Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Some therapies for it exist, although no known cure.
The most common starting point of the disease is the relapse-remitting subtype, characterized by an unexpected attack (recurrence) followed by a relatively period of remission with no new signs of disease activity. After several years, many people who have this subtype begin to experience a neurological decline without acute recurrence. When this happens it is called secondary progressive multiple sclerosis. Other, less commonly, the program of this disease is primary progressive (decreased from baseline without attack) and progressive relapse (stable neurologic decline and superimposed attacks). Different therapies are used for patients suffering from acute attacks, for patients with relapsing-remitting subtypes, for patients with progressive subtypes, for patients without MS diagnoses who have demyelinating events, and for managing the various consequences of MS.
The main purpose of therapy is to restore function after attack, prevent new attacks, and prevent disability. As with any medical treatment, drugs used in MS management may have some side effects, and many possible therapies are still under investigation. At the same time, different alternative treatments are being pursued by many, despite the fact that there is little scientific research supporting, comparable, and replicated. Stem cell therapy is being studied.
This article focuses on therapies for MS standards; MS boundary forms have excluded special care.
Video Management of multiple sclerosis
Acute attacks
Administration of high doses of intravenous corticosteroids, such as methylprednisolone, is a routine therapy for acute relapse. This is done for three to five days, and has a strong efficacy in promoting a faster recovery from disability after an attack. There is, however, considerable evidence to show a significant impact on long-term disability of corticosteroid treatment. Oral steroids have the same effectiveness and safety profile to treat MS symptoms as an intravenous treatment. The consequences of severe attacks that do not respond to corticosteroids can be treated with plasmapheresis.
Maps Management of multiple sclerosis
Treatments that modify the disease
Beginning in 2017, several treatment-altering treatments have been approved by regulators from various countries, including the US Food and Drug Administration (FDA), the European Drug Agency (EMEA) and the Japan Medical and Pharmaceutical and Equipment Agency (PMDA) from Japan. Ministry of Health, Labor and Welfare.
Drugs approved by the FDA currently include eleven drugs: interferon beta-1a and beta-1b, four monoclonal antibodies: natalizumab, alemtuzumab, daclizumab and ocrelizumab, and five immunomodulators: acetate glatiramer, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate.
Drugs
In 1993 interferon beta-1b was the first drug ever approved for MS, which was soon followed by interferon beta-1a and glatiramer acetate.
Interferon beta-1a is injected either weekly (intramuscular injection) or three times a week (subcutaneous injection) depending on commercial formulation, while interferon beta-1b is injected subcutaneously every second day. In 2014, the interferon beta-1a pegylation form is introduced with the Plegridy brand name, which is available as a subcutaneous injection. This Peginterferon beta 1-a attaches polyethylene glycol to the interferon molecule allowing longer biological effects in the body while reducing the frequency of administration to once every two weeks. Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood-brain barrier. Overall, therapy with interferon beta leads to a reduction in neuron inflammation. In addition, it is also considered to increase the production of nerve growth factors and consequently improve neuronal survival.
Glatiramer acetate is a mixture of random polymers of four amino acids that are antigenically similar to the myelin base protein, a component of neural myelin sheath that competes for presentation to T cells. It is injected subcutaneously daily.
Mitoxantrone is an immunosuppressant that is also used in cancer chemotherapy approved for MS in 2000; while natalizumab was a monoclonal antibody initially approved in 2004. Both were administered by intravenous infusion at monthly intervals in the case of natalizumab and every three months in the case of mitoxantrone.
In 2010 fingolimod, the sphingosine-1-phosphate receptor modulator, became the first oral drug approved by the FDA, followed in 2012 by teriflunomide, a drug that inhibits pyrimidine synthesis and disrupts the interaction of T cells with antigen-presenting cells. Fingolimod and teriflunomide are taken by a single dose every day. In 2013 one further oral drug, dimethyl fumarate-or BG12- (which is an improved version of fumaric acid, an existing drug), has been approved by the FDA. Dimethyl fumarate is taken twice a day.
Another oral drug, cladribine, was approved in Russia and Australia in 2010. Its application was rejected by the FDA and EMEA in 2011 due to safety concerns regardless of the promising efficacy of the drug. This causes pharmaceuticals to stop commercialization and attract all marketing applications.
Most of these drugs are only approved for relapse-remitting multiple sclerosis (RRMS).
Side effects
Both interferon and glatiramer acetate are available only in injection form, and both can cause skin reactions at the injection site, especially with subcutaneous administration. Skin reactions vary widely in their clinical presentation and may include bruising, erythema, pain, pruritus, irritation, swelling and in the most extreme cases of skin necrosis. They usually appear within the first month of treatment even though their frequency and importance diminish after six months of use. Mild skin reactions usually do not inhibit treatment while necrosis appears in about 5% of patients and lead to discontinuation of therapy. Also over time, the dents seen at the injection site due to local destruction of fatty tissue, known as lipoatrophy, can develop.
Interferon, a subclass of cytokines, is produced in the body during diseases such as influenza to help fight infection. They are responsible for many symptoms of influenza infection, including fever, muscle aches, fatigue, and headaches. Many patients report influenza-like symptoms several hours after taking interferon-beta which usually improves within 24 hours, becoming symptoms associated with increased temporary cytokines. This reaction tends to disappear after 3 months of treatment and the symptoms can be treated with non-steroidal anti-inflammatory drugs that are sold freely, such as ibuprofen, which reduces fever and pain. Another common transient secondary effect with interferon-beta is the functional malfunction of the symptoms of an existing disease. Such damage is similar to that produced in MS patients because heat, fever or stress (Uhthoff phenomenon), usually appear within 24 hours of treatment, is more common in the early months of treatment, and may last several days. Specific symptoms that are sensitive to worsening are flexibility. Interferon-beta can also reduce the number of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), and affect liver function. In many cases, these effects are harmless and may reverse after discontinuation or reduction of treatment. However, the recommendation is that all patients should be monitored through laboratory blood analysis, including liver function tests, to ensure safe use of interferon.
Glatiramer acetate is generally well tolerated. The most common secondary effect with glatiramer acetate after skin problems is a post-injection reaction manifested by flushing, chest tightness, heart palpitations, shortness of breath, and anxiety, which usually lasts less than thirty minutes and requires no additional treatment.
Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; But the most dangerous side effect is the dose-related cardiac toxicity. Proper compliance with 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 risk is too great. It is recommended that mitoxantrone be stopped at the first signs of heart damage, infection or liver dysfunction during therapy. Cardiac problems (especially systolic dysfunction) occur in more than 10% of patients, whereas the prevalence of leukemia is 0.8%.
Immediately after its approval, natalizumab was withdrawn from the market by its producers after being linked with three cases of dangerous rare neurological conditions called progressive multifocal leukocephalopathy (PML). PML is an opportunistic infection with progressive neurologic symptoms caused by JC virus replication in the glial cells of the brain. All 3 initial cases took natalizumab in combination with interferon beta-1a. After a safety review, the drug was returned to the market in 2006 as monotherapy for MS under a special prescription program. As of May 2011, more than 130 cases of PML have been reported, all in patients who have been drinking natalizumab for more than a year. Although none of them use this drug in combination with other disease-modifying treatments, the use of previous MS treatments increases the risk of PML between 3 and 4-fold. The estimated prevalence of PML is 1.5 cases per thousand users of natalizumab. Approximately 20% of MS patients with PML die, while most of the rest are very poor.
During clinical trials, fingolimod causes side effects such as hypertension and bradycardia, macular edema, elevated liver enzymes or decreased lymphocyte levels. Teriflunomide is considered a very safe drug. However, there are reports of liver failure, and PML. Teriflunomide is also known to be harmful to the development of the fetus. The most common secondary effects of dimethyl fumarate during clinical trials are flushing and gastrointestinal problems. These problems are generally mild and occur more frequently during the first month of treatment. While dimethyl fumarate causes a decrease in the number of white blood cells and levels should be monitored in patients, no cases of opportunistic infections are reported during clinical trials. In addition, fumaric acid is also used to treat psoriasis, other autoinmune disorders, and there is long-term safety data from more than 14 years of use without further adverse secondary effects indication.
Clinically isolated syndrome
The earliest clinical presentation of RRMS is a clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During CIS, there is a subacute attack that demonstrates demyelination but the patient does not meet the criteria for the diagnosis of multiple sclerosis. Treatment with interferon or glatiramer acetate after the initial attack reduces the risk of definite MS clinical development.
Relapseing-remitting MS
Drugs are highly effective in reducing the number of attacks in RRMS and reducing brain-accumulated lesions, as measured by gadolinium-enhanced magnetic resonance imaging (MRI). Interferon and glatiramer acetate are roughly equivalent, reducing relapse by about 30% and their secure profile makes it a first-line treatment. However, not all patients are responsive to this therapy. It is known that 30% of MS patients are unresponsive to interferon beta. One of the factors associated with non-respondance is the presence of high levels of beta interferon neutralizing antibodies. Interferon therapy, and in particular interferon beta-1b, induces the production of neutralizing antibodies, usually within the second 6 months of treatment, in 5 to 30% of treated patients. In addition, a subset of RRMS patients with specific active MS, sometimes called "rapidly worsening MS" usually does not respond to immunomodulators and are treated with mitoxantrone or natalizumab.
Natalizumab and mitoxantrone are considered very effective both in terms of decreasing recurrence rates and stopping the development of disability, however, they are associated with harmful side effects that have caused them to be considered second-line treatment. Natalizumab divides the risk of relapse when compared with interferon, having an overall efficacy of over 70%. In addition, mitoxantrone is also very useful for reducing attacks and disabilities, but it is generally not considered a long-term therapy due to severe cardiac toxicity.
There is no official guidance on the use of oral medication that alters the disease because of their recent development. While some believe that they will probably reduce the use of first-line long-term safety treatments interferon and glatiramer acetate may slow this trend. It has been recommended that at present oral care should be especially offered in cases where the patient does not use the existing treatment due to a needle phobia or other reasons such as the perceived inefficiency of interferon and glatiramer acetate. They can also be used in patients who use natalizumab who have developed JC virus antibodies and therefore at an increased risk of PML. Dimethyl fumarate is potentially one of the most interesting oral medications because of the long-term data from the use of psoriasis leading to an excellent safety profile.
While further studies on the long-term effects of drugs are needed, especially for the latest treatments, existing data on the effects of interferon and glatiramer acetate show that long-term therapy that begins early is safe and associated with better outcomes.
Oral contraceptive pills have conflicting results from different studies on the effect of decreased recurrence rates in women with multiple sclerosis. Certain medications for MS symptoms, such as carbamazepine (used to treat seizures and pain) and modafinil (used to treat fatigue) can make oral contraceptive pills less effective.
Even with proper drug use, for various levels, most people with recurrent MS still have multiple attacks and many develop disability.
Secondary progressive_MS_and_progressive_relapsing_MS MS secondary progressive and progressive relapse MS
Advanced form care of MS is more difficult than recurrent MS. Various drugs have been used to try to slow the progression of the disease, with the most just results.
Mitoxantrone has shown a positive effect on people with progressive and progressive secondary relapse programs. This is quite effective in reducing disease progression and the frequency of relapse in people after two years. In 2007 it was the only drug approved in the US for progressive multiple and progressive secondary sclerosis; However, it causes cardiac toxicity depending on the dose limiting its long-term use. It is also not approved in Europe. Natalizumab has demonstrated efficacy and has been approved for secondary MS progressive with relapse. Studies on the use of Interferon-beta-1b in progressive secondary and progressive MS relapse do not support that slow the progression of the disease, although effective in reducing the number of recurrences.
Primary progressive MS
Treatment of progressive multiple progressive sclerosis (PPMS) is problematic because many patients do not respond to the available therapy, and no treatment has been specifically approved for use in this form of the disease. There are several trials that investigate the efficacy of different drugs for PPMS without positive results. The drugs tested included interferon beta, mitoxantrone, glatiramer acetate or riluzole. People with PPMS have also been included in trials of azathioprine, methotrexate, intravenous immunoglobulin, cyclophosphamide and hematopoietic stem cell transplantation.
Managing MS effects
Treatments that modify the disease only reduce the rate of disease progression but do not stop it. As multiple sclerosis develops, the symptoms tend to increase. The disease is associated with a variety of symptoms and functional deficits that result in a variety of progressive and disability disorders. This deficit management is very important.
Rehabilitation
Physical therapy
MS symptoms that can be increased include fatigue, suppleness, depression, bladder dysfunction, and neurological symptoms. These symptoms can be improved by physical therapy and treatment. Physical therapists may demonstrate strengthening exercises and ways to stretch; ultimately making daily tasks easier and reducing fatigue while muscle strength increases as flexibility increases. Drugs can help with fatigue, muscle tone (elasticity), depression, bladder dysfunction, and neurological symptoms. All the common symptoms among MS patients.
Both drug therapy and neurorehabilitation have shown relieve some of the symptoms, although they do not affect disease progression. For other symptoms, the efficacy of treatment is still very limited.
Neurorehabilitation
Although there are relatively few rehabilitation studies in MS, the effectiveness generally, when performed by a team of specialists, has been clearly demonstrated in other diseases such as stroke or head trauma. Like patients with neurological deficits, a multidisciplinary approach is the key to limiting and overcoming disability; but there are specific difficulties in determining 'core teams' because people with MS may need help from almost any profession or health service at some point. Neurologists are primarily involved in the diagnosis and continuous management of multiple sclerosis, and any exacerbations. A comprehensive rehabilitation process for patients with multiple sclerosis is generally administered by physiatrists. Allied treatment such as physiotherapy, speech and language therapy or occupational therapy can also help manage some symptoms and maintain quality of life. Treatment of neuropsychiatric symptoms such as emotional stress and clinical depression should involve mental health professionals such as therapists, psychologists, and psychiatrists, while neurologists can help to evaluate and manage cognitive deficits. This multidisciplinary approach has proven effective in increasing the level of activity and participation in multiple sclerosis. Because of the lack of randomized controlled studies, there is limited evidence of the overall efficacy of individual therapy disciplines, although there is good evidence that specific approaches, such as exercise, psychological therapy, especially cognitive behavioral approaches and effective energy conservation instructions. More specific psychological interventions appear to be useful in the treatment of depression, while evidence of effectiveness for other uses such as treatment of cognitive impairment or vocational counseling is less powerful. It is difficult to be specific about what type of rehabilitation is most beneficial because the therapy is tailored to meet the specific needs of the individual.
In terms of well-being, physical therapy focusing on gait training can be important to maximize MS patient participation through reduced fatigue during walking and daily life activities (ADLs). Most gait training is done on the ground (ie, in the gym or out on uneven ground), on a treadmill or, more rarely, using robot-assisted devices. The treadmill training supported by the body with the help of robots can be an effective treatment option in MS patients with severe walking disorders. Conversely, on-ground gait training may be most effective in increasing walking speed in MS patients with less severe disorders. Horse-assisted therapies such as horse riding therapy and hippotherapy are additional treatments that can positively affect gait, balance and quality of life in people with MS.
Historically, individuals with MS were advised against participation in physical activity as symptoms worsened. However, under the direction of an expert, participation in physical activity can be safe and has proven beneficial to people with MS. Research has supported the role of physical activity rehabilitation in improving muscle strength, mobility, mood, intestinal health, general conditioning and quality of life. Depending on the person, activities may include endurance training, walking, swimming, yoga, tai chi, and others. Determining the right and safe exercise program is a challenge and should be carefully individualized for everyone who ensures to take into account all contraindications and precautions.
Increased core temperatures, leading to increased presentation symptoms have been noted during exercise, due to variations in circadian body temperature throughout the day, and due to exposure to heat including warm temperatures, warm baths, sun baths, etc. Care should be taken not to overheat someone with MS during exercise. There is some evidence that cooling steps are effective in allowing greater exercise levels: cold water baths, cold water limb immersion, applying ice packs, and drinking cold drinks. This strategy is effective when trying to lower core temperature after exercise, and as a pre-cooling method prior to physical activity or heat exposure. The interaction between elevated core temperature and pathological demyelination can lead to a transient nerve conduction block that causes temporary physical and cognitive impairment. These effects translate to reduce patient safety and ADL performance, but there is a reasonable prevention strategy. Behavior strategies to minimize exposure to heat include doing physical activity outdoors when the temperature is cooler, or installing air conditioning.
Medical treatment for symptoms
Unfortunately, other symptoms, such as ataxia, tremors, or sensory loss, have no proven treatment.
Research
Direction of research on MS care including investigation of MS pathogenesis and heterogeneity; research on new treatments that are more effective, convenient, or tolerable for RRMS; the creation of therapy for progressive subtypes; strategy of neuroprotection; and seek effective symptomatic treatment.
Progress over the past decade has led to recent approval of some oral medications. These drugs are expected to gain popularity and frequency of use at the expense of existing therapies. Further oral drugs are still under investigation, the most notable example being laquinimod, announced in August 2012 to be the focus of third phase III trials after mixed results on the previous ones. Similarly, other studies aim to improve the efficacy and ease of use of existing therapies through the use of new preparations. As well as the interferon - 1 - 1a PEGylated version, which has a longer lifetime than normal interferon and therefore is studied if given in less frequent doses having the same efficacy of existing products. With the completion of a strong two-year study, this suggests that interferon PEGylated beta-1a has greater efficacy in reducing relapse rates and developmental disability compared with placebo for MS patients.
The monoclonal antibody, which is a drug of the same family as natalizumab, has also aroused high interest and research. Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab all show some benefits and are being studied as potential treatments for MS. However, its use is also accompanied by the emergence of dangerous side effects, the most important is opportunistic infections. Associated with this investigation are recent developments in tests on JC antibody viruses that may help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy while taking natalizumab. While monoclonal antibodies may have a role in the treatment of future illnesses, it is believed that it will be small due to the risks associated with them.
Another research strategy is to evaluate the combined effectiveness of two or more drugs. The main reason for politerapi in MS is that the treatments involved target different mechanisms of the disease and therefore its use is not always exclusive. In addition, synergies, in which drugs potentiate the effects of others are also possible. However, there may also arise important weaknesses such as opposite mechanisms of action or potentially destructive secondary effects. Although there are several clinical trials of combination therapy none have shown a positive enough effect to be considered as a viable treatment for MS.
Likewise, there is no effective treatment for this progressive variant of the disease. Many of the newest medications as well as those being developed may be evaluated as therapies for PPMS or SPMS, and their increased effectiveness when compared to existing drugs may ultimately lead to positive outcomes in this patient group.
Stem cell transplant
Finally, concerning specific neuroprotective and regenerative care, such as stem cell therapy, while their research is considered very important when they only promise a future therapy approach.
A 2018 study found promising results in recurrent MS but more research is needed.
CCSVI
In 2008, vascular surgeon Paolo Zamboni suggested that MS involves a vascular process that he calls chronic cerebrospinal venous insufficiency (CCSVI), in which the vein of the brain is limited. He found CCSVI in all 65 patients with MS in his studies. This theory gained important attention in the media and among people with MS, especially in Canada. Concern has risen with Zamboni research because it is not blind or controlled, and additional assumptions about the pathophysiology of the disease may not be supported by known data. Also further research has not found a relationship or found less powerful. This has raised objections to the CCSVI hypothesis from MS. The "release procedure" has been criticized for the possibility of causing serious complications and death while its benefits have not been proven. It is currently recommended not to use the proposed treatment unless its effectiveness is confirmed by controlled studies. Research on CCSVI has been traced rapidly but researchers can not confirm whether CCSVI has a role in causing MS.
Alternative care
Over 50% of MS patients can use complementary and alternative medicine, although the amount varies greatly depending on the definition of alternative medicine used. In the United States, it is estimated that 75% of the MS patient population uses at least one complementary and alternative treatment for symptom treatment and control. Evidence of effectiveness for such treatment in many cases is weak or non-existent. Examples of treatments used by patients include dietary supplements and regimens such as vitamin D, calcium, vitamin B12, and antioxidants. The reason behind the use of vitamin D supplementation is that studies show a link between vitamin D deficiency and increased MS development, as well as anti-inflammatory effects of vitamin D.
For antioxidant therapy, studies show that reactive oxidative species lead to the formation of multiple sclerosis lesions in which antioxidants can help induce neuroprotective and immunomodulatory effects. Perhaps the most obvious (worse) disease modification factor is smoking, and therefore quitting smoking should be considered.
Other alternative treatments include relaxation techniques such as yoga, herbal medicine (including the use of medical marijuana), hyperbaric oxygenation, infection with hookworm (commonly known as worm therapy) and bee venom, reflexology or acupuncture therapy. Regarding user characteristics, they are more often women, have MS for longer periods and tend to be more disabled. In addition, they also have lower levels of satisfaction with conventional healthcare.
References
Further reading
Clinical guidelines: clinical guidelines are documents with the aim of guiding decisions and criteria in a particular field of health, as defined by an authoritative examination of the current evidence (evidence-based medicine).
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The Royal College of Physicians (2004). Multiple Sclerosis. National clinical guidelines for diagnosis and management in primary and secondary care . Salisbury, Wiltshire: Sarour ColourView Group. ISBN: 1-86016-182-0. Ã, Full text is free. Retrieved on 2007-10-01. - Multiple sclerosis. Understand NICE guides. Information for people with multiple sclerosis, their families and caregivers, and the public . London: National Institute of Clinical Excellence. 2003. ISBNÃ, 1-84257-445-0. Ã, Full text free (2003- 11-26). Obtained in 2007-10-25.
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