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Category Archives: Batten Disease Treatment
Posted: December 16, 2017 at 7:43 pm
What Is MS?
Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system attacks its own central nervous system (the brain and spinal cord). In MS, the immune system attacks and damages or destroys the myelin, a substance that surrounds and insulates the nerves. The myelin destruction causes a distortion or interruption in nerve impulses traveling to and from the brain. This results in a wide variety of symptoms.
Multiple sclerosis is estimated to affect 2.3 million people worldwide. Most people are diagnosed between the ages of 20 to 50, though it can also occur in young children and the elderly.
Multiple sclerosis is three times more common in women than in men. In addition, nearly all women afflicted with MS get the condition before menopause. This could mean that hormones play an important role in the disease’s development.
Usually, MS in men is more severe than it is in women. They typically get MS in their 30s and 40s, just as their testosterone levels begin to decline.
Although MS is more common in women than men overall, one form of the disease contradicts this pattern. People with primary progressive (PP) MS are about as likely to be male as female. (The four main types of MS are described later).
People who smoke are more likely to develop MS, and to develop it more severely and with a faster progression.
MS is more prevalent among Caucasians than other ethnicities. MS is believed to have a genetic component as people with a first-degree relative with the disease have a higher incidence than the general population.
The exact cause of multiple sclerosis is unknown, but it is believed to be some combination of immunologic, environmental, infectious, or genetic factors. Researchers are examining the possible role of viruses in the cause of MS, but this is still unproven.
A range of scientific disciplines are being employed to find the cause of MS. Immunologists, epidemiologists and geneticists are all working to narrow in on the cause of multiple sclerosis.
One unusual finding that has emerged is that MS occurs more frequently the farther people live from the equator. This suggests a possible connection between the condition and vitamin D deficiency.
Multiple sclerosis (MS) is an autoimmune disorder where the immune system mistakenly perceives its own myelin (the sheath around the nerves) as an intruder and attacks it, as it would a virus or other foreign infectious agent. To understand how this harms the body, it helps to understand how nerves work.
A nerve can be seen by the naked eye, but it is made up of hundreds or even thousands of microscopic nerve fibers wrapped by connective tissue. Nerves conduct messages to and from the brain by way of electrical impulses.
Often the nerve fibers that make up a nerve are all individually wrapped in myelin, a protective sheath that causes electric impulses to conduct down the nerve much faster than fibers that lack myelin. (The same principle is used to improve electric wires by covering them with a plastic outer layer.)
In multiple sclerosis, the immune system’s T cells attack the myelin sheath. By attacking myelin, the immune system in a person with MS causes inflammation and degeneration of the myelin that can lead to demyelination, or stripping of the myelin covering of the nerves. It can also cause scarring (the sclerosis in the name multiple sclerosis). This causes electrical impulses to travel more slowly along the nerves resulting in deterioration of function in body processes such as vision, speech, walking, writing, and memory.
While multiple sclerosis is not hereditary, genetics are believed to play a role. In the U.S., the chances of developing MS are one in 750. Having a first-degree relative (parent, sibling) increases the risk to up to 5%. An identical twin of someone with MS has a 25% chance of being diagnosed with the disorder. It is thought there is an outside trigger and genetics only makes certain people susceptible to getting MS. which is why the disease is not considered hereditary. Genes may make a person more likely to develop the disease, but it is believed that there still is an additional outside trigger that makes it happen.
There are four different types of multiple sclerosis that have been identified and each type can have symptoms ranging from mild to severe. The different types of MS can help predict the course of the disease and the patient’s response to treatment. The four types of MS are discussed on the next four slides.
Relapsing-remitting multiple sclerosis (RR-MS) is the most common type of MS, affecting about 85% of MS sufferers. RR-MS is defined by inflammatory attacks on the myelin and nerve fibers causing a worsening of neurologic function. Symptoms vary from patient to patient, and symptoms can flare up (called relapses or exacerbations) unexpectedly, and then disappear (remission).
Primary-progressive multiple sclerosis (PP-MS) is characterized by steady worsening of neurologic functioning, without any relapses or remissions. There may be occasional plateaus, but overall the progression of the disability is continuous. This form of MS occurs equally in men and women, and the age of onset is about 10 years later than in relapsing-remitting MS.
Secondary-progressive multiple sclerosis (SP-MS) is a form of MS that follows relapsing-remitting MS. The majority of people diagnosed with RR-MS will eventually transition to having SP-MS. After a period of relapses (also called attacks, or exacerbations) and remissions the disease will start to progress steadily. People with SP-MS may or may not experience remissions.
Progressive-relapsing multiple sclerosis (PR-MS) is the least common form of MS, occurring in about 5% of MS patients. People with PR-MS experience steady disease progression and worsening neurological function as seen in primary-progressive multiple sclerosis (PP-MS), along with occasional relapses like people with relapsing-remitting multiple sclerosis (RR-MS).
Symptoms of multiple sclerosis may be single or multiple and may range from mild to severe in intensity and from short to long in duration.
Multiple sclerosis is often difficult to diagnose as symptoms are so varied and can resemble other diseases. It is often diagnosed by a process of exclusion that is, by ruling out other neurological diseases so the diagnosis of MS may take months to years. A physician will do a complete history and neurological exam, along with tests to evaluate mental, emotional and language functions, strength, coordination, balance, reflexes, gait, and vision.
One of the main ways to diagnose multiple sclerosis is an MRI (magnetic resonance imaging) scan. Characteristic areas of demyelination will show up as lesions on an MRI scan. On the left is a brain MRI scan of a 35-year-old man with relapsing remitting multiple sclerosis that reveals multiple lesions with high T2 signal intensity and one large white matter lesion. The right image shows the cervical spinal cord of a 27-year-old woman representing a multiple sclerosis demyelination and plaque (see arrow).
There are several aspects to treating multiple sclerosis.
Treatment for multiple sclerosis may include drugs to manage attacks, symptoms, or both. Many medications carry the risk of some side effects so patients need to manage their treatment with their doctors.
Corticosteroids are drugs that reduce inflammation in the body and affect the function of the immune system. They are often used to manage MS attacks, but can have numerous side effects.
There are currently 10 medications approved for disease modification
Many medications are used to treat and manage symptoms associated with multiple sclerosis. Here are some common multiple sclerosis symptoms, followed by the medical treatments often used to treat them.
Continued from the last slide, here are some common multiple sclerosis symptoms, followed by the medical treatments often used to treat them.
There has been a lot of progress over the years in managing multiple sclerosis, and research is ongoing into new therapies. There are several new avenues of research including techniques to allow brain cells to generate new myelin or prevent the death of nerves. Other research involves use of stem cells that might be implanted into the brain or spinal cord to regrow the cells that have been destroyed by the disease. Some therapies being investigated include methods that would improve the nerve impulse signals. In addition the effects of diet and the environment on multiple sclerosis are being investigated.
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Multiple Sclerosis (MS) Symptoms and Treatment
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Pill for Relapsing MS | RRMS Treatment | GILENYA (fingolimod)
Posted: December 1, 2017 at 1:43 pm
Disease-modifying therapies have shown beneficial effects in patients with relapsing MS, including reduced frequency and severity of clinical attacks. These agents appear to slow the progression of disability and the reduce accumulation of lesions within the brain and spinal cord. The disease-modifying agents for MS (DMAMS) currently approved for use by the US Food and Drug Administration (FDA) include the following:
Fingolimod, teriflunomide, and dimethyl fumarate are administered orally; natalizumab and mitoxantrone are administered by intravenous infusion; interferon beta-1a (Avonex) is administered intramuscularly; and interferon beta-1a (Rebif), interferon beta-1b, and glatiramer acetate are administered by subcutaneous injection.
Note that in January 2013, the FDA approved a single-use autoinjector (Rebidose, EMD Serono Inc./Pfizer Inc) for self-injection of interferon beta-1a (Rebif) in patients with relapsing forms of MS.  The ease of use, patient satisfaction and acceptability, and functional reliability of the Rebidose are supported by data from a 12-week open-label, single-group study in 109 patients. The autoinjector is available in a monthly pack in 22 and 44 g doses and in a titration pack. 
Patient lifestyle, patient tolerance, and adverse effects of injections should be considered in the choice of DMAMS. To a certain extent, health-care-provider preference and experience with the medications also play a role in determining which drug is appropriate in a particular situation.
Acase-control study from the MSBase longitudinal cohort found that MSpatients who are well controlled on injectable drugs but switch to oral therapies aren’t at greater risk of early relapse.This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy.Results showedthere were no differences in the rate of first relapse or disability progression over the first 6 months. 
The first medication approved by the FDA for MS, in 1993, was interferon beta-1b (Betaseron, Extavia). It is indicated for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode of MS and have MRI features consistent with MS. 
In a double-blind, placebo-controlled trial of 372 patients with relapsing-remitting MS, interferon beta-1b (8 million IU every other day) decreased the frequency of relapses by 34% after 2 years. In treated patients, the MRI T2 lesion burden increased 3.6% over 5 years, compared with 30.2% in the placebo group. At 5 year follow-up, the incidence of disease progression was lower in the interferon beta-1b group compared with the placebo group (35% versus 45%). 
Interferon beta-1b is administered every other day subcutaneously by self-injection. The most frequently reported adverse reactions include asthenia, depression, flu-like symptoms, hypertonia, increased liver enzymes, injection site reactions, leukopenia, and myasthenia. Interferon beta-1b can be coadministered with analgesics or antipyretics to help with the occurrence of flu-like symptoms. 
In a study of 301 patients with relapsing-remitting disease who were given weekly intramuscular injections (6 million U [30 g]) of interferon beta-1a (Avonex), the annual exacerbation rate decreased 29%.  Over 2 years, disease progression occurred in 21.9% of patients in the interferon beta-1a group and 34.9% of those in the placebo group. In addition, MRI data showed a decrease in the mean lesion volume and number of enhancing lesions in the interferon beta-1a group.
In Europe and Canada, higher doses of subcutaneous interferon beta-1a (Rebif) were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study.  The dose-comparison study of interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 g/wk and a 33% reduction in those receiving 132 g/wk. This study, of 560 patients with relapsing-remitting disease, also demonstrated a significant reduction in accrual of disability and MRI lesion burden with the higher dose. 
In 2002, the FDA approved interferon beta-1a (Rebif) in 22 g and 44 g formulations given 3 times per week.
In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 g 3 times weekly (Rebif) than with 30 g once weekly (Avonex) (25% vs 37%).  In addition, the mean number of active unique MRI lesions per patient per scan was lower in the Rebif than in the Avonex group (0.17 vs 0.33). Patients on Rebif experienced fewer flulike symptoms, but more injection site reactions, hepatic function disorders, and white blood cell disorders. Rebif-treated patients had a higher incidence of neutralizing antibodies (Nabs). A reduced MRI effect was noted for Nab-positive patients on Rebif compared with Nab-negative patients on Rebif. However, Nab-positive Rebif patients had better clinical and comparable MRI results to Avonex patients. 
In a subsequent crossover phase of the EVIDENCE trial, patients who were originally randomized to low-dose weekly treatment were switched to the high-dose 3-times-weekly regimen for an additional 8 months. These patients demonstrated significant reductions in mean relapse rates compared with the last 6 months on Avonex (P
In patients with uncontrolled depression, interferons should be used with caution. Glatiramer may be an appropriate choice in such cases.
Peginterferon beta-1a (Plegridy) was approved by the FDA in August 2014 for treatment of relapsing forms of MS. It is the first pegylated interferon approved for MS and can be self-administered by SC injection every 2 weeks. 
Approval was based on results from the ADVANCE trial of >1,500 patients with MS over a 2-year period. In the first year of the trial, peginterferon beta-1a dosed every 2 weeks significantly reduced annualized relapse rate (ARR) at 1 year by 36% compared with placebo (P = 0.0007). Risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, was also reduced with peginterferon beta-1a by 38% (P = 0.0383) compared with placebo. Peginterferon beta-1a also significantly reduced the number of new gadolinium-enhanced [Gd+] lesions by 86% (P
Glatiramer acetate (Copaxone) is a synthetic polypeptide approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetates mechanism of action is unknown, but this agent could theoretically modify some of the immune processes thought to be involved in the pathogenesis of MS. 
In a double-blind trial that included 251 patients with relapsing-remitting MS (RRMS), treatment with glatiramer acetate 20 mg SC once daily resulted in a 29% reduction in the relapse rate over 2 years; a positive effect on disability was suggested but this effect was not shown on predetermined disability measures in this trial.  For this reason, glatiramer acetate is not approved by the FDA for slowing disability progression in MS. A follow-up open-label study demonstrated continued efficacy of glatiramer over 6 years. 
In January 2014, a higher dose and lower-frequency dosage regimen of glatiramer was approved. The 20-mg/mL SC injection is specific for the original once-daily regimen, whereas the new 40-mg/mL SC injection is specific for the 3-times-per-week dosage regimen. Approval for the new regimen was based on the phase 3 Glatiramer Acetate Low-Frequency Administration (GALA) study. The GALA trial included 1,404 patients and showed that treatment with 40 mg SC 3 times/wk reduced mean annualized relapse rates by 34% compared with placebo (0.331 vs 0.505; P
Natalizumab (Tysabri) is a humanized monoclonal antibody that binds to the adhesion molecule alpha-4 integrin, inhibiting its adherence to its receptors. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is generally used in patients who have not responded to a first-line disease-modifying therapy or who have very active disease. 
In a placebo-controlled clinical trial, the use of natalizumab reduced the relapse rate (68%) and progression of disability (42%) over a period of 2 years.  Natalizumab is given as a 300 mg IV infusion over 1 hour every 4 weeks.
Natalizumab has been associated with progressive multifocal leukocephalopathy (PML), an opportunistic infection of the brain that can lead to death or severe disability. The risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity.
Three cases of PML associated with natalizumab use prompted its temporary withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as Tysabri Outreach Unified Commitment to Health (TOUCH). Use of natalizumab is limited to patients, physicians, and infusion centers that are registered with the TOUCH program.
A retrospective review of 906 patients from 5 clinical trials by Cadavid et al found that after treatment with natalizumab, disabled patients with relapsing-remitting MS were more likely to complete a timed 25-foot walk significantly faster; responders took an average of 2444% less time to walk 25 ft than nonresponders. Natalizumab also appeared to have some efficacy in disabled patients with SPMS. 
Fingolimod (Gilenya) is the first oral disease modifying treatment for relapsing forms of MS approved by the FDA. Like other disease-modifying agents for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day. 
Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate receptors, which are a subset of a larger family of cell-surface, G proteincoupled receptors that mediate the effects of bioactive lipids known as lysophospholipids. Lysophospholipids are membrane-derived bioactive lipid mediators that can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.
The mechanism of action of fingolimod is incompletely understood but appears to be fundamentally different from other MS medications. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Fingolimod promotes sequestration of lymphocytes within the lymph nodes, which may reduce lymphocyte migration into the central nervous system. 
Fingolimod can be associated with macular edema, pulmonary dysfunction, and cardiac adverse effects.
In 2012, the FDA determined that new label changes are required for fingolimod. Within an hour of administering fingolimod, heart rate decreases are noted. The nadir in heart rate typically occurs at 6 hours, but it can be observed up to 24 hours after the first dose in some patients. Because of its cardiac adverse effects, the first dose of fingolimod should be administered in a setting in which resources are available to appropriately manage symptomatic bradycardia. Therefore, all patients started on fingolimod must be monitored for at least 6 hours following the first dose. Additionally, an ECG should be performed prior to dosing fingolimod, blood pressure and pulse should be monitored hourly, and an ECG should be performed at the end of the observation period.
Additional observation beyond 6 hours should be instituted if bradycardia occurs and until the finding has resolved in the following situations: the heart rate 6 hours post dose is less than 45 beats per minute, the heart rate 6 hours post dose is the lowest value observed post dose, or the ECG 6 hours post dose shows new-onset second-degree or higher (atrioventricular) AV block.
Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy (described above) should be repeated after the second dose of fingolimod.
Fingolimod is now contraindicated in patients with recent myocardial infarction, unstable angina, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III/IV heart failure; history or presence of Mobitz type II second- or third-degree AV block or sick-sinus syndrome, unless the patient has a functioning pacemaker; baseline QTc interval greater than or equal to 500 ms; or treatment with class Ia or class III antiarrhythmic drugs.
The following are recommendations for the use of fingolimod in patients with preexisting cardiovascular conditions:
Patients with some preexisting conditions (eg, ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, and sinoatrial heart block) may poorly tolerate the fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose of fingolimod.
Prior to treatment, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such an evaluation, and, if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose.
The following are recommendations for the use of fingolimod with concomitant medications that slow the heart rate or AV conduction:
Experience is limited when coadministered with drugs that slow the heart rate or AV conduction (eg, beta-blockers, heart ratelowering calcium channel blockers such as diltiazem, verapamil, or digoxin).
Because the initiation of fingolimod treatment is also associated with slowing of the heart rate, coadministration of other drugs that cause bradycardia may be associated with severe bradycardia or heart block.
The possibility to switch to drugs that do not slow the heart rate or AV conduction should be evaluated by the prescribing physician before initiating fingolimod. In patients who cannot switch, overnight continuous ECG monitoring is recommended after the first dose.
The reduction of peripheral lymphocyte count by fingolimod can possibly lead to an increased risk of infection. Reversible, asymptomatic elevations of liver enzymes may also occur. Other adverse reactions that have been commonly reported include headache, diarrhea, ALT/AST elevations and back pain.
If an MS patient is being switched from natalizumab to fingolimod oral therapy, a washout period of 8 weeks or less is advisable. In an observational cohort study involving 350 such patients, those with a washout time longer than 2 months had a higher risk of relapse; in a second study involving 142 patients, shorter washout periods of 8 or 12 weeks were associated with fewer active lesions and less disease recurrence than was a washout period of 16 weeks. [94, 95, 96]
Teriflunomide (Aubagio) was approved by the FDA in September 2012 for the treatment of patients with relapsing forms of MS (approved tablet forms are 7 mg and 14 mg). The prescribing information contains a black box warning for the risks of hepatotoxicity and teratogenicity (pregnancy category X). It is an oral pyrimidine synthesis inhibitor for treatment of relapsing forms of MS. Approval was based on a randomized trial (TEMSO) of 1088 patients with a minimum of 1 relapse in the previous year or 2 relapses in the last 2 years. Teriflunomide was shown to significantly reduce annualized relapse rates (31% relative risk reduction compared with placebo [P
Phase III of the TEMSO studyfound that teriflunomide significantly slowed brain volume loss compared with placebo over 2 years in patients with relapsing MS. Data obtained from MRI were used to assess patients treated with 14 mgor 7 mg of the drug, or placebo. By month 12, median percent reduction from baseline in brain volume was 0.39, 0.40, and 0.61 for teriflunomide 14 mg, 7 mg, and placebo, respectively. 
The most common adverse reactions of teriflunomide are headache, alopecia, diarrhea, nausea, increased ALT, influenza, and paresthesias.
Teriflunomide can predispose to infections (due to a decrease in the white blood cell count that remains throughout treatment) and increases in blood pressure. To assess safety, it is recommended to obtain transaminase levels, bilirubin levels, and a CBC count within 6 months before initiation; screen for latent tuberculosis infection with a tuberculin skin test; and check the blood pressure before the first dose and periodically thereafter.
Teriflunomide is contraindicated in patients with severe hepatic impairment, patients who are pregnant or women of childbearing potential not using reliable contraception, or patients on current treatment with leflunomide. If liver injury occurs, teriflunomide should be immediately discontinued and an accelerated elimination procedure using either activated charcoal or cholestyramine should be initiated. Monitor liver tests weekly until normalized.
Upon discontinuing teriflunomide and based on the teratogenicity risk, it is recommended that all women of child-bearing potential undergo the accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to pose minimal risk. Without an accelerated elimination procedure, it takes teriflunomide on average of 8 months (and up to 2 y) to reach plasma concentrations less than 0.02 mg/L.
Teriflunomide or its parent compound, leflunomide, can also be associated with peripheral neuropathy and acute renal failure, hyperkalemia, hypophosphatemia, serious skin reactions, and interstitial lung disease.
Other trials for teriflunomide (TOWER) are completed (not yet published) or ongoing. Results from the TENERE study (n= 324) observed similar efficacy and safety between teriflunomide and interferon beta-1a for relapsing forms of MS.  Another study of teriflunomide added to beta interferon therapy is currently ongoing. 
Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of MS. The active metabolite, monomethyl fumarate (MMF), activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene.
FDA approval for DMF in adults with relapsing forms of multiple sclerosis [15, 16] was based on data from 2 phase 3 studies, the DEFINE  and CONFIRM  studies, that involved more than 2600 patients. An ongoing extension study (ENDORSE) includes some patients that have been followed for longer than 4 years.
In the DEFINE trial, dimethyl fumarate significantly reduced  : (1) the proportion of patients who relapsed by 49%, (2) the annualized relapse rate by 53%, and (3) the 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), by 38% relative to placebo at 2 years. In the CONFIRM study, dimethyl fumarate significantly reduced the annualized relapse rate by 44% and the proportion of patients who relapsed by 34% compared with placebo at 2 years.  Although not statistically significant, dimethyl fumarate also showed a 21% reduction in the CONFIRM trial’s 12-week confirmed disability progression.  Both studies also showed that dimethyl fumarate significantly reduced lesions in the brain relative to placebo, as measured by magnetic resonance imaging. [17, 18]
Alemtuzumab (Lemtrada) was approved by the FDA in November 2014 for relapsing forms of multiple sclerosis. Because of the risk for severe autoimmune adverse effects, it is reserved for use in patients who have an inadequate response to 2 or more other drugs for MS. Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis.
Approval was based on 2 randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance.  In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was also significantly slowed.  The clinical development program for alemtuzumab use in MS involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up. 
In a single-arm, open-label study in 45 patients with MS that was refractory to treatment with interferon, alemtuzumab effectively reduced relapse rates and improved clinical scores. 
In subsequent subgroup analysis of 101 MS patients with multiple recent relapses and MRI-detected gadolinium-enhancing lesions, researchers found alemtuzumab to be more effective than interferon.  The study showed that after 2 years, almost a quarter of patients had achieved a disease activityfree state, whereas none of those treated with interferon and reached such a state.
In this study, disease activityfree was defined as no relapse, no sustained accumulation of disability (SAD) as measured by the Expanded Disability Status Scale (EDSS), and no new gadolinium-enhancing lesions or new or enlarging T2-hyperintense lesions.  Relapses occurred in 35.8% of the alemtuzumab group and 60.0% of the interferon group. Respective percentages for SAD were 7.4% and 17.5%; for gadolinium-enhancing lesion activity, 22.1% and 52.5%; and for T2 lesion activity, 60.0% and 92.5%.
Daclizumab (Zinbryta) was approved by the FDA in May 2016 for relapsing forms of MS. It is a humanized monoclonal antibody that binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25). These subunits are expressed at high levels on T-cells that become abnormally activated in multiple sclerosis. Approval was based on results from 2 trials, DECIDE and SELECT, in which daclizumab 150 mg was administered SC every 4 wk in people with relapsing-remitting MS. In the DECIDE trial, daclizumab was compared with interferon beta-1a (30 mcg/wk IM). The annualized relapse rate was lower with daclizumab than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab; P
Ocrelizumab (Ocrevus) was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for RRMS was based on the OPERA 1 and 2 phase 3 trials that included about 800 patients with RMS who received intravenous ocrelizumab or subcutaneous interferon-beta1a. Results showed the annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P
Further analysis of participants from the OPERA studies in October 2017 showed that ocrelizumab may improve visual outcomes in adult patients with RMS. Patients who received the drug intravenously had significantly greater improvement on low-contrast letter acuity (LCLA) tests compared with those who received subcutaneous interferon -1a. Within the visually impaired subgroup, significantly more patients receivingocrelizumab showed at least a 7-letter improvement at 12 weeks compared to the interferon group. 
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Multiple Sclerosis Treatment & Management: Approach …
Posted: at 1:43 pm
Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, trouble with sensation, or trouble with coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially as the disease advances.
While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors such as being triggered by a viral infection. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.
There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Medications used to treat MS, while modestly effective, can have side effects and be poorly tolerated.Physical therapy can help with people’s ability to function. Many people pursue alternative treatments, despite a lack of evidence. The long-term outcome is difficult to predict, with good outcomes more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.Life expectancy is on average 5 to 10 years lower than that of an unaffected population.
Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. In 2015, about 2.3 million people were affected globally with rates varying widely in different regions and among different populations. That year about 18,900 people died from MS, up from 12,000 in 1990. The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men. MS was first described in 1868 by Jean-Martin Charcot. The name multiple sclerosis refers to the numerous scars (scleraebetter known as plaques or lesions) that develop on the white matter of the brain and spinal cord. A number of new treatments and diagnostic methods are under development.
A person with MS can have almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common. The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, blurred vision,very pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others. Difficulties thinking and emotional problems such as depression or unstable mood are also common.Uhthoff’s phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte’s sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS. The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research.
The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (1015% of cases). A combination of these two patterns may also occur or people may start in a relapsing and remitting course that then becomes progressive later on. Relapses are usually not predictable, occurring without warning. Exacerbations rarely occur more frequently than twice per year. Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer. Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.Stress may also trigger an attack. Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases. Overall, pregnancy does not seem to influence long-term disability. Many events have been found not to affect relapse rates including vaccination, breast feeding, physical trauma, and Uhthoff’s phenomenon.
The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents. Theories try to combine the data into likely explanations, but none has proved definitive. While there are a number of environmental risk factors and although some are partly modifiable, further research is needed to determine whether their elimination can prevent MS.
MS is more common in people who live farther from the equator, although exceptions exist. These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Mori, and Canada’s Inuit, as well as groups that have a relatively high risk close to the equator such as Sardinians, inland Sicilians,Palestinians and Parsis. The cause of this geographical pattern is not clear. While the north-south gradient of incidence is decreasing, as of 2010 it is still present.
MS is more common in regions with northern European populations and the geographic variation may simply reflect the global distribution of these high-risk populations. Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation. A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life. Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region’s risk to MS. If migration takes place after age 15, however, the person retains the risk of his home country. There is some evidence that the effect of moving may still apply to people older than 15.
MS is not considered a hereditary disease; however, a number of genetic variations have been shown to increase the risk. Some of these genes appear to have higher levels of expression in microglial cells than expected by chance. The probability of developing the disease is higher in relatives of an affected person, with a greater risk among those more closely related. In identical twins both are affected about 30% of the time, while around 5% for non-identical twins and 2.5% of siblings are affected with a lower percentage of half-siblings. If both parents are affected the risk in their children is 10 times that of the general population. MS is also more common in some ethnic groups than others.
Specific genes that have been linked with MS include differences in the human leukocyte antigen (HLA) systema group of genes on chromosome 6 that serves as the major histocompatibility complex (MHC). That changes in the HLA region are related to susceptibility has been known since the 1980s, and additionally this same region has been implicated in the development of other autoimmune diseases such as diabetes type I and systemic lupus erythematosus. The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11. Overall, it has been estimated that HLA changes account for between 20 and 60% of the genetic predisposition. Modern genetic methods (genome-wide association studies) have discovered at least twelve other genes outside the HLA locus that modestly increase the probability of MS.
Many microbes have been proposed as triggers of MS, but none have been confirmed. Moving at an early age from one location in the world to another alters a person’s subsequent risk of MS. An explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare one, is related to the disease. Proposed mechanisms include the hygiene hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective, the disease being a response to a late encounter with such agents. The prevalence hypothesis proposes that the disease is due to an infectious agent more common in regions where MS is common and where in most individuals it causes an ongoing infection without symptoms. Only in a few cases and after many years does it cause demyelination. The hygiene hypothesis has received more support than the prevalence hypothesis.
Evidence for a virus as a cause include the presence of oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelination encephalomyelitis, and the occurrence of demyelination in animals caused by some viral infections.Human herpes viruses are a candidate group of viruses. Individuals having never been infected by the EpsteinBarr virus are at a reduced risk of getting MS, whereas those infected as young adults are at a greater risk than those having had it at a younger age. Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing, others believe that there is no contradiction, since it is a first encounter with the causative virus relatively late in life that is the trigger for the disease. Other diseases that may be related include measles, mumps and rubella.
Smoking has been shown to be an independent risk factor for MS.Stress may be a risk factor although the evidence to support this is weak. Association with occupational exposures and toxinsmainly solventshas been evaluated, but no clear conclusions have been reached.Vaccinations were studied as causal factors; however, most studies show no association. Several other possible risk factors, such as diet and hormone intake, have been looked at; however, evidence on their relation with the disease is “sparse and unpersuasive”.Gout occurs less than would be expected and lower levels of uric acid have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown.
The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease. Additionally, MS is believed to be an immune-mediated disorder that develops from an interaction of the individual’s genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous system by a person’s own immune system.
The name multiple sclerosis refers to the scars (sclerae better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.
To be specific, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining a fatty layerknown as the myelin sheathwhich helps the neurons carry electrical signals (action potentials). This results in a thinning or complete loss of myelin and, as the disease advances, the breakdown of the axons of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals. A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell’s myelin sheath. Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons. These scars are the origin of the symptoms and during an attack magnetic resonance imaging (MRI) often shows more than ten new plaques. This could indicate that there are a number of lesions below which the brain is capable of repairing itself without producing noticeable consequences. Another process involved in the creation of lesions is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons. A number of lesion patterns have been described.
Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocyte that plays an important role in the body’s defenses. T cells gain entry into the brain via disruptions in the bloodbrain barrier. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called “autoreactive lymphocytes”.
The attack of myelin starts inflammatory processes, which triggers other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the bloodbrain barrier in turn causes a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins. Inflammation can potentially reduce transmission of information between neurons in at least three ways. The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.
The bloodbrain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.Gadolinium cannot cross a normal BBB and, therefore, gadolinium-enhanced MRI is used to show BBB breakdowns.
Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing. It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems. The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis with the Schumacher and Poser criteria being of mostly historical significance.
Clinical data alone may be sufficient for a diagnosis of MS if an individual has had separate episodes of neurological symptoms characteristic of the disease. In those who seek medical attention after only one attack, other testing is needed for the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast agent to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation. Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 7585% of people with MS. The nervous system in MS may respond less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual- and sensory-evoked potentials.
While the above criteria allow for a non-invasive diagnosis, and even though some state that the only definitive proof is an autopsy or biopsy where lesions typical of MS are detected, currently, as of 2017, there is no single test (including biopsy) that can provide a definitive diagnosis of this disease
Several phenotypes (commonly termed types), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. Currently, the United States National Multiple Sclerosis Society and the Multiple Sclerosis International Federation, describes four types of MS (revised in 2013):
Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign MS, although people will still build up some degree of disability in the long term. On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons experiencing CIS later develop MS.
Primary progressive MS occurs in approximately 1020% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.
Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19years.
Other, unusual types of MS have been described; these include Devic’s disease, Balo concentric sclerosis, Schilder’s diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases. Multiple sclerosis behaves differently in children, taking more time to reach the progressive stage. Nevertheless, they still reach it at a lower average age than adults usually do.
Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence.
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy, with oral corticosteroids seeming to have a similar efficacy and safety profile. Although, in general, effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.
As of 2017, eleven disease-modifying medications have been approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS). They are interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide,dimethyl fumarate,alemtuzumab,daclizumab, and ocrelizumab.
Their cost effectiveness as of 2012 is unclear. In May 2016 the FDA approved daclizumab for the treatment of relapsing multiple sclerosis in adults, with requirements for postmarketing studies and submission of a formal risk evaluation and mitigation strategy. In March 2017 the FDA approved ocrelizumab, a humanized anti-CD20 monoclonal antibody, as a treatment for RRMS, with requirements for several Phase IV clinical trials.
In RRMS they are modestly effective at decreasing the number of attacks. The interferons and glatiramer acetate are first-line treatments and are roughly equivalent, reducing relapses by approximately 30%. Early-initiated long-term therapy is safe and improves outcomes. Natalizumab reduces the relapse rate more than first-line agents; however, due to issues of adverse effects is a second-line agent reserved for those who do not respond to other treatments or with severe disease. Mitoxantrone, whose use is limited by severe adverse effects, is a third-line option for those who do not respond to other medications. Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS. Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults. The role of some newer agents such as fingolimod, teriflunomide, and dimethyl fumarate, as of 2011, is not yet entirely clear.
As of 2017, rituximab was widely used off-label to treat RRMS.
As of 2017, rituximab has been widely used off-label to treat progressive primary MS. In March 2017 the FDA approved ocrelizumab, as a treatment for primary progressive MS, the first drug to gain that approval, with requirements for several Phase IV clinical trials.
As of 2011[update], only one medication, mitoxantrone, has been approved for secondary progressive MS. In this population tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.
The disease-modifying treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections). Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons may produce flu-like symptoms; some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes. More dangerous but much less common are liver damage from interferons,systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone, and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).
Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes or a reduction in lymphocyte levels. Tentative evidence supports the short-term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain. There have also been reports of liver failure and PML with its use and it is dangerous for fetal development. Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems. While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.
Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease. Some symptoms have a good response to medication, such as an unstable bladder and spasticity, while others are little changed. For neurologic problems, a multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a ‘core team’ as many health services may be needed at different points in time. Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level. There is limited evidence for the overall efficacy of individual therapeutic disciplines, though there is good evidence that specific approaches, such as exercise, and psychology therapies, in particular cognitive behavioral approaches are effective.
Over 50% of people with MS may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined. The evidence for the effectiveness for such treatments in most cases is weak or absent. Treatments of unproven benefit used by people with MS include dietary supplementation and regimens, vitamin D,relaxation techniques such as yoga,herbal medicine (including medical cannabis),hyperbaric oxygen therapy,self-infection with hookworms, reflexology, acupuncture, and mindfulness. Regarding the characteristics of users, they are more frequently women, have had MS for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare.
The expected future course of the disease depends on the subtype of the disease; the individual’s sex, age, and initial symptoms; and the degree of disability the person has. Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.
The average life expectancy is 30 years from the start of the disease, which is 5 to 10 years less than that of unaffected people. Almost 40% of people with MS reach the seventh decade of life. Nevertheless, two-thirds of the deaths are directly related to the consequences of the disease.Suicide is more common, while infections and other complications are especially dangerous for the more disabled. Although most people lose the ability to walk before death, 90% are capable of independent walking at 10 years from onset, and 75% at 15 years.[needs update?]
MS is the most common autoimmune disorder of the central nervous system. As of 2010, the number of people with MS was 22.5million (approximately 30 per 100,000) globally, with rates varying widely in different regions. It is estimated to have resulted in 18,000 deaths that year. In Africa rates are less than 0.5 per 100,000, while they are 2.8 per 100,000 in South East Asia, 8.3 per 100,000 in the Americas, and 80 per 100,000 in Europe. Rates surpass 200 per 100,000 in certain populations of Northern European descent. The number of new cases that develop per year is about 2.5 per 100,000.
Rates of MS appear to be increasing; this, however, may be explained simply by better diagnosis. Studies on populational and geographical patterns have been common and have led to a number of theories about the cause.
MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age. The primary progressive subtype is more common in people in their fifties. Similar to many autoimmune disorders, the disease is more common in women, and the trend may be increasing. As of 2008, globally it is about two times more common in women than in men. In children, it is even more common in females than males, while in people over fifty, it affects males and females almost equally.
Robert Carswell (17931857), a British professor of pathology, and Jean Cruveilhier (17911873), a French professor of pathologic anatomy, described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease. Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”. Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (18361908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.
The French neurologist Jean-Martin Charcot (18251893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques.
The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the “Charcot Triad”, consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech) Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”.
Diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that “signs and symptoms cannot be explained better by another disease process”. Both requirements were later inherited by Poser criteria and McDonald criteria, whose 2010 version is currently in use.
During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s. Since the beginning of the 21st century, refinements of the concepts have taken place. The 2010 revision of the McDonald criteria allowed for the diagnosis of MS with only one proved lesion (CIS). Subsequently, three years later, the 2013 revision of the “phenotypes for the disease course” were forced to consider CIS as one of the phenotypes of MS, making obsolete some expressions like “conversion from CIS to MS”.
There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot.
A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (13801433), a Dutch nun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs, and vision losssymptoms typical of MS. Both cases have led to the proposal of a “Viking gene” hypothesis for the dissemination of the disease.
Augustus Frederick d’Este (17941848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of GeorgeIII of the United Kingdom, almost certainly had MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life. Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (18891919), who maintained a detailed log of his diagnosis and struggle. His diary was published in 1919 as The Journal of a Disappointed Man.
There is ongoing research looking for more effective, convenient, and tolerable treatments for relapsing-remitting MS; creation of therapies for the progressive subtypes; neuroprotection strategies; and effective symptomatic treatments.
During the 2000s and 2010s, there has been approval of several oral drugs that are expected to gain in popularity and frequency of use. Several more oral drugs are under investigation, including ozanimod, laquinimod, and estriol. Laquinimod was announced in August 2012 and is in a third phase III trial after mixed results in the previous ones. Similarly, studies aimed to improve the efficacy and ease of use of already existing therapies are occurring. This includes the use of new preparations such as the PEGylated version of interferon–1a, which it is hoped may be given at less frequent doses with similar effects. Estriol, a female sex hormone found at high concentrations during late pregnancy, has been identified as a candidate therapy for women with relapsing-remitting MS and has progressed through Phase II trials. Request for approval of peginterferon beta-1a is expected during 2013.
Monoclonal antibodies have also raised high levels of interest. As of 2012 alemtuzumab, daclizumab, and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab had all shown some benefit and were under study as potential treatments, and the FDA approved ocrelizumab for relapsing and primary MS in March, 2017. Their use has also been accompanied by the appearance of potentially dangerous adverse effects, the most important of which being opportunistic infections. Related to these investigations is the development of a test for JC virus antibodies, which might help to determine who is at greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab. While monoclonal antibodies will probably have some role in the treatment of the disease in the future, 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 rationale for using a number of medications in MS is that the involved treatments target different mechanisms and, therefore, their use is not necessarily exclusive.Synergies, in which one drug improves the effect of another are also possible, but there can also be drawbacks such as the blocking of the action of the other or worsened side-effects. There have been several trials of combined therapy, yet none have shown positive enough results to be considered as a useful treatment for MS.
Research on neuroprotection and regenerative treatments, such as stem cell therapy, while of high importance, are in the early stages. Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS.
While diagnostic criteria are not expected to change in the near future, work to develop biomarkers that help with diagnosis and prediction of disease progression is ongoing. New diagnostic methods that are being investigated include work with anti-myelin antibodies, and studies with serum and cerebrospinal fluid, but none of them has yielded reliably positive results.
At the current time, there are no laboratory investigations that can predict prognosis. Several promising approaches have been proposed including: interleukin-6, nitric oxide and nitric oxide synthase, osteopontin, and fetuin-A. Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and N-acetylaspartate are under investigation. Other effects include looking for biomarkers that distinguish between those who will and will not respond to medications.
Improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) carry a promise for better diagnosis and prognosis predictions, although the effect of such improvements in daily medical practice may take several decades. Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, magnetization transfer, diffusion tensor, and functional magnetic resonance imaging. These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values. There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction, and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion. Similarly, new PET radiotracers might serve as markers of altered processes such as brain inflammation, cortical pathology, apoptosis, or remylienation. Antibiodies against the Kir4.1 potassium channel may be related to MS.
In 2008, vascular surgeon Paolo Zamboni suggested that MS involves narrowing of the veins draining the brain, which he referred to as chronic cerebrospinal venous insufficiency (CCSVI). He found CCSVI in all patients with MS in his study, performed a surgical procedure, later called in the media the “liberation procedure” to correct it, and claimed that 73% of participants improved. This theory received significant attention in the media and among those with MS, especially in Canada. Concerns have been raised with Zamboni’s research as it was neither blinded nor controlled, and its assumptions about the underlying cause of the disease are not backed by known data. Also, further studies have either not found a similar relationship or found one that is much less strong, raising serious objections to the hypothesis. The “liberation procedure” has been criticized for resulting in serious complications and deaths with unproven benefits. It is, thus, as of 2013 not recommended for the treatment of MS. Additional research investigating the CCSVI hypothesis are under way.
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Multiple sclerosis – Wikipedia