Multiple Sclerosis Newsletter

Multiple Sclerosis Newsletter
Northern Colorado Edition

April - May 2006

Research Updates

We interrupt this Research Update for a local bulletin: The Forty Plus Motorcycle Club of Fort Collins is having their 13th Annual M.S. Poker Run June 13th starting at the Fort Collins Motorsports. Sign-up is from 8-10 am. The cost per hand is still $10. Again this year folks with MS who can't ride the run can buy a poker hand and have one of the riders draw cards for them. The cost for each MS Ghost Rider poker hand is $10 and players are eligible for ALL prizes. All proceeds from this run go to fight MS. If interested, please call 970-223-1794 before Saturday June 12th.

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Whoa Nellie - forgot about the other new item: It's called a "corrections column" and includes anything observant readers have picked up from the preceding issue which we have tried to correct.

` Corrections Column
1) The free online resource for children who have parents with MS - we didn't get the website for kids. That website is: http://www.msforkids.com - sorry.
2) This is just a note to tell you all that we are looking into the article from last issue that said that stress did not affect Multiple Sclerosis [Pg. 1, col. 2, 2nd para.] and said specifically "This review also indicates that immune cells are insensitive [sic] to the stress hormones and adrenaline and this may play a role during relapses." We had several calls from eagle eyed folks wondering about that. We were delighted because that tells us YOU READ IT! We had the same concerns. The article was rechecked for a typo on our part. No typo - that is what the article said. We have tried to make contact with the original authors to verify that is what they meant to say, but so far no luck. We shall keep trying - mostly because personal experience has taught us that stress definitely does make MS worse in cases we have experienced. However, not being scientists, we shall just try to contact the folks who wrote this to verify (or see if they had a typo). Donita.

Now back to our regular Research Updates:

EFFECTS OF A COGNITIVE-BEHAVIORAL PROGRAM FOR WOMEN WITH MULTIPLE SCLEROSIS
VG Sinclair, J Scroggie J Neurosci Nurs 05 Oct;37(5):249-57,276

The purpose of this quasi-experimental study was to evaluate the effectiveness of a cognitive-behavioral intervention for women with multiple sclerosis (MS). Thirty-seven adult women with MS participated in a group-based intervention program titled "Beyond MS," which was led by master's-prepared psychiatric nurses. For participants, the program involved reading a manual and meeting for five weekly group sessions. Perceived health competence, coping behaviors, psychological well-being, quality of life, and fatigue were measured at four time periods: 5 weeks before the beginning of the intervention, immediately before the intervention, at the end of the 5-week intervention, and at a 6-month follow-up. There were significant improvements in the participants' perceived health competence (p<.01), indices of adaptive and maladaptive coping (p<.04), and most measures of psychological well-being (p<.05) from pre- to post-intervention. The positive changes brought about by this relatively brief intervention program were maintained during the 6-month follow-up periods. This cognitive-behavioral intervention has also been used effectively in the rheumatoid arthritis population and may be adaptable to benefit individuals with other chronic conditions.

PROTEIN TEST COULD SPOT MULTIPLE SCLEROSIS EARLY
Robert Preidt HealthDay 09/2006

A spinal fluid protein may prove useful in identifying people with the earliest stages of multiple sclerosis (MS), say researchers at Johns Hopkins University in Baltimore. Currently, MS cannot be diagnosed with a simple blood sample or any other type of test.

"There is the possibility now that the protein we identified, 12.5 kDa cystatin, can be used to diagnose MS, perhaps in its earliest stages, and also to monitor treatment by measuring its levels in cerebrospinal fluid," study author Dr. Avindra Nath, a professor in the department of neurology at Johns Hopkins University School of Medicine, said in a prepared statement.

She and her colleagues analyzed samples of cerebrospinal fluid from 29 people with MS or pre-MS symptoms, and found 12.5 kDa present in about two-thirds of the patients.

The Hopkins scientists showed that 12.5 kDa is a breakdown product of a larger protein called cystatin C, which blocks the activity of some enzymes, including cathepsin B. This enzyme has been linked to the demyelination - nerve sheath destruction - that occurs in people with MS.

About 10,000 Americans, mostly women, are diagnosed with MS each year. The disease causes muscle weakness, numbness, loss of muscle coordination, and problems with speech, vision and bladder control. In people with MS, the immune system destroys myelin, the covering of the nerves that helps transmit signals.

TYSABRI EFFECTIVE FOR MS BUT CARRIES SOME RISK
Karla Gale New England J Med, 3/2/06

Tysabri, a drug made by Biogen Idec and Elan Pharmaceuticals, significantly reduces the rate of disease progression in patients with relapsing multiple sclerosis (MS), according to the result of two trials reported in this week's New England Journal of Medicine.

"The available drugs for MS, Interferon and Copaxone, have been shown in trials to reduce relapse rate by one third," Dr. Richard A. Rudick, of the Cleveland Clinic Foundation in Ohio, told Reuters Health. The two current trials show that "the effectiveness of Tysabri was very excellent," far better than that of the other available drugs.

However, a review of more than 3000 patients treated with Tysasbri (which is known as natalizumab, generically) in clinical trials revealed that the drug is associate with a small risk of a serious neurological disease called progressive multifocal leukoencephalopathy or PML.

Tysabri was approved by the US Food and Drug Administration in November 2004 for the treatment of MS, but it was suspended in February 2005 after PML cases were reported.

In one of the new studies, Dr. Chris H. Polman, from the VU Medical Center in Amsterdam, and his team recruited 942 patients with relapsing remitting MS, who were randomly assigned to receive natalizumab every four weeks or an inactive placebo injection.

After two years of treatment, compared with placebo, natalizumab was associated with a 42 percent decrease in the risk of a sustained progression of disability and 59 percent reduction in the risk of relapse. The active treatment also reduced the number of new or enlarging MS lesions in the brain by 83 percent.

In the second trial, Dr. Rudick and his colleagues enrolled 1171 MS patients who had at least one relapse during a 12-month period while they were being treated with interferon. Patients were randomly assigned to natalizumab every four weeks or placebo while continuing on interferon.

Combined treatment over 2 years resulted in a 24 percent decrease in the risk of sustained disability progression, a 55 percent reduction in rate of relapse, and an 83 percent reduction in new or enlarging lesions, compared with interferon alone.

After the three original cases of PML were reported in patients being treated with natalizumab, Dr. Eugene O. Major, from the National Institute of Neurological Disorders and Strokes in Bethesda, Maryland, and colleagues established an independent committee to evaluate suspected cases of PML in 3417 patients exposed to natalzumab in recent clinical trials.

Forty-four patients with possible PML were referred to the committee. PML was ruled out in 43, and 1 case was classified as indeterminate. The three previously reported cases did not seem to be actual PML.

When the FDA suspended Tysabri, "patients were devastated," Rudick said. "Imagine being 1 of 7000 patients for whom current therapies are of little benefit and starting a new drug that is known to be a significant advance, then having it suspended abruptly because of this question about safety. We had patients crying in our offices."

He hopes that the FDA will again approve natalizumab under careful conditions for patients "who really need it," with close monitoring so that the early symptoms of PML could be recognized and the Tysabri stopped.

If Tysabri does become available again, Dr. Rudick added, "The decision to use it should be made by the doctor and the patient together. The doctor's job is going to be to decide whether it's a necessary option, and if so, to be sure it's given and monitored properly. Patients should be fully informed so they can make the decision to take on a risk of that magnitude."

Meanwhile, Elan Corporation said on Tuesday it agreed to suspend trading in its shares during the upcoming FDA review of Tysabri, for two days beginning March 7 before the opening bell in New York coinciding with a 1300 GMT suspension on the London and Irish Stock Exchanges.

The company will request that all stock exchanges resume trading at the end of the FDA's Advisory Committee meeting to review the product.

LIPITOR-COPAXONE COMBOMAY FIGHT MS
Daniel DeNoon WebMD 05/16/2006

Study with mice shows Statin and MS drug may prevent paralysis from multiple sclerosis. A combination of two currently approved drugs prevents and even reverses paralysis in mice with multiple sclerosis. One of the drugs is the MS drug Copaxone. It's now approved for the treatment of relapsing-remitting MS.

The second drug is Lipitor, one of the group of so-called statin drugs. Lipitor and its sister drugs lower cholesterol levels. However, the anti-MS activity of Lipitor appears to be separate from its cholesterol-lowering action.

A team led by University of California, San Francisco researcher Scott S. Zambvil, MD, PhD, in 2002 reported that Lipitor has anti-MS action in mice. An NIH-sponsored clinical trial is now enrolling people with first-episode MS to see if Lipitor can prevent more serious disease.

Powerful Combo: Now Zamvil's team reports that low doses of Lipitor and Copaxone - doses too low to have any effect by themselves - pack a powerful anti-MS punch. The combination prevents paralysis in mice with an induced MS -like disease. Perhaps even more impressive, the combination treatment reverses paralysis in these mice.

"We have two drugs that are relatively safe in people. At the preclinical level we have shown they have a marked effect on MS," Zamvil tells WebMD. "We hope that by testing this in clinical trials there may be an added benefit of these two drugs when given in combination."

VIEWPOINT ON MS NEWSLETTER
NEW BRAIN IMAGING TECHNIQUES AND COGNITIVE DYSFUNCTION IN MS
Maria K. Houtchens, M.D., Instructor in Neurology, Harvard Medical School Veritas Medicine

The following information is reprinted with permission from Veritas Medicine. This information does not necessarily reflect the opinions of Biogen Idec. Investigational drugs and procedures have not been thoroughly studied or approved by the FDA. Please consult your physician if you have questions about any of the material presented.

This month we will continue our discussion of how new methods of looking at the brain are helping us to understand the underlying processes that lead to cognitive ands physical disability in MS patients. While these modalities are primarily being used in research for the moment, they may someday be useful tools in clinical practice to help diagnose and evaluate patients with MS.

One such new way to look at the brain is called Magnetization Transfer MRI (MT-MRI), which is a technique based on interactions between free and restricted protons. In the central nervous system (CNS), free protons are found in free water, and restricted protons are located in cell membranes and in myelin. This imaging modality can provide information about the tissue composition of the entire brain as well as of specific structures within CNS. In a study by Filippi et al (2000) MT-MRI signal was significantly lower in a group of MS patients with cognitive dysfunction, and this low MT-MRI signal is thought to reflect loss of myelin and reduction in axonal density in surrounding tissues. MT-MRI measurements are reproducible, sensitive to longitudinal disease changes and correlate with physical disability and cognitive impairment.

Another technique, called Diffusion-weighted MRI (DT-MRI), is based upon the variable ability of water molecules to move through tissues and fluids. Pathologic (abnormal) processes that make tissues more permeable to water influence this ability. DT-MRI measures give information on size, orientation, shape and direction of brain fibers. It has been demonstrated that the regional distribution of white matter lesions defines unique patterns of cognitive deficits. Specifically, abnormalities in the corpus callosum (a structure that connects two brain hemispheres) as measured by DT-MRI techniques, have been clearly associated with impaired performance on tests of sustained attention and concentration in MS patients. Loss of integrity of specific white matter tracts assessed by DT-MRI has also been shown to correlate with severity of dementia in Alzheimer's disease and schizophrenia. Research studies using DT-MRI techniques are ongoing to further define the specific pattern of white matter tract disruption and how this correlates with cognitive impairment.

A third new brain imaging technique is called Proton MR Spectroscopy (MRS). This provides a quantitative and continuous measure of the biochemical composition of brain tissues. Four major substances can be detected in the brain using this technique: choline (a major component of cell membranes), creatine, N-acetylaspartate (localized only to neurons and axons) and lactate (associated with tissue injury, inflammation, mitochondrial dysfunction and ischemia). MS is associated with specific patterns of and relationships between these substances reflecting demyelination, inflammation and axonal loss. Christodoulou et al. looked at correlations between poor cognitive performance and MR markers of cerebral injury (2003). His results indicate that MRS measures of the right hemisphere correlate most strongly with cognition. SDMT, a test of attention, as discussed in prior viewpoints, showed the strongest correlation among all other neuropsychological tests.

Finally, Functional MRI (FMRI) is a technique measuring brain activation during motor, sensory and cognitive operations. This technique depends on changes in blood oxygenation and blood flows to the more active areas of the brain. It is thought that these changes reflect increased neuronal activity in the "working" compared to "silent" areas of the brain. This tool allows us to assess changes in the brain in response to a specific cognitive task as well as the brain's ability to change in response to treatment or other interventions. Parry et al. assessed 10 patients with MS by administering fMRI. They studied a particular counting task that measures speed of information processing before and after administration of Rivastigmine - a medicine used in dementia treatments. Researchers observed normalization of brain activation patterns in MS patients who received the treatment, versus control subjects who didn't. This change in brain activation seen before and after treatment reflects improved compensation mechanisms in MS patients. This might be one of many mechanisms that are responsible for the improvement of cognitive or physical symptoms following MS relapses.

All four of these MRI techniques give us new insights into what goes wrong in the brains of patients with MS, and how this relates to their cognitive impairments. The hope is that this level of deep understanding will eventually lead to more effective treatments and rehabilitation techniques for the cognitive disability in MS.

References:
Filippi, M. et al. Changes in normal-appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg and Psychiatry 2000; 68:157-161.
Filippi, M., Grossman, R. MRI techniques to monitor MS evolution. Neurology 2002;58:1147-1153.
Desmond, D.W. Cognition and White Matter Lesions. Cerebrovascular Diseases. 2002, 13(suppl 2)53-57.
Christodoulou, C., Krupp, L.B., et al. Cognitive Performance and MR markers of cerebral injury in cognitively impaired MS patients. Neurology 2003;60:1793-1798.
Parry AM et al. Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain. 126(Pt 12):2750-60, 2003.

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