Diagram of the ODFS

They found that people with multiple sclerosis using the stimulator increased walking performance, compared to the exercise group and also experienced fewer falls.

authors: Esnouf J, Taylor P, Mann G, Barrett C.

source: Mult Scler. 2010 Jul 2

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Introduction

Multiple sclerosis presents in various ways and subsequently shows variable disease courses. If we knew early on what the disease course for Multiple Sclerosis would be then we could better target the medication in each individual case. To date it has been unpredictable right from disease onset but, knowing the disease course is of crucial importance in guiding treatment.

Now “The Department of Neurosciences” at Cardiff University has recently been looking into factor H as a biomarker for multiple sclerosis and the findings are promising.

Effective and accessible biomarkers are needed in order to stratify (separate into groups) patients and inform treatment. The team at Cardiff University decided to look into factor H as such a marker. Regulator factor H, has recently been implicated as a biomarker in other chronic inflammatory central nervous system conditions. Could it identify or predict specific pathological processes and outcomes in multiple sclerosis?

Method

They measured factor H in blood serum from 350 patients with multiple sclerosis classified according to disease course and relapse status. Controls were found for variables including disease duration, age, gender, disability and treatment. I have decided not to go into the full method in this document as the details will be somewhat turgid to the average reader. However, the findings are fairly clear and very encouraging.

Results

1) Factor H levels were significantly higher in progressive disease compared to controls and relapsing patients. Thus factor H levels were capable of distinguishing secondary progressive from relapsing remitting disease (excluding patients in clinical relapse)

2) Acute relapse was also associated with temporarily increased factor H levels compared to stable relapsing disease.

3) In clinically stable patients, factor H levels remained constant over 1 year but in patients in transition from relapsing to progressive disease, factor H levels significantly increased over a period of 2 years. This is a crucial point as the transition between relapsing and progressive signals the need for therapy change.

Conclusion

Serum factor H could be an effective indicator of progression and a practical and accessible tool to split patients into groups and to predict disease course, Once we have this information we have objective evidence which can help guide therapeutic decisions. As we have known for some time, the earlier you can pick up a disease pattern the better chance of success you have with the treatment.

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Introduction

Vascular co-morbidity means that as well as MS you have  hypertension, hypercholesterolemia, diabetes, or heart disease too. It has recently been found that whether present at symptom onset, diagnosis, or later in the disease course, it  is associated with a substantially increased risk of disability progression.

Who found this ?

Published in Neurology. 2010 Mar 30;74(13):1041-7. was a study by

Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T.

Health Sciences Center, Winnipeg, Canada.

Background

On October 29 in Neurology, researchers outlined how co-morbidities may contribute to diagnostic delay in multiple sclerosis (MS) and increased disability at diagnosis. But Vascular co-morbidity adversely influences health outcomes in several chronic conditions so it became a question that needed to be answered about MS.( Vascular co-morbidities are common in multiple sclerosis (MS), but their impact on disease severity was unknown).

It could be that these “vascular co-morbidities” may contribute to the poorly understood variability in MS disease severity. So,  A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study.

Method

Time from symptom onset or diagnosis until ambulatory disability was compared in these 8933 patients with or without vascular co-morbidities to determine their impact on MS

Models were adjusted in the analysis for sex, race, age at symptom onset, year of symptom onset, socioeconomic status, and region of residence.

Results

Participants reporting one or more vascular co-morbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular co-morbidities.

CONCLUSIONS

Vascular co-morbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple sclerosis. The impact of treating vascular co-morbidities on disease progression deserves investigation as treatment of vascular co-morbidities may represent an avenue for treating MS

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These results suggest that UVR is likely suppressing the disease independent of vitamin D production, and that vitamin D supplementation alone may not replace the ability of sunlight to reduce MS susceptibility.

This of course reinforces the fact that there is a much higher incidence and prevalence of MS as you move away from the equator

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One patient died from a brain haemorrhage.

Another required emergency open heart surgery

The article on the MS Society site can be seen here

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“Interferon beta (IFNb) is a first-line treatment for people with MS. However, increasing evidence suggests that the presence of neutralising antibodies during treatment is associated with a reduction in treatment efficacy. The authors of this study found that anti-IFNb neutralising antibodies could persist after treatment cessation and were associated with higher disease activity and poorer clinical outcome.”

The antibodies are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and is supported by the observed need for more aggressive therapy after interferon beta treatment cessation. Prospective studies are warranted to confirm these results.

authors: van der Voort LF, Gilli F, Bertolotto A, Knol DL, Uitdehaag BM, Polman CH, Killestein J

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The Glasgow researchers suggest that a mother’s lack of exposure to sunlight during her unborn baby’s development may explain the results, published in the European Journal of Neurology.

Vitamin D is produced through exposure to sunlight and has been linked to genes thought to be associated with MS. Scientists have suggested that a lack of vitamin D could trigger a predisposition to MS in a person’s genetic makeup.

Director for MS Society Scotland, David McNiven, said: “These intriguing results add weight to the evidence that the environment, and in particular sunlight, plays a part in MS and we’re pleased scientists are piecing together the complex puzzle of what may cause this debilitating condition.”

You may racall from an earlier article that research published in the journal PLoS Genetics suggests that vitamin D deficiency during pregnancy and the early years may increase the risk of the offspring developing MS later in life. See also the article about megadoses of vitamin D lowering the risk of relapse.

If you live ina temperate climate (as of course they do in Scotland) then it is always worth investing in an artificuial sunlight lamp to give you and possibley your child the best chance for a better life. You can find these in lot of places or go here to  chevk out the sunlight page

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Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. It  is believed to be primarily an autoimmune disorder with an initial trigger suspected among environmental factors (including viral infection and bacterial) impacting a genetic predisposition. The initial trigger facilitates the movement of T-cells and demyelinating antibodies from the blood into the brain through disruption of the blood–brain barrier.

Interestingly, from the time of the first histologic description by Charcot in 1868, MS plaques ( seen now on and MRI scan) were known to be venocentric. Additionally, and in common with several neurodegenerative disorders, the brain and spinal cord of MS-affected patients contain abnormally high levels of some metals, particularly iron. The advanced MRI and histologic studies show the peculiar deposition of the iron stores in MS constantly encircling the venous wall. These iron deposits, curiously, resemble iron stores commonly seen in peripheral venous disease.

It has been recently shown that MS is significantly associated with a condition defined as chronic cerebrospinal venous insufficiency (CCSVI) (Zamboni et al, 2009a, 2009b, 2009c). In CCSVI, put simply, there is a narrowing of the vessels draining blood away from the brain.Blocked venous blood outflow causes a high rate of cerebral venous reflux in MS patients.

This detected reflux, propagated from the chest and neck veins, may have an important function in explaining the mechanism of iron overload in MS. By contrast, venous reflux has not been found in patients affected by other neurodegenerative diseases with increased iron stores, such as Alzheimer’s and Parkinson’s diseases.

More specifically, the rate of venous reflux flow detected in the main cervical veins of MS patients was 70% as opposed to 0%  in the three control populations. It has been shown that extracranial reflux was also transmitted up to the deep cerebral venous system in 50% of MS cases, but was detected neither in healthy controls nor in patients with other neurologic diseases

Despite the strong association found between CCSVI and MS, it has not yet been clarified whether such venous obstructions can be considered a cause or an effect of MS.

How does this differ from other diseases?

Starting from histology, there is an impressive parallel between the inflammatory process activated in the course of chronic venous disorders (CVDs), and that studied in MS. However, two important things have happened in the past 2 years:

(1) a demonstration of altered venous flow in the cerebral venous system in the course of MS and (2) the development of advanced MRI techniques that have brought about an extraordinary improvement in the capacity to assess iron stores and cerebral veins.

There is thus a hypothesis that iron overload in MS is secondary to disturbed venous flow in the cerebral veins.

So when  does iron accumulate in the brain ?

With advancing age, iron accumulates in the brain and has been associated with senile dementia, many cognitive dysfunctions, and neurodegenerative disorders. The reason may include

• dysregulation of the proteins involved in iron influx and sensing of intracellular iron;
• iron accumulation in ventral motor neurons
• increased mitochondrial iron load .

This finding may pave the way to a better understanding of iron accumulation in the aged brain.

Iron Overload in Multiple Sclerosis

Although investigations into the role of iron in MS are still few, many high-resolution MR techniques have shown stored iron regions inside the brain and spinal cord.

If we look at experimental autoimmune encephalomyelitis (EAE), an animal model of MS, dietary modifications have revealed an incidence of EAE in 70% of mice with a normal iron level or iron overload, but 0% in iron-deficient mice. This is clear evidence that iron deficiency protects against the progress of MS in mice with induced EAE, with obvious clinical implications (Grant et al, 2003).

Authors have speculated that the failure of iron-deficient mice to develop EAE is impressive, but controversial as iron deficiency may lead to much more serious health hazards. However, they conclude that any of the pharmaceutical approaches to inhibiting EAE are less effective than iron deficiency.

At present, despite the intriguing mechanisms of iron deposition in CCSVI  we cannot definitely prove this hypothesis.

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Oral medications
A number of medications have been used to treat generalised spasticity. Although there is variability in response to and tolerability of different medications, most practitioners will suggest baclofen as a first line agent. It works at the level of the spinal cord to help the body inhibit muscle movement. A number of studies have shown that baclofen is effective in reducing pain, improving gait and overall function, as well as decreasing spasm frequency.

However, baclofen can cause fatigue, dry mouth, dizziness and nausea and many people start on baclofen and say it doesn’t work for them. However, if assessed carefully and consideration is given to dose and timing, the results may be more positive. A written regime, with slowly increasing doses that help a person with MS assess how baclofen affects them over a period of time, and regular review can make the use of baclofen much more successful. Even so, some people with MS still find they cannot tolerate the dose of baclofen required for efficacy because of the side effects.

Another medication clinicians frequently prescribe is tizanidine. Again starting at a low dose, tizanidine appears to be particularly effective for painful spasms at night. Like baclofen, it can cause sleepiness, dry mouth, dizziness and fatigue.

Diazepam is also effective in treating spasticity in some people. It appears to have a greater risk of causing sleepiness and muscle weakness, and it has the potential for dependence and addiction which can affect adherence.

Dantrolene can be used for spasticity and it works at the level of the muscles to limit contractions.

Besides sharing most of the side-effects of diazepam, baclofen and tizanidine, dantrolene also requires frequent laboratory monitoring to ensure the medication does not damage the liver. As a result, dantrolene is not prescribed as frequently as the other medications.

Other medications that may be prescribed include clonazepam and gabapentin, although again, side effects can be problematic.

A combination of therapies may also be helpful for some people, and this approach has become increasingly utilised by clinicians.

Local treatments for spasticity
For those with spasticity affecting a small area (focal spasticity), or who do not get relief from oral medications, local injections of botulinum toxin or phenol into the muscles can improve quality of life. You probably know that “Botox” is now a well known and frequently used poison which paralyses the muscles and is used in non-surgical cosmetic treatment of moderate to severe frown lines.
A typical example of spasticity treatable with botulinum toxin would be the overactivity of muscles that flex the wrist, reducing the ability to reach and grasp objects. Making those muscles weaker can improve both function and pain.

There are two types of botulinum toxin, type A, known as Botox® in the United States and Dysport® in Europe; and type B, Myoblock®. A local injection of botulinim toxin can last 3–6 months and make functional activities easier to undertake.

Phenol or alcohol blocks are done less frequently, and involve identifying a point where nerve and muscle meet. Phenol is injected to destroy the nerve endings in that area only.

With both phenol and botulinum toxin, the effects are temporary and may require frequent injections. Also, individuals can build up antibodies to the botulinum toxin over time, making it ineffective. Some people are able to switch from the type A toxin to type B to prolong the therapeutic effect. The most appropriate treatment plan usually includes work with a physical and/or occupational therapist after the injection to improve functional movement of the affected area.

Surgery for spasticity
Orthopaedic surgeons and neurosurgeons might get involved in the management of spasticity in two ways. If a person experiences spasticity that has caused permanent deformity, a surgeon can lengthen tendons or fuse joints or otherwise address malformations. Surgical correction of deformity coupled with proper rehabilitation interventions can prolong sitting times in a chair, prevent skin breakdown or its recurrence, and reduce pain.

Cannabinoids and spasticity

Experimental pharmacological studies support the hypothesis that cannabinoid chemicals within cannabis, such as delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), exert muscle relaxant effects. While delta-9-THC does this via a specific cannabinoid receptor (the CB1 receptor) which was discovered in the central nervous system in the late 1980’s, CBD appears to have more complicated actions and may affect cytokines (proteins that are released by cells of the immune system and play a role in the generation of an immune response).

Initial clinical trial data did not support the efficacy of delta-9-THC in reducing spasticity. The first report from the “Cannabinoids in Multiple Sclerosis” (CAMS) trial, a blind and placebo-controlled trial in the UK, suggested that delta-9-THC had no statistically significant effect on spasticity when evaluated by the objective Ashworth scale.

However, in a 12-month follow-up study involving 630 patients, delta-9-THC was shown to have a small but significant effect. Nonetheless, in both studies the patients reported a subjective improvement in spasticity. It is a matter of some controversy whether the initial lack of effect using the Ashworth scale reflects the lack of sensitivity of that scale for quantifying spasticity.

The natural cannabis extract in the pharmaceutical product marketed as Sativex® has been reported to alleviate spasticity in a number of clinical trials. Clearly , since cannabis is illegal a pharmaceutical product would be welcomed.

The most common adverse side effects reported have been oral pain, dizziness, diarrhoea and nausea. Of the other cannabinoids that have been investigated, the synthetic cannabinoid, nabilone, has been reported to reduce pain related to spasticity in one recent study.

There have now been more than 12 clinical trials published on the effects of cannabinoids on spasticity and pain in MS. Although not all of these studies demonstrate a significant improvement in symptoms with delta-9-THC or CBD, evidence is accumulating that cannabinoid drugs may be useful in at least a subset of patients, and at least as an adjuvant therapy.

Long-term studies suggest that cannabinoids are reasonably well tolerated by patients but there is still concern about potential long-term adverse effects, such as cognitive impairment, impaired foetal development and psychiatric side effects. However, it must be recognised that many conventional anti-spasticity drugs such as baclofen also have significant side effects. It should also be noted that in many countries cannabis is an illegal drug, which affects its accessibility.

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Spasticity, ( feelings of muscle stiffness and involuntary muscle spasms), is a well defined consequence of MS.

It is recognised through various studies that spasticity occurs frequently in people with MS with Male gender, older age, and longer duration of the disease showing an increased severity of spasticity.

Quality of life can be affected with troublesome symptoms and functional limitations, and severe spasticity may even lead to medical complications such as skin breakdown or contractures, where a limb can become fixed in one position. So, as you can see, there is a  need to recognise and address spasticity and its consequences.

In many cases, initial interventions such as stretching, exercise and rehabilitation are helpful, but
they also enhance the efficacy of other interventions such as medication. Medications can  be useful and are usually safe, although the dosing and timing must be optimised to minimise potential side effects.

For some individuals a degree of spasticity serves as a functional crutch and helps them to walk or carry out other physical activities, so the biggest challenge with spasticity management is determining what the optimal level of muscle tone is for an individual.

What’s going on?

What is happening with the nervous system to cause spasticity? To explain this you must review the fact that there are two types of motor neurones.

The nerve pathway connecting the brain and spinal cord is made of upper motor neurones. The pathway between the spinal cord and muscles is made of lower motor neurones. Spasticity is a consequence of an “upper motor neuron (UMN) syndrome”. The interruption of signals caused by MS lesions means that the upper motor neurones can no longer regulate messages to the lower motor neurones. The lower motor neurones can then become overactive and hypersensitive, causing stiffness or spasms in the muscles.

Some of the detrimental consequences associated with spasticity are:

• interference with mobility, ability to exercise and the range of motion in joints
• negative impact on endurance and energy expenditure
• interference with the activities of daily living
• discomfort or pain
• sleep disturbance
• increased difficulty for caregivers (for example with transfers or hygiene).

Treating Spasticity .

Hot temperatures may cause a decrease in spasticity for people with MS while infections and exacerbations may cause a significant increase in spasticity. The cause of any change must first be identified. If it is due to an infection, it is crucial that the infection be treated first. Many people with MS recognise increased spasticity as a sign of a bladder or other infection, or of the increase in core body temperature that is associated with a fever or excessive exercise, or of a full bladder or colon.

When treating spasticity it is important to focus the aim on management and not necessarily on the elimination of the spasticity since some individuals use their spasticity to assist with functional movements. In addition, for individuals who have restricted movement, spasticity may help promote circulation by maintaining muscle contractions which can promote the return of blood to the heart.

The most important principle of treating spasticity is to develop reasonable and flexible goals that target specific manifestations of spasticity – pain, fatigue, stiffness or weakness – and, together with the person with MS, frequently reassess the effectiveness of treatments.

Spasticity can affect just a few parts of the body (focal spasticity), or it can manifest in multiple places (generalised spasticity). It can range from insignificant to incapacitating, with many levels in between. Spasticity can also increase and decrease.

Other causes of increased spasticity include:

• noxious stimuli such as a skin lesion
• a bladder or kidney stone
• fractures
• tight clothing
• menstruation
• psychological stress
• extreme environmental temperature
• hunger
• an MS exacerbation
• treatment with some disease modifying or antidepressant pharmaceutical agents.

In the next article I will be dealing with the treatments used in spasticity

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