It's been said that "the only constant is change," and while this applies to everyone, it applies even more to people with MS. A study in the American Journal of Occupational Therapy describes how the effects of MS can change a person's ability to engage in occupations or activities they need or want to participate in. The study was based on in-depth interviews with 10 people with MS who described how their disease has limited their participation in activities, and how these restrictions have affected their self-identity. Continual change meant continual struggle for these people, and often resulted in a significantly different life.

Some of the themes emerging from the analysis include the following: Difficulties in performing activities, limitations in the choices available, and lack of ability to plan ahead each contribute to decreased engagement in occupations. The struggle to stay involved in activities is influenced by society (e.g., availability of social service support), by social interactions and attitudes, and physical restrictions such as fatigue. However, self-esteem is influenced by one's capability to do things -- and therefore incapability can lead to feelings of being a burden or a "nobody." Although some of the interviewees felt that restrictions on activities diminished their life, others hoped to regain some of their former activities in the future, or found a "silver lining" in their more restrained life, such as having more time to spend with children.

This article is addressed to occupational therapists who work with people with MS. The authors wanted their readers to understand the factors affecting engagement in activities that go beyond just the physical ability to perform tasks. However, it may also be of interest to people with MS or their families and friends in anticipating and adapting to changes resulting from MS so that engagement in meaningful activities remains a part of life. A full-text version is available here (try to ignore the ads...).

The New England Journal of Medicine recently published the results of three major studies of oral therapies being tested for treating MS:

• FREEDOMS -- a two-year trial of fingolimod (aka FTY720) that was completed by 1,033 subjects given either high-dose or low-dose fingolimod or placebo
• TRANSFORMS -- a one-year trial of fingolimod that was completed by 1,153 subjects given either high-dose or low-dose fingolimod or Avonex (interferon-1a)
• CLARITY -- a two-year trial of oral cladribine that was completed by 1,184 subjects given either high-dose or low-dose oral cladribine or placebo

Oral cladribine is being developed by Merck Serono and fingolimod is being developed by Novartis. These two drugs are thought to have the best chances to become the first oral disease-modifying drugs approved for treating MS. Their biological effects are different. Fingolimod works to trap immune cells in lymph nodes, preventing them from circulating; it may also have a neuroprotective effect. Cladribine wipes out T and B immune cells and thereby dampens the inflammatory response. Fingolimod is taken on a daily basis, while cladribine is taken over the course of a few weeks in a year.

Each of these trials found the study drug to be significantly superior to placebo (CLARITY and FREEDOMS) or Avonex (TRANSFORMS) in multiple aspects. Both drugs showed a relative reduction in relapse rate (on the order of 40-60%) compared to placebo or Avonex, as well as better MRI results. CLARITY and FREEDOMS also found a beneficial effect of the two drugs on delaying disability progression. However, the results also describe a number of adverse events that occurred during the trials. Most of these were mild or moderate, but there were also some serious adverse events including a few fatalities. Reported adverse events included infections, such as herpes virus infections, cardiac abnormalities, macular edema (swelling of the retina), and various cancers/tumors. In addition, as we've seen with Tysabri, other adverse events may come to light with longer-term usage of these drugs. As the authors of the studies themselves point out, fingolimod and cladribine may have many potential benefits for treating MS, but these benefits need to be weighed against the potential risks.

These results are available to read for FREE on the journal's website (just click on the name of the study in the list above). You can also read an editorial by Dr. William Carroll discussing these studies, or see the press releases provided by Novartis and EMD Serono. I highly encourage anyone who is considering trying cladribine or fingolimod if/when they are approved by the FDA to take advantage of this opportunity to learn more about these drugs.

Dr. Eric Roter, an emergency room doctor who also happens to be a Juilliard-trained cellist, is leveraging his talent to raise funds for 36 disease-related charities through a campaign called Bach to Health. Paying homage to his days of street busking, for each charity he has created a recorded video of himself playing one of J.S. Bach's masterpiece "Cello Suites" on a Manhattan street scene that also includes medical information about the disease. This ABC News story on Dr. Roter explains how he exchanged a career in music for one in medicine and how he came up with the idea to blend the two.

Accelerated Cure Project is one of the charities Dr. Roter has chosen to support from among the highest rated nonprofits on American Institute of Philanthropy and Charity Navigator. Click here to see ACP's video -- we're the first entry in the top row, and our selection is the Prelude from Suite #1 in G major. Lovely!

(Thanks to Melissa O'Shea for sending this information.)

One question about MS that really interests me is why severity of symptoms can vary so widely among people with the same diagnosis. It seems that if this was better understood, perhaps the knowledge about the less-severe forms could be turned into therapies, or at least people diagnosed with MS could get a better sense of what may lie ahead for them. Here are a couple of recent studies from research teams looking into this topic.

The first study comes from a group of Italian researchers who looked carefully at MRIs from people with benign MS (EDSS <=3 with disease duration >= 10 years) for clues as to why their motor function was relatively unimpaired. These subjects were first screened for cognitive function to rule out significant problems which would contradict the determination of "benign MS." By analyzing MRI measurements in motor-related brain regions and the spinal cord, and comparing them against those from healthy controls, the researchers found something interesting. In the people with benign MS, there was evidence of gray matter volume loss in the brain and extensive demyelination in the spinal cord. However, a measurement called fractional anisotropy (FA) that reflects the integrity of the axonal pathways in the spinal cord was the same in the MS group compared with the controls. Whether the disease mechanisms at work in MS tend to spare spinal cord axons in benign MS, or whether these results are due to strong axonal repair/plasticity mechanisms in people with benign MS, still remains to be seen.

The second study looked at why intellectual enrichment appears to protect against cognitive decline in MS and other neurological diseases. This study was carried out at UMDNJ-New Jersey Medical School where 18 people with MS were recruited. Each person was assessed for vocabulary knowledge as a measure of educational attainment, and each was given MRIs, including functional MRIs showing which brain areas were active while the subjects performed cognitive tests.

Having greater educational enrichment didn't result in less brain atrophy or better performance on simple cognitive tests. However, greater enrichment was associated with better scores on more complicated tests. Furthermore, enrichment level appeared to affect the types of brain networks that were used while performing these cognitive tests. MS subjects with higher intellectual enrichment were able to use their "default network" (brain areas active during rest) during the cognitive tests more than those with lower enrichment, who had to recruit other brain areas more heavily while performing the tests. This shift away from the default network has been seen in other neurological conditions as well as in aging, and is thought to represent cerebral inefficiency. The authors interpret these results to mean that greater intellectual enrichment doesn't provide complete protection against brain atrophy and cognitive decline, but does give people with MS more of a buffer before cognitive effects become apparent. Also, exactly how intellectual enrichment connects with cerebral efficiency is not yet known, but if it turns out that there's a direct effect, perhaps cognitive training of people with MS can help build up this buffer as well.

If you, like me, watch the TV show "House," you'll be familiar with the concept that tumors in the body can over-secrete all kinds of substances which can cause baffling symptoms (baffling to the doctors on "House," anyway!). Here's a very interesting case study of that exact phenomenon in a man diagnosed with MS. (This link should lead to an open-access copy if you'd like to read the article for yourself.)

As the case study describes, the man went to the doctor at age 32 with symptoms of optic neuritis and leg weakness. MRI imaging revealed demyelinating lesions as well as a tumor on his pituitary gland (an adenoma) that was secreting excess prolactin. Prolactin is a hormone that stimulates the production of breast milk, but it can also have strong effects on the immune system (both stimulatory and inhibitory effects depending on other factors). CSF testing also revealed the presence of oligoclonal bands, a strong diagnostic marker of MS. The man's tumor was removed and he remained MS symptom-free and prolactin-normal for the next 12 years. Then the tumor came back, his prolactin levels rose, and he simultaneously developed new MS symptoms and MRI lesions. The man is now being treated with a prolactin-lowering drug, and has been in remission apart from one breakthrough episode of high prolactin levels and new MS lesions.

Although suppressing prolactin in this man correlated with suppression of his MS activity as well, it's hard to generalize this example to others with MS. Interestingly, prolactin levels in pregnant women reach levels that are many times higher than reported in this case study, and pregnancy and breastfeeding are both associated with lower relapse rates in women with MS. Furthermore, case-control studies have not found significantly higher levels of prolactin in people with MS. Still, unusual cases like this can sometimes be very informative -- so understanding why prolactin seems to be such a strong MS trigger in this man could lead to new insights about MS.

I always enjoy learning about whizzy new technologies -- especially those that are developed for medical research -- and especially those that are applied to understanding MS, because we need all the help we can get! This gene expression study takes advantage of a new technology called laser capture microdissection (LCM) to isolate individual cells in a tissue sample for analysis.

Studying gene expression in MS brain lesions vs. MS normal appearing brain tissue vs. non-MS control brain tissue has provided many insights into the proteins that the different cells in the brain are producing. These studies show which genes are activated (or de-activated), either as part of the disease or as part of the body's response to the disease. Most of these studies have looked at gene expression in blocks of tissue which contain many different cell types. However, by using LCM, scientists are able to analyze gene expression in just a certain type of cell -- in the case of this study, endothelial cells which form the blood-brain barrier. It's a painstaking process but it provides for a clearer picture of gene expression differences in just that specific type of cell.

The study did identify several genes that were expressed at higher or lower levels in the endothelial cells within MS lesions. For example, ICAM-2, which helps immune cells adhere to the surface of blood vessels so they can migrate into the tissue, was expressed at higher levels in lesions. By fine-tuning the measurement of gene expression in certain types of brain cells, LCM can increase our understanding of disease mechanisms and perhaps lead to new drug targets for MS.

Through brain tissue studies, scientists have known for a long time that the presence and activity of immune cells in the brain is a characteristic of MS. However, not much is known about how and why they are there. For instance, these cells need to cross the blood-brain barrier, a tight formation of blood vessel cells and cells surrounding the blood vessels that limits access to the brain. How they do this is not known.

However, a team of German scientists have now described part of this process, at least as it occurs in rats with the mouse model EAE. I encourage you to read the very interesting press release from the Max Planck Institute and watch the video from the experiment. They rigged a special optical camera to monitor the activities of fluorescently labeled T cells as they moved through blood vessels in the animal. The cells flowed normally in areas outside the brain, but when they got to the brain, some of the cells were seen to cling to the inside surface of the blood vessel. Furthermore, they began to "crawl" on the surface of the blood vessel, even going upstream, as if moving toward the source of a signal. After a while, some of the cells squeezed through the blood vessel walls into the brain. Once there, the T cells crawled again on the outside surface of the vessel until they touched a phagocyte (a type of cell that cleans up debris and can activate T cells). The scientists observed that many more T cells came through the barrier in locations where an inside T cell had made contact with a phagocyte -- indicating that the T cell had been activated and was sending out its own signals.

Finally, the team reported that MS antibody-based drugs (e.g., Tysabri) inhibited the crawling behavior of the T cells.

This type of imaging is something that could not ethically be done in humans, but it seems likely that the cellular behavior seen in this experiment is representative of what happens in other species as well. The team would next like to identify what signals guide the T cell behaviors (stopping, crawling, etc.) that they observed and potentially use this information to develop new MS treatments.

You can think of the human body as a machine, and you can also think of its individual components (cells, structures, organs) as components of this machine. The structural and mechanical properties of the body's components affect how well the machine operates -- that is, they play a role in sickness and health. These properties of the body don't receive much attention in MS, compared with other aspects such as immune activation and signaling. However, as shown by two recent papers dealing with mechanical properties and functions, perhaps they play key roles and could potentially provide new areas for therapies.

The first paper presents a theory that remyelination (or lack thereof) in MS is influenced by two types of physical forces -- forces within the oligodendrocyte precursor cells that move into a demyelinated lesion, and forces outside those cells. Studies suggest that a balance between these forces is needed for these precursor cells to become oligodendrocytes and start extending myelin sheets to wrap around neighboring axons. If that balance is off -- for example, if astrocyte scarring in a lesion results in a more physically rigid environment -- then the precursors may be inhibited from initiating the remyelination process. Factors within the precursor cell that control its own rigidity and ability to contract can also influence the activities of the cell including myelination. Further study of these factors could therefore result in ideas for therapies to enhance remyelination in people with MS or similar diseases.

The second paper presents results from a study of how interferon-beta (IFN-b) affects the mechanical properties of astrocytes. Among other functions, astrocytes provide structural support in the brain and as mentioned above, can form rigid scar tissue in MS lesions. In a series of experiments, astrocytes in a cell culture were exposed to IFN-b and then analyzed by special microscopes to see whether their shape and rigidity had changed. After IFN-b exposure, the cells retained the same basic shape -- cell bodies with a few armlike extensions -- although the post-IFN-b cells had a smoother surface texture. However, rigidity of the cells was affected (decreased) by IFN-b exposure. Further analysis revealed changes in the generation of certain proteins by the astrocytes that would appear to be responsible for this decreased stiffness.

Although it's too soon to draw a solid line between these two studies, it may be that one of the benefits of IFN-b in MS is to change the properties of astrocytes so that they are less rigid and more permissive of remyelination activities.

Both of these papers are available to read online (the first one permanently, the second one for at least another week or two), so if you have an engineering background like me, you might find them particularly interesting. The second paper also has some nice images of living astrocytes in case you're curious about what they look like!

I received a pamphlet in the mail from James Gips, a professor at Boston College, whose team has developed a software program (Camera Mouse) allowing people with significant disabilities to use a computer. The software works with the computer's webcam to detect the user's head movements, and moves and clicks the mouse accordingly. Best part -- the software can be downloaded and installed for free! The software currently only works with Windows Vista and XP, although it will run on a Mac that runs Windows. More information about how the program works can be found at the site's FAQ page. The page notes that there are other commercial head-tracking systems (and voice recognition systems for people who can speak) that may work better, but Camera Mouse is free and therefore available to anyone regardless of budget. It might be worth checking out if this is something that could help you or someone you know.

EMD Serono announced this week that it has filed a new drug application with the FDA to allow oral cladribine to be marketed for treating MS. This application is based on results from the CLARITY study, which were presented at this year's AAN and ECTRIMS conferences. The company had submitted a similar application to the European agency EMEA in July of this year. Now the FDA will get to pore over the data and make its decision about whether cladribine will be the first oral drug approved for MS in the US.

Another company with an oral drug candidate, Novartis, released initial results from its two-year placebo-controlled FREEDOMS trial of FTY720 (fingolimod) in relapsing-remitting MS. The drug successfully met the study endpoints including reduction in relapse rate, disability progression, and MRI lesions. Compared with placebo, the two doses of FTY720 used reduced relapse rates by 54-60% and disability progression by 30-32%. The FREEDOMS trial did not identify any new safety concerns and no cases of macular edema or melanoma that had been seen in previous trials were detected. Results from the TRANSFORMS study that compared FTY720 to interferon-beta were reported earlier this year. Novartis says that it plans to file new drug applications with both the FDA and EMEA before the end of the year. So it may be that people with MS will have two oral drugs among their therapy choices next year!

Finally, earlier this week Merck reported that it was ending its phase II trial of atacicept, an injectable drug that affects B cell development. An independent data monitoring committee tasked with reviewing trial data on an ongoing basis reported that the subjects receiving atacicept were having more relapses and new MRI lesions than those on the placebo. This is a good example of the importance of these independent boards for the protection of the health and safety of the people who volunteer for clinical trials.