Tuesday, June 21, 2011

CCSVI and MS: Cause, Effect, or Neither?


Image by Getty Images via @daylife

It's now been over 18 months since the news of Dr. Zamboni's vascular theory of MS, the CCSVI hypothesis, first made its way into the consciousness of the greater Multiple Sclerosis patient population. Touched off by news reports on Canadian television channel CTV, an inferno of hope raced through MS patients worldwide, and a firestorm of controversy regarding almost every aspect of the hypothesis was ignited, a conflagration that seems to only burn more intensely with each passing week. The relatively simple CCSVI hypothesis (which postulates that blockages in the veins draining the central nervous system lead to or contribute to the MS disease process) has managed to pit physician against physician, physician against patient, and patient against patient. While the various factions duke it out, an estimated 15,000-20,000 MS sufferers have undergone CCSVI venoplasty, with a wide variety of resulting outcomes, ranging from dramatic benefit to no benefit whatsoever to, in rare cases, a worsening of disease symptoms.

Several key questions have emerged regarding CCSVI during the last year and a half, primary among them whether or not CCSVI and MS have any link whatsoever, and if so, whether the venous anomalies collectively known as CCSVI are the cause or an effect of the disease. We've seen a steadily increasing flow of CCSVI research results, providing enough conflicting data to fuel all sides of the argument. As with all things Multiple Sclerosis, CCSVI presents a complex picture, and despite evangelical believers/nonbelievers on all sides of the squabble, at present the ultimate outcome of the CCSVI conundrum is as clear as mud. Here then is a brief look at some of the issues currently being batted about, with some small attempt on my part to make some sense of it all.

My personal belief is that CCSVI and MS do indeed have a relationship, at least in some MS patients. However, I acknowledge that my opinion is based primarily on anecdotal evidence, and anecdotal evidence alone is not enough to state anything with scientific certainty. Despite the insistence of many in the CCSVI advocacy community, the link between CCSVI and MS has not yet been established with evidence that measures up to the scientific standard. On its face, the basic premise of CCSVI, that restricted blood flow through the central nervous system, caused by vascular abnormalities that are very likely congenital, slowly cause damage to the CNS over the course of decades, eventually becoming significant enough to result in a clinical diagnosis of Multiple Sclerosis, seems simple and makes perfect sense. Yet upon closer inspection, the picture is not quite so clear-cut.

There have been several very convincing studies demonstrating that venous abnormalities now known as CCSVI occur more often in MS patients, and even in patients with other neurologic diseases, than in healthy control subjects. Conversely, there have also been quite a few studies disputing this. Almost all of these studies, pro and con, have relied on noninvasive imaging techniques (Doppler ultrasound or MRV) to ascertain the presence of these abnormalities. Unfortunately, neither of these noninvasive imaging techniques has proven to be entirely accurate, though Doppler ultrasound, in the hands of a skilled and well trained technician, does appear to be the more reliable of the two techniques. Still, we have research groups reporting widely divergent findings, and some of that divergence could possibly be attributed to the relative inaccuracy of the diagnostic methods being utilized.

Complicating matters further is the fact that human venous anatomy, with a few exceptions, has been very little studied. So little, in fact, that no clear-cut definition of "normal" exists when it comes to the anatomy of the veins that drain the central nervous system. It had previously been assumed that since the veins in question had so many built-in redundancies, any blockages encountered would be easily compensated for. While the Interventional Radiologists performing the CCSVI treatment procedure are reporting that the overwhelming majority of MS patients are indeed displaying a large number of venous abnormalities, we cannot state with any certainty that a significant portion of the healthy population does not also present with such abnormalities.

What are desperately needed are trials using catheter venography to ascertain the prevalence of CNS venous abnormalities in healthy control subjects. However, there are some ethical questions involved in performing this minimally invasive procedure simply for research purposes. Although the risk is low, catheter venography, like any invasive procedure, does carry with it the potential for dangerous complications, and the prospect of exposing healthy subjects to these risks has inhibited such studies from taking place. Until it can be established beyond dispute that vascular abnormalities in the jugulars, azygos, and other veins that drain the CNS are more prevalent in MS patients than in the general population, the question of the CCSVI/MS relationship will not be put to bed.

Let's assume, though, based on the anecdotal reports, that there is a connection between CCSVI and MS. The big question then becomes whether CCSVI is the cause of the disease, or an effect of the Multiple Sclerosis disease process. Again, there is enough conflicting data to support both sides of the argument.

Those who support CCSVI as the cause of MS site several compelling reasons for their belief. One of these is that many of the abnormalities being seen in the veins of MS patients, such as anomalous membranes and fused valves, appear to be congenital in nature, that is, patients have had them since birth (click here). If these defects are congenital, and occur in greater preponderance in MS patients than the healthy population, it would seem reasonable to assume that they play a causative role in MS disease etiology. Another argument in favor of CCSVI as the cause of MS is the growing body of evidence that suggests that nervous system tissues in MS patients are damaged before the immune system comes into play (click here for one such study), findings that would seem to contradict the prevailing theory of MS, the "autoimmune theory". The autoimmune theory states that, for reasons unknown, the immune systems of MS patients go rogue and start attacking the patients' own central nervous system tissues. If some studies done within the last decade are correct, and CNS damage occurs before immune system involvement, this would apparently discredit many of the basic assumptions of the autoimmune theory, and CCSVI provides an explanation as to how this damage occurs.

While I've long held the autoimmune theory in contempt, and I'm convinced that the aberrant immune response seen in MS patients is a symptom of some larger underlying and as yet undiscovered cause, I'm not sure that cause is CCSVI. While the CCSVI hypothesis does in some ways elegantly account for some of the mysteries surrounding MS (the venocentric nature of MS lesions, the reduced volume of blood flow through MS brains, etc.), it does not account for several of the more confounding aspects of the disease. It's difficult for CCSVI to explain the geographical distribution of the MS population, which sees a far greater prevalence of MS the further away one gets from the equator (click here). Related to this geographic distribution, CCSVI also can't explain some of the migratory observations made in regard to disease prevalence (click here). When a person below the age of 15 migrates from an area of higher disease prevalence to one of lower prevalence, they take on the characteristics of their new home. When the migrant is over the age of 15, though, they retain the propensity for the disease of the area they migrated from. In other words, a person under the age of 15 migrating from Maine (high prevalence) to Florida (low prevalence) has the same low chance of getting the disease as a Florida native. However, older migrants retain the higher chance of getting the disease seen in Maine. Furthermore, children of these older migrants, born after the move south, take on the same lower chance of developing MS as children born to the native population.

Similarly, CCSVI cannot account for the existence of "MS clusters", which are small concentrations of population in which MS appears to be epidemic (click here). The most famous of these clusters is in the Faroe Islands, an island group situated between the Norwegian Sea and the North Atlantic Ocean. Prior to World War II, MS was virtually unknown among the native islanders. During World War II, the British, who have a high incidence of MS, occupied the island, and subsequent to this occupation, MS has become epidemic among the native population. Another such cluster was recently identified in a small town in Ohio, where over two dozen MS cases were discovered within a six block radius.

The geographic and migratory components of MS epidemeology, as well as the existence of MS clusters, are heavily suggestive of an environmental (infectious or toxic) element to the MS disease process, and indeed, recent studies have linked several viruses, most of them in the herpes family, to MS. Just within the last week or two, a study out of Taiwan, which looked at hundreds of thousands of subjects, found that people suffering an outbreak of shingles, a painful skin condition caused by the varicella zoster virus (which also causes chickenpox), are three times as likely to develop MS within the year as those who didn't suffer from shingles (click here). Likewise, the Epstein-Barr virus has also been cited as a possible infectious trigger of the disease, with some scientists stating that if a patient isn't infected with EBV, they won't get MS (click here).

Another potential problem with CCSVI as the cause of MS is the inflammatory patterns seen in patients afflicted with the disease. According to CCSVI theory, disrupted blood flow through the CNS creates damage and inflammation to the cells contained within, through a variety of possible mechanisms. This would lead one to expect that the longer the condition persisted, a patient's levels of inflammation would slowly increase over time, in a steady upward slope. However, in reality, RRMS patients see their greatest amount of inflammation early in the disease, during its relapsing remitting stage. Once the disease moves into the progressive stage, and RRMS turns into SPMS (normally within 10-15 years when left untreated) inflammation levels decrease dramatically. Patients with PPMS, who start out with progressive disease, very often show very little signs of CNS inflammation. As a matter of fact, this lack of inflammation, seen as enhancing lesions on MRI images, is a hallmark of progressive disease. This is why anti-inflammatory therapies such as steroids generally have little effect on patients with progressive illness.

Of course, none of this directly contradicts the idea that CCSVI may play some causative role in the disease of some MS patients, but it strongly argues against the idea that CCSVI is the primary cause of the disease.

Some compelling evidence that CCSVI may be an effect of MS has been presented by several researchers, most notably Dr. Robert Zivadinov and the researchers at the Buffalo Neuroimaging Analysis Center. Although Dr. Zivadinov's findings have been savaged by some of the most fervent "CCSVI as cause" proponents, the totality of the research done under his direction does point to the possibility that at least some of the venous abnormalities now called CCSVI are a result of the MS disease process. Although Dr. Zivadinov's opinions only recently made headlines (click here), he in fact implied them in research presented in October, 2010 at the annual ECTRIMS (European Committee on Treatment and Research in Multiple Sclerosis) conference. One paper presented at that time demonstrated that the severity of CCSVI increases with the severity of Multiple Sclerosis symptoms experienced by patients, and with a more advanced disease course (click here). These findings were backed up by papers presented by researchers from Beirut (click here) and Italy (click here). Another study presented by Dr. Zivadinov found that subjects who presented with CCSVI had significantly more lesions and brain atrophy as measured by MRI than those MS patients without vascular abnormalities (click here). Yet another investigation presented by Dr. Zivadinov looked at the correlation between a gene implicated with MS, and CCSVI, and found that the data supported an association between MS disease progression and CCSVI separate from the suspect gene. The implications of these findings are that CCSVI could be a risk factor in developing the disease, or a result of the progression of MS (click here).

Additionally, it would seem to me that the high rate of restenosis in patients who have undergone CCSVI treatment venoplasty could also hint that CCSVI is more an effect rather than the cause of MS. Despite the wide range of treatment methodologies being employed, patients are still experiencing a re-narrowing of their previously unblocked veins far too frequently. This has been seen even in patients who have had stents placed in their veins, only to see their veins stenosing in areas not stented. If CCSVI were an effect of the MS disease process, one would expect to see repeated restenosis of the veins as that disease process continued to impact a patient's vasculature.

So then, what conclusion can be drawn? Is CCSVI the cause of MS, an effect of the disease, or does it have no relation to Multiple Sclerosis at all? My honest belief is that the answer could be all three, depending on the individual patient.

Multiple Sclerosis is a remarkably heterogeneous disease, meaning that it impacts different patients in vastly different ways. Across the wide spectrum of MS patients, the primary symptom of the disease may be fatigue, cognitive dysfunction, muscle weakness, spasticity, eye trouble, nerve pain, or any combination thereof. Some patients can have the disease for decades and show very little physical disability, while others find themselves in a wheelchair (or worse) in less than 10 years (sometimes much less). Some patients have a great many lesions and very little disability, others have few lesions but devastating disability. Confounding the issue even more, MS comes in several different flavors, from Relapsing Remitting to Primary Progressive, and evidence suggests that the disease process at work in progressive disease may be quite different than that underlying Relapsing Remitting MS.

Given such a wide array of disease presentations, and thus the likelihood that a variety of mechanisms may be at play, it could very well turn out that CCSVI plays no role at all in the disease of some patients, a more causative role in the disease of others, and could be an effect of MS in yet another patient population. Very likely the line between cause and effect may be quite blurred, with CCSVI playing an exacerbating role in a disease that almost certainly has, in addition to a vascular component, very strong genetic and infectious components as well. The mix may be dramatically different from patient to patient, and indeed, CCSVI may be THE major factor in the disease of some patients, but play absolutely no role in the disease of others.

This may be reflected in the breakdown of outcomes reported by some of the Interventional Radiologists doing the CCSVI treatment procedure. The most widely quoted is Dr. Gary Siskin, of Albany New York, whose group has done over 700 procedures. Dr. Siskin has found that one third of his patients experience dramatic improvements, another one third experience mild improvements, and a final one third experience no improvement whatsoever. Further complicating this equation is the definition of just what constitutes a dramatic improvement. For somebody who's most disabling symptom is fatigue, a lifting of that fatigue would undoubtedly be called dramatic. For somebody more disabled, like I am, a lifting of fatigue, while certainly welcome, would hardly be defined as a dramatic improvement.

As I stated earlier, clear as mud…

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Thursday, June 9, 2011

Bits and Pieces: Sex Sells Edition

☜ Sexuality continues.

Image by Nick Sherman via Flickr

Note: For the many readers who receive my posts via e-mail, please be aware that embedded videos in these posts do not show up in the e-mailed version. To view the embedded videos, please visit the blog page itself by clicking on the title of the post. Thanks.

Well, I wonder if my Internet hit count will go up because the word sex appears in the title of this post. Such is the power of titillation, long known by advertisers. Funny, the word titillating is itself kind of titillating. Come to think of it, so are the words "Bits and Pieces". Anyway, on with some titillating tidbits (yet another word with titillating tendencies)…

Don't worry, I'm not about to descend into the tawdry. Not that I'm above tawdry, mind you. Back in my healthy, single days, I always believed that a little occasional debauchery did a soul some good, as long as all parties involved took part in the monkeyshines of their own free will, and no harm, emotional or physical, was done to any living thing. Eat, drink, and be merry, and all that. Life is full of uncertainties, sometimes you've gotta eat dessert first.

Unfortunately, the effects of MS and many other chronic diseases can dramatically impact the ability to partake of such shenanigans, and a few recent news items got me thinking about how sexuality is quite often a silent casualty to such illnesses, much to the detriment of those suffering from them. Sexuality is an important part of the human experience, and of all the losses meted out by disabling diseases, the effect on the sexual self may be one of the most keenly felt, yet least often talked about.

So, I submit to you the following news items, which I think shine some light on the issue …

· A new documentary film, "Scarlett Road", details the efforts of Rachel Wotton, an Australian sex worker who specializes in catering to the needs of a very specialized clientele, people with severe physical disability (click here). Among her clients is John, a severely disabled multiple sclerosis patient who relies on a chin controlled wheelchair. According to the film's website (click here), the benefits John has received have not only been emotional, but physical as well. In addition to increased self-esteem, he's regained some physical functionality that he thought was lost forever (and not just in his nether regions).

Human beings are incredibly social creatures, and the power of touch and a warm embrace are very real indeed. Loneliness is difficult enough to deal with for those lucky enough to be healthy, but for those poor souls locked in dramatically unresponsive bodies, the feeling of enforced solitude must be crushing. Though their bodies may be broken, their minds and spirits certainly are not, and for those so profoundly stricken the need for physical affection, for the exhilarating warmth of the intimate touch of another human being, for the feeling of somebody gently lying beside them, sharing a sensual embrace, must certainly be incredibly precious, its fulfillment tremendously and perhaps infinitely enriching.

Despite the supposed sophistication and enlightenment of modern societies, the severely disabled are still stigmatized and marginalized, and although lip service to their humanity is often paid, in reality far too many suffer the anguish of being a personality trapped in a useless prison of flesh and bone, their psychological and emotional needs barely even acknowledged. Some may question the morality of sex workers being paid to satisfy the needs of the severely disabled; I would question the morality of a society that forbids it, that denies the fulfillment of these most basic human wants and desires to those who need them most.

Thank you, Rachel Wotton, if for nothing else than simply caring. I wonder if there are similar services available to disabled females suffering from the same lack of physical attention?

"Scarlett Road " will be premiering at the Sydney Film Festival on June 11. Hopefully, it will soon be available for viewing outside of Australia.

Scarlet Road Video from Paradigm Pictures on Vimeo.

· A 66-year-old wheelchair dependent man with multiple sclerosis, Mr. Jim Keskeny, was kicked off a nudist cruise through the Caribbean after he injured himself while trying to use the toilet in his "accessible" cabin (click here). The man was traveling alone, and considered himself a "nudist at heart", although he hadn't previously participated in the nudist lifestyle, and decided at some point during the cruise that he didn't want to take his clothes off after all. Following his injury, the cruise line decided that he was in too debilitated a state to be traveling alone, although Mr. Keskeny was a seasoned traveler, and unceremoniously dropped him off in Mexico, leaving him to make his way back home to the states. The passenger claimed that he was perfectly able to take care of himself, and that the cruise line had simply used his accident as an excuse to get him off of the ship.

I'm embarrassed to admit that at first glance this story made me snicker. After all, the whole scenario seemed a bit absurd, a very disabled man signing up for a nudist cruise, sure to be populated with some extremely able-bodied naked people, a situation that seemed rife with all kinds of potentially (pun alert!) prickly situations and scenarios. One could easily question the man's motivations, and ridicule the almost predictable state of affairs he found himself in, but I quickly realized I was casting judgment on the man when perhaps all he was trying to do was be "normal", and satisfy some lifelong curiosities.

Putting aside all questions of infringements on the rights of the disabled and the legality of cruise line's actions, who among the afflicted doesn't yearn for some normalcy, to just once act on our wants and desires without having to account for the physical and emotional burdens wrought by bodily disability? Though taking a nudist cruise might not be everybody's cup of tea, it obviously was Mr. Keskeny's, and by God he went for it, torpedoes be damned. Certainly, his motivations for wanting to take the trip were no more or less prurient than those of his able-bodied fellow passengers, so why should the fact of his disability make any difference whatsoever? If he wanted to explore his sexuality in this manner, or simply just wanted to feel the freedom he perceived in the nudist lifestyle, more power to him. Rather than be subverted by his disability and assume the role of social outcast, Mr. Keskeny asserted his humanity and followed his heart's desire, certainly displaying some bravery in the process. Good for him.

· On another sexually related tangent, the drug sildenafil, better known as Viagra, has been shown in animal studies to reverse the course of multiple sclerosis symptoms (click here).

Upon seeing this headline, I reasoned that since Viagra works as a vasodilator, opening veins, this could play into the CCSVI scenario. Upon further investigation, though, it appears that the mechanism of action in regards to MS is the reduction of infiltration by inflammatory cells into the central nervous system. The mouse model of MS, called EAE, was used in the studies, and mice with EAE don't have blocked veins.

The fact of the matter is that EAE is a terrible model for human multiple sclerosis, and is induced by injecting the unfortunately targeted rodents with myelin proteins, provoking an allergic reaction within the animal that results in central nervous system damage. This bears little if any resemblance to the disease mechanism of the human illness, which is why so many loudly trumpeted "breakthroughs" in MS treatment on mice fail to translate into similar success stories when tried on humans. The simple fact of the matter is that mice don't get MS.

However, if Viagra does eventually prove to be beneficial in the treatment of multiple sclerosis, how ironic that a drug renowned for increasing stiffness in a certain body part might relieve a disease one of whose hallmarks is severe muscle stiffness. All I can say is that if the famous little blue pill is effective in treating multiple sclerosis, a lot of newly spry men are going to need to get their trousers altered, needing a little more room just below the waist…

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Saturday, June 4, 2011

Remembering Bobby Kennedy

Attorney General Kennedy and Rev. Dr. Martin L...

Image via Wikipedia

I am a man with very few heroes.

It disturbs me to see the word hero tossed around almost indiscriminately these days, as it belittles the few individuals truly deserving of the honor. Though I respect many people, some deeply, there are only a few whose words and deeds have led me to attempt, usually with pathetic results, to emulate the examples set by them. One such person is Robert F Kennedy, who was felled by an assassin's bullets late in the night of June 4, 1968, 43 years ago today.

Bobby Kennedy was by no means a perfect man, as has been well-documented by numerous tell-all books and our insatiably gossip hungry media. He was a complex individual, intelligent, introspective, and headstrong, possessed of ego and at times known to be ruthless. But he was also an idealist, a man whose thoughts, and the actions driven by them, evolved through a life that saw devastating personal tragedy. After the assassination of his brother, President John F. Kennedy, RFK went through a long dark night of the soul, only to emerge more resolute than ever to devote himself to public service and fight for his deeply held moral convictions, against societal injustice and for the weak and disenfranchised.

Robert Kennedy started his political career working in the office of Sen. Joseph McCarthy, who at the time was in the midst of his vile early 1950s anti-Communist witchhunt, which resulted in the destruction of the reputations and livelihoods of dozens of innocent victims. From those ignominious beginnings sprang a career that saw Robert Kennedy champion civil rights, advocate for the poor and marginalized, fight organized crime, and help pull the world back from the very brink of nuclear Armageddon during the Cuban Missile Crisis.

After his belated entry into the 1968 presidential race, his campaign to win the Democratic nomination gained increasing momentum, culminating with his victory in the California primary on June 4, 1968. Minutes after delivering his victory speech at the Ambassador Hotel in Los Angeles, he was shot while attempting to exit the building with his entourage. Though an assassin, Sirhan Sirhan, was named and convicted, controversy still rages over the tragic sequence of events that transpired that night. Robert Kennedy lingered for two days, and died on June 6, 1968.

Had Kennedy won the nomination, and eventually the presidency, the historical timeline would certainly have been significantly altered, probably beyond all recognition. There would have been no President Nixon, no Watergate scandal, a quicker end to the Vietnam War, and no massacre at Kent State. Without these traumas inflicted on the psyche of the United States, one can only imagine that the arc of history could very well have been much more benign than that which did ultimately become reality. The promise represented by Robert Kennedy cannot be overstated, nor can the tragedy of his loss.

Perhaps the best way to illustrate the merits of Sen. Kennedy is to let the man speak for himself. On April 4, 1968, just two months before his own assassination, Dr. Martin Luther King Jr. was assassinated in Memphis, Tennessee. On the evening of the King assassination, Bobby Kennedy was scheduled to address an inner-city audience in the heart of Indianapolis, Indiana. Knowing that his audience would be largely black, and almost certainly unaware of Dr. King's assassination, Kennedy had little time to formulate his thoughts, much less write a polished speech. Without the help of aides or speechwriters, he jotted a few notes to himself on the ride to the site of the rally, and then delivered, almost completely extemporaneously, an eloquent and profoundly emotional speech. No teleprompters, no calculations of political consequences, just intelligent and respectful words delivered from the soul. He didn't speak down to his audience, but addressed them as peers, sharing with them the anguish of having suffered the murder of a loved one. As a result, Indianapolis was one of the few American cities spared vicious riots in the wake of Dr. King's assassination.

Here is the speech Robert Kennedy delivered that night…

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Rest in peace, Bobby Kennedy.