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Multiple Sclerosis Research Paper Topic

Introduction
Multiple Sclerosis is a demyelization disorder of the central nervous system and the spinal cord; which leads to patches of plaques in the regions of the brain and spinal cord. (Stedman’s Medical Dictionary, 2000) There are many types of multiple sclerosis, however the severity and type of multiple sclerosis depends upon the size and location of the plaque.

There are five common types of multiple sclerosis: 1) Benign Sensory multiple sclerosis, which is a form of multiple sclerosis that does not get worse and is usually accompanied with numbness and blurred vision. 2) Benign exacerbating/remission Multiple Sclerosis, fluctuates but comes closely back to baseline after the attack. 3) Chronic Relapsing-Progressive Multiple Sclerosis is another type of MS where patients’ symptoms worsen after the attack. 4) Chronic Progressive Multiple Sclerosis is a progressive condition where symptoms get worse without a distinct attack. 5) Acute Progressive Multiple Sclerosis involves a rapidly progressive downhill course, where the symptoms become more and more severe.

Causes of multiple sclerosis may vary; however, research has linked many different causes to the onset of MS. Causes may include: a virus causing demyelization, violent trauma to the head or spinal cord, and or an immune system attack which cause the body to attack the myelin sheaths around the neurons in the ascending and descending pathways.

The most common symptoms and limitations for multiple sclerosis patients are fatigue, muscle weakness, difficulty walking, and loss of vision (Silverthorn, 1998). Patients may also experience stiffness and spacticity, balance and coordination impairment, bladder or bowel dysfunction, cognitive or emotional disturbances, or pain. Each individual may experience one or more symptoms sporadically, with temporary periods of remission (Whitney, 2001). Thus, limitations depend on the severity of the MS or if the MS is in remission or exacerbation state.

Since MS is a neurological disease, many limitations are caused by a lack of neuromuscular control. One limitation for MS patients is spacticity. Since the patient becomes more spastic and loses control of voluntary muscle, it becomes harder for them to control desired movement plans. Gait becomes a problem because the MS patient cannot always control the appropriate muscles needed to effectively and efficiently loco mote.

Efficiency of movement is also a limitation among patients with MS. Most MS patients become tired or weak due the amount of energy it takes to control muscle activity. Weakness is due to poor transmission of electrical impulse, thus server uphill locomotion may only fatigue the nerve and further increase the muscle weakness. However, Randall and Schapiro found that patients with MS who perform well balance exercises that involve weight lifting or repetitive movements of muscles to the point of fatigue do not increase their muscular strength. Rather they increase weakness and fatigue. (Randall & Schapiro, 1994)

Fatigue is another limitation for patients with MS because it makes it difficult to maintain proper workout intensity. Muscle fatigue leads to unproductive gait as well as putting the patient at a higher risk of injury due to the fact that fatigue often leads to nausea and disorientation. This in turn could lead the MS patient to even higher risk of injuring themselves because they are even less aware of there surrounding environment.

Another limitation for MS patients is muscle weakness. For many MS patients pain becomes a major issue as the condition begins to worsen. Thus, this causes muscle to weaken dramatically due to the fact that pain causes the patients to move less, and in turn leads to muscle atrophy. Since there is a decrease in muscle mass and strength the ability, gait also becomes altered.

In 1976, Baum and Rothschild found that 123,000 people were reportedly diagnosed with multiple sclerosis. Female were 1.7 times more likely than a male to be diagnosed, and a non-white person was half as likely to be diagnosed versus a white individual. Those living in areas considered as “high risk” were 1.9 times as likely to be diagnosed with the disease. “Prevalence rate by age rose sharply from the group below 20 years old to the 30-39 age groups, and then rapidly decreased for those 60 years and older (Baum and Rothschild, 1981).” More recently, from 1990 to 1992, the Centers for Disease Control and Prevention reported 180,000 new cases of MS, with 250,000 to 350,000 Americans living with the disease at that time. Women were stated to be three times more likely than men to get MS (Whitney, 2001). Over time it seems the prevalence of this disease has not increased sharply within the general population of Americans, although the likelihood of a female being diagnosed with the disease is increasing. This may be due to environmental or genetic risk factors.

Purpose
Locomotion is the most basic and yet most essential part of a human transportation. The purpose of this paper is to focus on how Multiple Sclerosis effects gait pattern.

Literature Review
In a study by Goldfarb & Simon 1984, research was conducted for the purpose of looking at the relationship between Amyotrophic MS and walking performance. They studied 7 women and 17 men who were all within normal height/weight ranges (all subjects were within 15 pounds of a standard height weight table). This was used to rule out obesity. Subject’s ages ranged from 31-81 years.

Eight muscles were identified for either the swing phase or stance phase. Swing muscles were anterior tibialis, hamstrings, quadriceps and hip flexors; Stance muscles included the gastronomies, quadriceps, adductors, gluteus medius and gluteus maximums.

Goldfarb, et al found that patients with Amyotrophic MS spend less time in the swing phase and more time in stance phase. Therefore, walking velocity decreased in patients Amyotrophic MS. They also found there was no correlation between velocity of walking and the following: 1) the number of months since patient was diagnosed, 2) pulmonary function and 3) the type of neurological involvement (Goldfarb & Simon 1984).

Another study on MS looked at the effects of an aquatic exercise program on gait parameters. 11 patients with MS volunteered for the study but two quit before the final test. All subjects participated in a 10 week aquatic exercise program consisting of aqua-calisthenics and freestyle swimming. Three sixty minute exercise sessions were held each day and exercise intensity was 60% to 75% sub maximal (Gehlsen, et al 1986)

Results indicated patients with MS showed decrease in stride length, slower free speed walking rates and higher walking cadence than those patients without MS. They also found that patients with MS have less vertical lift when walking.. Thus, according to there research aquatic fitness programs have no major effect on improving or impairing studied gait parameters.

A study by Rodgers et al 1999 also looked at gait characteristic before and after a six month aerobic training program. 18 patients (14 female and 4 male) with different stages of MS were studied. The exercise program consisted of a cycle ergo-meter protocol in which the subjects exercised three times a week for 30 minutes maintaining a heart rate in and around 65 to 70% (Rodgers, et al 1999). The subjects used a combined arm/leg ergo-meter for a total of 24 weeks.

They found that there was an increase hip abduction/adduction and internal/external rotation indicating that a specific range of motion pattern was favorable due to exercise. They also found that patients with MS have an increase tightness of the hip flexors.

However, because of the nature of the disease they were only able concluded that because neurological decline from MS occurred within the 6 month time frame for several subjects, it was difficult to differentiate the effects of intervention by exercise, form changes in status resulting from progressive of the disease (Rodgers, et al 1999).

Frzovic, Morris & Vowels 2000 looked at standing balance performance in patients with MS. Twenty eight subjects were used, 14 with MS and 14 without MS (14 control subject matched for age, gender and height). In this study subjects were measured on their standing balance with feet apart, feet together, stride stance, double support stance, single support stance and self generated perturbations.

Results illustrated that there were no differences between MS and the MS control group on the ability to maintain standing balance with feet apart, feet together or in stride stance. Patients with MS performed more poorly than control subjects in double and single leg stance and in the functional reach test, arm test, step test and in response to external perturbation (Frzovic, Morris & Vowels, 2000)

Not only was research conducted on the effects of MS on exercise and balance. Research was also conducted on the effects of drugs on MS and its effect on gait parameter. Several forms of treatment for the symptoms and progression of MS are currently being researched. For example, low-dose oral methotrexate (MTX), human interferons (IFNs), and the drug cladribine have all been approved to treat MS. Use of oral methotrexate was studied by Goodkin, et al. (1995) in an attempt to find a drug less toxic than drugs copolymer 1 and interferon beta-1b. A study conducted by Orsnes, Sorensen, Larsen & Ravnborg 2000 looked at the effects of baclofen on gait. 14 patients aging from 24-57 were studied. The study was a placebo-controlled, double-blind cross-over study, all patients were either assigned to baclofen or placebo. Doses of 5mg 3 times a day were taken, after 11 days measurements were taken, followed by a two week wash out period. After which the seven placebo patients were given baclofen and seven baclofen patients were given the placebo.

Results revealed that there was no significant difference between baclofen and placebo treatment in postural and gait instability with open and closed eyes (Orsnes, Sorensen, Larsen & Ravnborg 2000). Thus, they concluded that the effects of baclofen on gait in treatment of spacticity was not evident in their study

Conclusion
MS is a severe demyelization disease that has numerous effects on the human body’s functional ability. In the research discussed it is evident that gait patterns in patients with MS are determined by the progression to the disease, rather then exercise and training. Research concluded that aerobic and aquatic training have little to no significance in the maintance of gait patterns in MS patients. Drug therapies have more side effects then benefits. For example, Orsnes, Sorensen, Larsen & Ravnborg 2000 found that nine patients reported side effects of fatigue dizziness, nausea, bad temper, diarrhea and more frequent urination. Also the study found that the drug had also little to no effect on maintance of gait patterns.

Furthermore, according to the research, destruction of myelin on the axons is thought to be due to the development of lesions in the central nervous system. Loss of myelin makes it difficult for people suffering from Multiple Sclerosis to perform control voluntary movement (gait). This is because the axon potentials that are transmitted from one neuron to another in a healthy individual are lacking the insulation of myelin, which then delays conduction.

Impaired walking ability in spastic patients is probably caused by decrease voluntary force in the dorsiflexor muscles, increased passive stiffness of the ankle joint and increased threshold of the stretch reflexes along with impaired modulation of the H-reflex (Sinkjaer, Anderson & Nielsen 1996)

It is clear that further research must be conducted in order to find a cure or a form of inhabiting the onset of MS. Discovery of a medication that treats all symptoms and slows the progression of the disease internally to improve movement function would be ideal. For many sufferers of MS, the disease goes into remission frequently. With a drug that treats the disease as a whole would allow patients to be able to live symptom free live as well maintain there normal gait pattern.

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A new year is a fine reason to gaze back on the accomplishments of MS researchers. The task of choosing the most notable advances fell to Jiwon Oh, M.D., Ph.D., and Paul O’Connor, M.D., of St. Michael’s Hospital and the University of Toronto, Canada, who published their selections in the February 2015 Nature Review Neurology (Oh and O’Connor, 2015).

Their top-eight list samples representative articles from the highest impact neurology journals and spans topics including clinical trials, imaging, and basic science, Oh told MSDF in an email. MSDF explores each highlighted paper in a little more detail, below, in the same order Oh and O’Connor presented them in the original paper. That order is not a ranking but instead was chosen for its narrative flow.

MSDF invites readers to submit any additional picks for last year’s research highlights. Make your case in the comments section below. It’s all for the good of speeding progress toward a cure for MS.

1. Redefining MS

MS may need classifications beyond the standard relapsing-remitting, secondary progressive, progressive relapsing, and primary progressive categories. While the categories are helpful, the clinical course of MS subtypes in each is still strikingly heterogeneous, potentially complicating and even invalidating clinical trial results for new therapies.

Researchers from the International Advisory Committee on Clinical Trials of MS proposed the first major revisions for MS phenotypes since the originally published 1996 consensus description (Lublin et al., 2014; Lublin and Reingold, 1996). The update includes MRI and fluid biomarkers “to better characterize patients with MS and provide a framework for both clinical research and ongoing clinical care,” lead author Frank Lublin, M.D., of Mount Sinai Hospital said in a press release. In summary, the new guidelines would place relapsing patients in “active” or “nonactive” categories. The same categories apply to progressive patients, and the researchers suggest two more categories: “progression” or “no progression.”

In addition to adding disability and MRI data to the clinical definitions of MS, the researchers also recommended that clinically isolated syndrome—but not radiologically isolated syndrome—be added to the classification tree.

Key open questions

  • What future research is needed to better understand and define MS phenotypes?
  • Might the additional classifications hint at the idea that MS is a family of diseases rather than a single disease?

2. Statins Make Progress as Progressive MS Treatment

Progressive MS is still untreatable, but new hope may come from an old drug. Simvastatin is an inexpensive cholesterol-lowering drug that, when taken in high doses (80 mg daily), may slow the progression of MS, according to phase 2 clinical trial results published last March in The Lancet (Chataway et al., 2014). Due to the fact that the drug is relatively safe and well-tolerated, simvastatin is an appealing candidate to test for its effectiveness in progressive MS.

Researchers noted that after 2 years, the 70 patients with secondary progressive MS (SPMS) showed a 43% reduction in annualized brain atrophy rate compared to 70 patients on placebo. They even showed a “slight but significant” slowdown of disability progression.

“I think that underscores the need to move away from drugs we used in RRMS and hope that they work in progressive disease to novel neuroprotective drugs,” Jeremy Chataway, M.A., Ph.D., FRCP, of the University College London Hospitals told MSDF. The research has also drawn attention to the laborious process of repurposing drugs for off-patent use in the United Kingdom.

Chataway told MSDF that researchers are trying to uncover the mechanism by which simvastatin reduces brain atrophy. He also told MSDF that his group has embarked on another phase 2 trial called MS-SMART, looking at three other promising repurposed drugs (ibudilast, riluzole, or amiloride) that target one or more of the pivotal neurodegeneration-causing pathways implicated in SPMS.

Key open questions

  • How does simvastatin work to reduce brain atrophy in progressive MS?
  • Could people with progressive MS receive the same benefits from other cholesterol-lowering drugs?

3. Some PPMS Patients May Respond to Immune Therapy

Some primary progressive MS (PPMS) patients with a particular biomarker of highly active inflammatory disease may benefit from immunotherapy, according to research published in the Annals of Neurology in July (Villar et al., 2014). The findings suggest that the only available therapies for MS patients may have a role in treating some people with PPMS.

The biomarker is measured by oligoclonal bands (OCBs), which describe a pattern seen when a fluid sample (such as blood or cerebrospinal fluid) is separated into distinctive types of antibodies using an electrified gel. “Historically, attention has largely focused on OCBs made of immunoglobulin type G (IgG), which are present in essentially all MS patients—useful in diagnosis of MS but not so much in predicting response to treatment,” the study’s corresponding author, Amit Bar-Or, M.D., FRCP(C), of McGill University, wrote in an email to MSDF. So Bar-Or, who is a scientific advisory board member of the Accelerated Cure Project, the nonprofit publisher of MSDF, and his co-authors examined IgM OCB, which is only present in roughly 25% of PPMS patients—most of whom present with more aggressive disease. These patients may benefit from immunotherapy, Bar-Or said, potentially alleviating some of the “therapeutic nihilism” surrounding progressive MS research. However, the study was only done on a relatively small sample—103 patients—so the results are far from definitive.

Key open questions

  • Might this subset of IgM OCB-positive progressive MS patients be their own disease subtype?
  • If so, do they fall into a subcategory of the newly proposed guidelines?

4. Pegylated Interferon β Works Well, Costs a Lot

Researchers published phase 3 results from the ADVANCE trial in 2014 for a new type of interferon β that needs less frequent injections (Calebresi et al., 2014). The drug, called pegylated interferon β-1a (Plegridy, Biogen), is a longer-acting version of its original form, interferon β-1a (Avonex, Biogen). RRMS patients in the two treatment groups received injections every 2 or 4 weeks. Pegylated interferon reduced the annualized relapse rate by roughly one-third compared to the placebo group in both the 2-week and 4-week treatment groups. The convenience of having to inject every 2 weeks instead of three times a week may be a relief for many MS patients, but it comes at a hefty cost of $62,036 per patient per year, according to The Boston Globe. A spokesperson for Biogen told the Globe that the cost reflects “pricing for the innovation.”

Key open questions

  • What differences might the pegylated interferon have from regular interferon that may go unnoticed in clinical trials?
  • How can patients and clinicians best decide between pegylated interferon and other treatment options?

5. Titrating PML Risk on Natalizumab

Since it was approved in 2006, natalizumab (Tysabri, Biogen Idec) has been one of the most powerful therapies for active relapsing MS. Its usefulness is limited by the risk of a fatal demyelinating side effect known as progressive multifocal leukoencephalopathy (PML), now estimated to strike 3.72 in every 1,000 patients who have received at least one dose (Antoniol and Stankoff, 2015).

PML is caused by the JC virus (JCV), which infects glial cells, in particular the myelinmaking oligodendrocytes. About one-half of people with MS are positive for JCV antibodies, but only a small portion will develop PML. To improve the PML risk prediction, a Biogen team evaluated samples from three natalizumab clinical studies (AFFIRM, STRATIFY-1, and STRATIFY-2), totaling 71 PML patients and 2,522 non-PML, anti-JCV antibody-positive patients.

It may be possible to further stratify the PML risk based on how many antibodies to the JCV virus are circulating in the blood. Higher levels of serum or plasma anti-JCV antibodies are associated with higher PML risk in people with MS who had not previously taken an immunosuppressant, the authors reported (Plavina et al., 2014).

Neither the authors nor Biogen Idec spokespeople were available for comment. The potentially useful tool for assessing risk must “be further validated and is not yet recommended for general use, and clinical decisions are still mainly based on the positive or negative serological status,” given every 6 months, the authors of a recent review (Antoniol and Stankoff, 2015) conclude.

Key open questions

  • Will the quantitative anti-JCV antibody index be validated by other studies?
  • Will other markers or following people over time improve the PML risk estimate for an individual on nataluzimab?

6. From Radiologically Isolated Syndrome to MS

Early treatment is the new trend in MS care, born of a desire to ward off further relapses and cumulative damage to the central nervous system. One team of researchers wonders if treatment would work better if begun even earlier, before the first relapse, in people with MS-like brain scans but no clinical symptoms, also known as radiologically isolated syndrome (RIS).

But the cost and side effects of MS drugs means researchers first need to determine who is most at risk for that first relapse. Darin Okuda, M.D., at the University of Texas Southwestern Medical Center in Dallas and his colleagues in five countries published a study laying the groundwork for such a clinical trial in preventing MS. Okuda formally described RIS in 2009 as a probable early stage in MS (Okuda et al., 2009).

Not all people with RIS develop MS, he and his colleagues reported in the largest multicenter study of RIS so far. Okuda and his coauthors took a retrospective look at 451 people with RIS, based on MRIs taken for other reasons, such as migraine headaches, fertility workups, traumatic brain injuries, and family history of MS (only 10% of the overall group). About one-third converted to relapsing-remitting or primary progressive MS within 5 years of the first MRI. In the retrospective analysis, younger age, male sex, and the presence of spinal cord lesions elevated the risk of developing clinically definite MS (Okuda et al., 2014). In an upcoming paper, the researchers will report in more detail about a distinctive presymptomatic phase for people who developed primary progressive MS.

Key open questions

  • Will disease-modifying drugs prevent MS in at-risk people with RIS?
  • What protective mechanism in older people with RIS is preventing them from developing MS?

7. Disability Tied to Spinal Cord Gray Matter

MS has been considered a disease of the white matter, which is mostly myelin-covered axons. Recently, postmortem tissue studies and new imaging techniques have suggested that MS also attacks less-myelinated gray matter, first in the brain and now the spinal cord.

In an unexpected finding using a new imaging technique in a cross-sectional study of 113 people with relapsing-remitting and progressive MS, gray matter tissue loss in the cervical spinal cord was the strongest correlate of disability (Schlaeger et al., 2014). “Before, we would have assumed white matter atrophy was most important,” senior author Roland Henry, Ph.D., at University of California, San Francisco, told MSDF. Also surprising was the relatively minor impact of white matter damage on disability, including lesions.

In line with their findings, another study published last year also reported that gray matter abnormalities in the spinal cord explained 70% of the disabilities differences among people with clinically isolated syndrome, RRMS, and SPMS (Malkki, 2014; Kearney et al., 2014). Led by Regina Schlaeger, M.D., the Henry lab team has followed up to correlate the neck images with more functionally relevant damage lower in the cord, suggesting that the imaging could be a marker of motor disability.

Key open questions

  • Does the damage to the spinal cord in MS start with the gray matter or the white matter, and are the mechanisms different?
  • Is white matter inflammation and neurodegeneration confounding the imaging measures?

8. Imaging and Targeting Early Neurodegeneration

To explore the link between inflammation and early neurodegeneration in MS, researchers turned to an imaging technique that measures glutamate, a neurotransmitter that helps us speak, among many other things, but can be toxic in large amounts.

The problem in MS may be too much glutamate released by inflamed innate immune cells, compounded by oligodendrocytes and other glial cells bungling the job of sopping up the excess neurotransmitter, senior author Daniel Pelletier, M.D., of Yale University School of Medicine explained to MSDF.

In a 5-year prospective study of 343 people with MS and 42 healthy controls, the sustained elevation of glutamate in normal-appearing white matter preceded a cascade of detrimental effects. First, sustained higher glutamate predicted a higher rate of neuron and axon damage, as measured by the decline of N-acetylaspartate (NAA). In turn, the investigators found that high ratios of glutamate to NAA forecast more brain volume loss over 3 years and worse clinical decline over 4 years (Azevedo et al., 2014).

With a potential target to treat patients and additional supportive mouse data, Pelletier and others set up a phase 2 placebo-controlled trial of riluzole as an add-on therapy to interferon β-1a in early MS. The drug, given to extend the lives of people with amyotrophic lateral sclerosis, inhibits the release of glutamate and has other neuroprotective effects. Unfortunately, the clinical study showed that riluzole does not prevent progression of brain atrophy in early RRMS (Waubant et al., 2014).

Key open questions

  • Are there other aspects of the glutamate excitotoxicity pathway that could be targeted to protect neurons and axons?
  • What other drugs might work to limit the damaging cascade of excess glutamate?

Disclosures and sources of funding  

Dr. Oh reported research funding, consulting and speaking fees, and grant support from Biogen Idec, EMD Serono, Genzyme, and Novartis. Dr. O’Connor reported consulting fees and/or grant support from Actelion, Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Receptos, Roche, Sanofi–Genzyme, and Teva. For disclosures from the authors of the eight top papers, please consult the references below.

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