Research Roundup: CCSVI, New Drugs, and Other Items of MS Interest

The last two months have brought a deluge of MS research data, much of it coming out of October's ECTRIMS (European Council on Treatment and Research in Multiple Sclerosis) conference, this year held in Amsterdam. While the meeting was dominated by the release of drug study data (naturally), there was also tantalizing research data revealed regarding CCSVI as well as a number of other MS related matters. I'll attempt to provide a broad overview of the recent research goings-on, and will try my best to not put readers to sleep with too much scientific mumbo-jumbo. Just in case, better grab a blanket and a pillow, because I have a feeling this is going to be long…

♦ CCSVI - On the CCSVI front, ECTRIMS appears to have been the latest venue for the ongoing pissing war that's being waged between CCSVI supporters and detractors, featuring dueling research reports, most of which are entirely based on imaging studies finding greater or lesser degrees of venous abnormalities in MS patients. To my mind, the problem with all of these studies, both pro and con, is that the imaging techniques used (MRVs and Doppler sonography) are prone to technical and/or operator error, so the wide disparity in findings may more reflect the failings of the technology then the hypothesis being explored. MRVs are highly subject to artifacting, and sonography is extremely operator dependent. While time and experience has brought more accuracy to both technologies in regards to revealing CCSVI, the fact remains that the only way to assess the state of a patient's veins with a high degree of accuracy is to actually go in and explore those vessels with an invasive (minimally) catheter venography, which so far has proved impractical for large-scale study purposes, especially when it comes to subjecting healthy subjects to a potentially (again, minimally) risky procedure.

While quite a few studies were presented that refute the theory that multiple sclerosis has a vascular component (click here), some others provided intriguing finds that support the CCSVI hypothesis. The most striking of these was a small study out of the esteemed Cleveland Clinic that compared jugular and azygos veins taken postmortem from the cadavers of MS patients and healthy control subjects. This of course begs the question, can a cadaver truly be a healthy control subject? Certainly, healthy though they might once have been, at the very least they'd be terrible guests at dinner parties. But I digress… The unique aspect of this study is that investigators were actually able to hold and examine the veins in question, the only imaging technology utilized being the ever trusty human eye (presumably aided by some type of optical magnification).

Although quite small, limited to only 13 subjects, the study hints at some rather dramatic trends (click here). The researchers looked at the veins of 7 MS and 6 non-MS subjects, and found a variety of structural abnormalities and anatomic variations. Interestingly, vein wall stenosis (narrowing) occurred in equal numbers among the MS and non-MS samples. More prevalent in the MS veins, though, were abnormalities involving malformed valves and anomalous membranes (structures such as webs and septums that shouldn't be there) which could lead to disrupted blood flow. These types of abnormalities would be difficult to spot using noninvasive imaging methods, casting further doubt on studies reliant strictly on traditional MRV in particular, and also Doppler sonography unless the operators were well-versed in protocols specifically designed reveal such anatomic irregularities.

The findings of this study, if borne out by future, larger investigations, could shed light on the wide disparity in benefit (or, often, lack of benefit) experienced by those who have undergone CCSVI venoplasty (click here for a terrific discussion of this, written by Julie Stachowiak of about.com). Many CCSVI treatment procedures, especially those done within the first year or so after knowledge of CCSVI hit the mainstream MS population, concentrated primarily on areas of venous narrowing, which the Cleveland Clinic findings suggest are not as abnormal as first thought. Since these narrowings were seen in equal numbers among MS and non-MS subjects, they may fall within the parameters of normal anatomic variation, and have little actual significance.

The high prevalence of malformed or misplaced valves and other anatomic structures within the veins of MS patients, on the other hand, could very well prove to have considerable import. Although the goal of CCSVI treatment has in large part shifted away from simply expanding narrowed veins and moved more towards clearing malformed or otherwise broken valves, aberrant membranes  would in many cases be difficult to treat using the balloon venoplasty techniques currently employed to address CCSVI. In theory, some of these treatments may have coincidentally alleviated the effects of such abnormal membranes by disrupting them and compressing them against the vein walls of treated patients. If this were the case, and these membranes eventually returned to their original form, this might explain the far too common phenomenon of restenosis experienced by patients treated for CCSVI. The failure to properly treat malformed valves and abnormal and misplaced membranes within the veins might also explain the failure of CCSVI treatment to significantly benefit many of those who have undergone treatment. This of course assumes that the MS-CCSVI link exists, which despite a growing body of anecdotal evidence, still needs to be confirmed by scientifically robust studies.

The Cleveland Clinic cadaver study certainly illustrates how little we still actually know about CCSVI and the proper way to treat it, and that some of the initial assumptions upon which treatment methodologies were based might have been misguided. Certainly, should CCSVI prove to be a vital piece of the MS puzzle, CCSVI venoplasty techniques must be refined, and very likely equipment and devices specifically designed to treat the condition effectively need to be developed and put on the market. As I've mentioned in previous posts, the study and treatment of CCSVI is still in its infancy, and patients and physicians alike need to be careful not to put the cart before the horse, despite the tremendous amount of hope and excitement that CCSVI has generated.

Another interesting CCSVI research project, conducted by the Buffalo Neuroimaging Analysis Center (BNAC) looked at the phenomenon of CCSVI in healthy patients, and attempted to identify risk factors that might be involved in the development of the condition (click here). BNAC has imaged hundreds of MS patients and healthy controls, and found that CCSVI is present in roughly 25% of non-MS subjects. By pinpointing the factors that might lead to the development of CCSVI in otherwise healthy people and cross-referencing these with known risk factors for MS, the relationship between CCSVI and MS might better be assessed.

Since a picture is said to be worth a thousand words, I suppose a video made up of moving pictures would be worth several million words, so, in the interest of saving you pages and pages of reading, here is the head researcher at BNAC, Dr. Robert Zivadinov, discussing the results of this study:






Indeed, the findings of this study are fascinating, in that many of the known risk factors of MS (particularly infection with the Epstein-Barr virus) also seem to be prevalent in healthy subjects who exhibit CCSVI when subjected to noninvasive imaging techniques. As Dr. Zivadinov stated, study findings such as these only emphasize the need for continued, multidisciplinary research into the CCSVI-MS connection. My e-mail inbox sees a steady flow of notes from patients who have benefited from CCSVI treatment, but also a disturbingly high number of reports from patients disappointed in the lack of results they've experienced. The CCSVI story has only started to be written, and with more research results set to be released in the coming months, our knowledge of the condition should expand exponentially.

Perhaps the most well-known MS sufferer to undergo CCSVI treatment is Montel Williams, who recently discussed his experience in this video with the celebrity physician Dr. Oz. Unfortunately, Dr. Oz gets some of the particulars about CCSVI treatment wrong, but there certainly is value in Montel's testimony. Here is Montel's story, in his own words:





♦ Pharmaceuticals -some late stage MS drug trial results have been released recently, most describing extremely positive results. Disparaging Big Pharma is a favorite pastime of mine, and I think the pharmaceutical companies deserve all the disparaging they can get, due to their sometimes devious and deceitful ways of doing business, and their iron grip on most of the medical research that takes place in the USA. Unlike some other MS advocates, though, who disparage all Big Pharma MS products as snake oil, I've come to realize the value of the ever-expanding arsenal of disease modifying drugs. Though none of them offers anything close to a cure, for those patients who find them effective, they do increase quality of life, sometimes dramatically so. Of course, many of them do come with a laundry list of frightening potential side effects, but by reducing relapse rates and in some cases alleviating the burdens of disability, the current crop of disease modifying drugs has been a godsend to the patients on whom they are effective. Hopefully some of the newer compounds on the horizon will be all the more effective while at the same time limiting deleterious side effects.

One of the most promising new compounds is BG 12, an oral MS drug being developed by Biogen. Also known as oral fumarate, BG 12 has been shown in late stage phase 3 trials to not only dramatically decrease relapse rates and the number of lesions seen in the MRIs of treated patients, but also appears to significantly delay the progression of the disease in some patients (click here). Research results showed that BG 12 reduced relapse rates by 50% when compared to placebo, and also reduced the risk of disease progression by 38% over placebo. The drug works in a way very different than any existing MS medication, by suppressing pro-inflammatory factors called cytokines, and possibly providing some protection against nerve cell death. Encouragingly, the drug also appears to have a very benign side effect profile, with the most common side effects being gastric disturbances and diarrhea. The drug does not appear to open patients up to opportunistic infections or cancers, as do some of the other available MS pharmaceutical therapies. Given that BG 12 is an oral drug that seems to be very effective, and carries with it a relatively benign side effect profile, I expect this drug may prove to be very popular with patients and the doctors who treat them.

Genzyme announced the results of phase 3 trials of the drug Alemtuzumab, which was previously known as Campath and will be marketed under the name Lemtrada (click here). This very powerful drug is given intravenously, with infusions once a day for 5 consecutive days for the first treatment and then, a year later, 3 infusions during 3 consecutive days. Lemtrada severely depletes the human immune system, acting on both lymphocytes and monocytes, which are then reconstituted by the body, resulting in permanent changes in the immune systems of patients treated with the drug. In effect, Lemtrada "reboots" the immune system, in the hopes that the reconstituted immune system will no longer attack a patient's own nerve cells. Trial results showed Lemtrada to reduce relapse rates by 49% when compared to patients taking Rebif, along with a 42 percent reduction in the risk of sustained accumulation (worsening) of disability as measured by the Expanded Disability Status Scale (EDSS). Previous trials have shown that the effects of Lemtrada are very long-lasting, with patients showing significant benefit five years after initial treatment ended (click here). However, while these results are very impressive, Lemtrada does carry with it the risk of some serious side effects. About 16 % of treated patients develop autoimmune thyroid disease, and 1% develop a potentially lethal autoimmune blood disorder known as ITP. Because of this, patients using the drug must be carefully monitored, and use of Lemtrada may be limited to patients with highly active disease. Research is currently underway to develop ways to identify patients most at risk for the autoimmune side effects of Lemtrada, to more easily identify patients who should be excluded from this treatment option (click here).

The potential MS vaccine Tovaxin has been granted fast-track status for the treatment of SPMS by the FDA (click here). Fast-track status can cut in half the time it takes a drug to be approved, and if Tovaxin does eventually get such an approval, it will only be the second drug specifically approved for the treatment of secondary progressive multiple sclerosis in the United States. Tovaxin is a compound individualized for each patient, which desensitizes a treated patients immune system T cells to their own nerve cells, thereby stopping the autoimmune reaction (click here). Several years ago, Tovaxin failed to meet the goals of its phase 2 trials (click here), and although it had shown great promise, was left for dead. The company developing it, Opexa, later re-examined the failed trial data and determined that Tovaxin had indeed demonstrated positive effect, and now Tovaxin has risen like Lazarus, giving it (and Opexa's stockholders) new life…

A study done to assess the risk of stopping Tysabri for "drug holidays" showed that this practice significantly increases the risk of patients suffering MS relapses within six months after stoppage (click here). The idea of drug holidays came about because Tysabri is linked with PML, a potentially fatal brain infection, the risk of which increases with the amount of time a patient is on Tysabri. It was thought that taking occasional breaks from Tysabri might allow the immune system to reconstitute itself enough to combat the emergence of PML, but this study suggests that temporarily switching to another MS therapy unfortunately carries with it an increased risk of patients suffering an MS relapse. Kind of a "damned if you do, damned if you don't" scenario…

♦ Miscellaneous Studies - A variety of other MS related research results have also recently been announced. The active ingredient in the spice saffron may prove to be effective in combating MS (click here). In experiments, this ingredient was shown to combat inflammation and cell stress, at least in petri dishes and test tubes. Interestingly, saffron is often used in Asian cuisines, and the incidence of MS is much lower in Asian countries than it is here in the West. The spice tumeric (cumin) has also been shown to have strong anti-inflammatory properties, and this spice too is used heavily in some Asian cuisines. So go out and have some Indian food, it's good for you. Chicken Tikka Masala, yum…

Researchers in Sweden have discovered that young people between the ages of 16 and 20 who work overnight shifts or odd hours are twice as likely to develop multiple sclerosis as those who never worked such hours (click here). The researchers explained the sleep restriction associated with working the night shift has already been shown to increase the risk for certain health problems, including heart disease, thyroid disorders and cancer, likely by interfering with melatonin secretion and increasing inflammatory responses. Kind of an odd finding, but upsetting circadian rhythms has been shown to have an adverse effect on health, so these Swedish meatballs might be on to something…

German researchers have linked gut bacteria to multiple sclerosis (click here). We all have millions of microbes living in our guts, normally to no ill effect. However, more and more research links these bacteria to some autoimmune diseases. The researchers who did this study used mice genetically engineered to develop a Multiple Sclerosis like disease, and allowed some to develop gut bacteria, and others to remain gut microbe free. About 80% of the mice with gut bacteria went on to develop MS like symptoms, while none of the sterile mice did. While it's a far cry to go from mice to humans, this study does demonstrate that intestinal microbes do interact with the immune system, something that has long been suspected. Of course, most of the bacteria are in our guts is harmless, and some even serve a beneficial effect, but these research results certainly warrant further investigation.

Well, let's call it a wrap. There's an astounding amount of MS research being conducted, much of it driven by the huge profits to be made treating MS patients with hyper expensive drugs that tamper with the little understood human immune system. Still, as is evidenced by the last few investigations I mentioned, the breadth of MS research is quite wide, and each bit of knowledge uncovered may hold the key that finally unlocks the puzzle that is MS. Certainly, research into CCSVI has the potential to upend much of the conventional wisdom regarding the disease, and it's of the utmost importance that MS patients themselves drive such research forward, by educating themselves, advocating for energetic and innovative research into the disease, and agitating against those who stand in the way. Power to the people, y'all…

Related articles

• Risk Factors For CCSVI Are Similar To Risk Factors For Developing MS (medicalnewstoday.com)