNA is negative the patient should be carefully followed and a reanalysis made.[40]

Management of the effects of MS

Disease modifying treatments only reduce the progression rate of the disease but don't stop it. As multiple sclerosis progresses the symptomatology tends to increase; being MS associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Management of these deficits is therefore very important.

Both different medications and neurorehabilitation even though not having influence on disease progression have shown to ease the burden of some symptoms. For other symptoms the efficacy of treatments is still very limited.[41]

Neurorehabilitation

Supervised physical therapy may be helpful to overcome some symptoms.

As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability. Neurologists will be the main physicians involved, however depending on the symptom doctors of other medical specialities may also be helpful. Other treatments such as physical therapy,[42][43] or speech therapy[44] can also help to manage some symptoms and maintain quality of life. Treatment of neuropsychiatric symptoms such as emotional distress and depression should involve mental health professionals such as therapists, psychologists, and psychiatrists;[45] while neuropsychologists can help to evaluate and manage cognitive deficits.[46] Although occupational therapy has shown its efficacy in other chronic and neurologic conditions;[47] and some preliminary data suggests that it may be useful in MS;[48] there aren't enough randomized controlled studies to establish its effectiveness.[47][49]

Medical treatments for symptoms

Further information: [[:Multiple sclerosis signs and symptoms]]

Multiple sclerosis can cause a variety of symptoms, including changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, or difficulty to move; difficulties with coordination and balance; problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptomatology (mainly depression). The main clinical measure of disability progression and severity of the symptoms is the Expanded Disability Status Scale or EDSS.[50] At the same time for each symptom there are different treatment options. Therefore treatments should be individualized depending both on the patient and the physician.

Pharmacological treatments for bladder problems vary greatly depending on the origin or type of dysfunction; however some examples of the medications used are:[51] alfuzosin for retention,[52] trospium and flavoxate for urgency and incontinence,[53][54] or desmopressin for nocturia.[55][56] Non pharmacological treatments involve the use of pelvic floor muscle training, stimulation, biofeedback, pessaries, bladder retraining, and sometimes intermittent catheterization.[57]

Depression can be treated with a variety of antidepressants;[58] selective serotonin reuptake inhibitors (SSRIs) are most commonly employed.[59] Anticholinesterase drugs such as donepezil,[60] commonly used in Alzheimer disease; although not approved yet for multiple sclerosis; have shown efficacy improving cognitive functions.[61][62]

Different drugs as well as optic compensatory systems and prisms can be used to improve the symptoms of nystagmus.;[63][64][65] Surgery can also be used in some cases for this problem.[66]

Acute pain is mainly due to optic neuritis, being corticosteroids the best treatment available; to trigeminal neuralgia, to Lhermitte's sign or to dysesthesias.[67] Subacute pain is usually secondary to the disease and can be consequence of being to much time in the same position, urinary retention, infected skin ulcers and many others. Treatment will depend on cause. Chronic pain is very common and the harder to treat being its most common cause dysesthesias. Acute pain can be Trigeminal neuralgia it's usually successfully treated with anticonvulsants such as carbamazepine[68] or phenytoin.[69][70][71] Both Lhermitte's sign and painful dysesthesias usually have a good answer to treatment with carbamazepine, clonazepam,[72] or amitriptyline.[73][74] Sativex is approved for treatment of pain in MS in different countries but due to its use of cannabis it is currently not available in others; such as the USA.[75] This medication is also being investigated for the management of other MS symptoms, such as spasticity;[76] and has shown its long term safety and efficacy.[77]

Therapies under investigation

Main article: Therapies under investigation for multiple sclerosis

Scientists continue their extensive efforts to create new and better therapies for MS. There are a number of treatments under investigation that may curtail attacks or improve function. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis; such as the combination of mitoxantrone and glatiramer acetate (Copaxone).[78] However most treatments already in clinical trials involve drugs that are used in other diseases. These are the cases of alemtuzumab (trade name Campath),[79] daclizumab (trade name Zenapax),[80] and inosine.[81]Other drugs in clinical trials have been designed specifically for MS, like fingolimod,[82] laquinimod,[83] or Neurovax.[84] Finally there are also many basic investigations that in the future may be able to find new treatments. Examples of these are the studies trying to understand the influence of Chlamydophila pneumoniae or vitamin D in the origin of the disease.[85][86]

Alternative treatments

Further information: [[:Dietary treatments for multiple sclerosis and Endocannabinoid system and Multiple Sclerosis]]
Many patients use medical marijuana as an alternative treatment to help them alleviate some symptoms.

Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids, and vitamins might improve outcomes in people with multiple sclerosis.[87][88] Many diets have been proposed for treating the symptoms of the disease. Patients have reported a decrease of symptoms after long-term application of the diets; however no controlled trials have been able to proof their efficacy.[89] Even if these diets really are beneficial for people with MS, it is uncertain whether this fact is due to some special traits of the diets or simply that they are beneficial for whole body health. Some examples of these kind of diets are the Swank Multiple Sclerosis Diet or the The Optimal Diet.[90]

Herbal medicine is another source for alternative treatments. Andrographis paniculata, Glycyrrhiza uralensis and Forsythia suspensa; three medicinal plants traditionally used in China for treating conditions associated with inflammation and viral infection reduced the inflammation of epithelial cells infected by influenza A virus. Since inflammation is crucial in MS in the future these plants could be utilized to ease the progression of the disease.[91] Many patients also use medical marijuana to help alleviate symptoms; however, the results of experimental studies are scarce; but at least a subgroup with greater disability appears to derive some symptomatic benefit.[92][93]

Hyperbaric oxygenation has been the subject of several small studies with heterogeneous results which, overall, do not support its use.[94]

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