A Controversial ‘Cure’ for M.S
By PAUL TULLIS
The defining element of Adam Gottschalk’s life today is that he has multiple sclerosis. This wasn’t always the case. He lived a more-or-less-normal life for a while, even after his diagnosis, but like most people with M.S., he was always bracing for the next relapse of partial paralysis or numbness or vision failure or any of the other attacks the disease unleashes unpredictably on the nervous system. Thirteen years after his diagnosis, Adam is now a case study of the degeneration that eventually occurs in everyone who gets M.S. He is only 42, but his physical capabilities are like those of an 80-year-old. His hands tremble, he walks with difficulty and his speech is labored and halting.
Adam Gottschalk, left, who has M.S., and his older brother, Chris, a neuorologist, have differing opinions on a treatment Adam received.
For a time in the early 1990s, Gottschalk busked outside the Shinjuku subway station in Tokyo, playing Dylan and Beatles songs, and of all the things M.S. robbed him of, it’s the ability to play guitar that he longs for the most. “I miss that part of myself,” he told me when we met at his home last winter. Because he can’t drive, Gottschalk spends most of his time inside his single-story house north of Tampa, Fla. He works part time operating a natural-perfume business, writes plays and poems, listens to obscure music at high volume and smokes a lot of pot (he says marijuana helps with the chronic pain that’s one of M.S.’s more baffling symptoms). Several times a day Gottschalk takes five different drugs: one to keep his M.S. from getting even worse, three for his seizures and an antidepressant that helps him sleep. Dietary supplements cover the buffet in his dining room.
In the last couple of decades, nine new drugs have come on the market to treat M.S.; at least four more are currently being tested on humans. Few diseases have seen such radical transformation of treatment options in such a short time. Yet for all the new options, many of the 2.1 million people worldwide afflicted with the disease (400,000 of them in the United States) have not seen improvements, and some M.S. patients find that the adverse reactions from the drugs aren’t worth the benefits.
Gottschalk’s neurologist started him on the M.S. drug Copaxone in 2000, but he had a relapse a few years later. So Gottschalk started taking Rebif, giving himself two shots a week until the drug’s side effects — severe flulike symptoms for 24 hours — became too much to bear. Next, about once a month for five years, Gottschalk was given an infusion of Tysabri, an even newer M.S. drug. A rare side effect landed him in the hospital in 2010 and almost killed him.
Surfing Facebook one day shortly after the Tysabri scare, Gottschalk learned that an Italian vascular surgeon named Paolo Zamboni had hypothesized that the real cause of M.S. was something called chronic cerebrospinal venous insufficiency, or CCSVI. For decades, doctors have been confident that M.S. comes about because the immune system attacks the brain, though they don’t know why it does so. Zamboni contended instead that blocked veins prevent blood from draining from the head, causing iron to back up in the brain and damage nerves that send messages to the body.
Zamboni’s first study, published in 2009 in a small neurological journal, purported to find CCSVI in 100 percent of M.S. sufferers at one stage of the disease, and he developed a surgical procedure to treat it: opening the veins that carry blood away from the head with the aim of restoring normal blood flow. This would be done by inflating a small balloon inside the vein to widen the passage, and in rare instances by placing a device to keep it open (as is commonly performed in the arteries of patients with heart disease). Zamboni’s study was small, just 65 subjects, and though he had compared them with a control group, he knew which patients had M.S. and which did not. But news of CCSVI traveled quickly, and M.S. patients started seeking diagnostic procedures to see if they had CCSVI, as well as the surgery to treat it.
Gottschalk remembers coming across a YouTube video of a man in a wheelchair, who says he has M.S. The video cut to a scene of the man walking around normally, announcing that the change is a result of the vein-opening CCSVI surgery. Gottschalk’s girlfriend, Mary Alvarez, watched the video and said, “You should do this.” He felt persuaded, too. He didn’t look at Zamboni’s studies or at any of the subsequent studies investigating CCSVI. “I was just kind of going on what other people were saying their experience was,” he said.
His willingness to try the procedure went against the advice of Gottschalk’s older brother, Chris, a neurologist who teaches at Yale School of Medicine and treats patients with M.S. Chris advised his brother of the risk of an invasive procedure that wasn’t demonstrated to be safe or effective, to treat something that wasn’t established as a legitimate condition in the literature. He tried telling Adam that other supposed cures for M.S., like bee-sting therapy and aloe infusions, fell apart when examined scientifically. But Adam was not persuaded by his brother’s expertise. “I have really, like, heavy M.S.,” he recalled one night. “And it was getting worse by the day. So by the time I got ready to do the CCSVI treatment, I was just: ‘I’ve had enough of this! I have to do something that maybe will help me.’ ”
In July 2011, Gottschalk flew to California and paid $11,000 to undergo the angioplasty procedure. I met him for lunch the following day, at his hotel around the corner from where he had the surgery. Although still using the cane I’d seen him with at an earlier meeting, he was buoyant as he sat down to eat. He said he could already notice improvement in his symptoms.
On a crisp October day, I met Paolo Zamboni in his office on the second floor of the Ospedale di Sant’Anna, just inside the medieval ramparts of the northern Italian city Ferrara. Zamboni, who is 55, was dressed in a blue Lacoste shirt and wore glasses with light blue frames. He rose with difficulty, and when he reached out to shake my hand, he could scarcely grip it. Zamboni has a rare degenerative neurological disorder called multifocal motor neuropathy.
Zamboni’s wife, Elena, received a diagnosis of M.S. in 1995, three years after he discovered his condition. The couple explained their illnesses to their daughter, who was then 16, on a train to Poland, where they were going to a conference. When they got to Warsaw, Zamboni recalled: “We had a night of forbidden things: cigarettes, beer and dancing on a table in a tavern. It was the last time I danced.”
For five years, drugs kept Elena’s M.S. at bay, but in 2000 “there was a terrible relapse, with heavy symptoms,” Zamboni said. As an expert on arteries and veins, Zamboni had relatively little knowledge of the brain. But when Elena’s condition worsened, he felt compelled to begin his own research into her disease. He went to Paris, where Dr. Jean-Martin Charcot was the first to systematically describe the disease in 1868. “I discovered, in an old library, a book of original discoveries of Charcot,” Zamboni told me, smiling at the memory. The most intriguing to Zamboni was finding that from Charcot’s time until the 1980s, researchers had searched for a link between blood flow and M.S. “There was an entire century where researchers were aware of a vascular component of M.S.,” Zamboni said.
He also came across a paper published in the 1980s by a London pathologist, C. W. Adams, on microscopic anatomical findings showing inflammation in the brains of M.S. patients. Adams’s slides were similar to what he had observed in chronic venous disease in other parts of the body. “It was amazing to see,” he told me. “I decided to look more to the veins of the brain.”
Back in Italy, he examined people who died with M.S. and found evidence of venous hypertension in the brain.
This was around 2002. At about that time, his wife had another relapse; she lost her sense of balance and was unable to walk for weeks. Meanwhile, Zamboni recalled, “my mind was bombarded by the question: Why are there signs of venous insufficiency in the brain? Nobody ever proposed such a parallel. Until one morning I wake up snapping my fingers.” The revelation hit him that he needed to look outside the brain, to the veins that drain blood from the head. “I hypothesized there were some blockages. Nobody found blockages in the brain, so I thought I have to explain them out of the brain.”
In 2006, Zamboni proposed that vein abnormalities or obstructions were partly reversing blood flow in neck veins of M.S. patients, creating an iron overload in the brain. The following year, in May, his own hand no longer capable of guiding a scalpel, Zamboni asked a fellow surgeon to widen the veins delivering blood from Elena’s head back to her heart. Though I didn’t meet Elena, Zamboni told me she hasn’t had a relapse since.
Since Elena’s surgery in 2006, as many as 20,000 people worldwide have undergone angioplasty in the main veins in the neck. This has been largely because of the efforts of a former opera singer named Joan Beal, whose husband, Jeff, was given a diagnosis of M.S. in 2007. A 49-year-old film composer, Jeff recalls that after his diagnosis, Joan “immediately launched into hypervigilant great-wife mode” and began researching the disease and interacting with M.S. patients online.
“I didn’t like that the doctor said, ‘We don’t know what causes it,’ ” Joan says. “ ‘We don’t know how it’s going to progress, we don’t know if the medicine’s going to work.’ ” She started looking into the disease and sent research she collected, including one of Zamboni’s studies, to a medical researcher, who passed it along to Michael Dake, a cardiothoracic surgeon at Stanford. In May 2009, he performed on Jeff Beals what is thought to be the first CCSVI surgery in the United States.
A couple of weeks later, on a blog called This Is MS, Beal posted that during the procedure, he experienced “a sensation of more alertness . . . and more blood flowing. . . . [This] alertness has continued and improved.” He concluded, “To see something as promising and revolutionary as this come forward is nothing short of miraculous from where I sit.”
Four hours later, a This Is MS member called Rokkit posted, “Your story is an inspiration that is giving me hope for the future.”
That August, Joan Beal started the first Facebook page devoted to CCSVI, and in November the Canadian television newsmagazine program “W-Five” broadcast a segment about CCSVI and the angioplasty treatment in which the show’s host, Lloyd Robertson, spoke of “a stunning medical discovery — a revolutionary treatment for a most debilitating disease.” (Canada has among the world’s highest per capita incidence of M.S.) Zamboni appeared on the program saying that he was convinced that CCSVI is “a very important factor” in M.S. and also that “this factor can be treated.”
The procedure Zamboni pioneered isn’t offered in Canada, because of restrictions in its national health system, but patients traveled to the United States, Costa Rica, Egypt, Poland and Bulgaria to have it done. Positive reports about the results of the surgery started popping up in social media, where people began to refer to it as “liberation treatment.” These online recommendations set off a patients’ crusade — one prominent M.S. researcher calls it “an international frenzy” — for research into CCSVI. A bill was introduced into the Canadian Parliament to conduct a clinical trial on the Zamboni method. Patients pressured the U.S. National Multiple Sclerosis Society, and in June 2010, the society announced that $2.4 million — about 7 percent of its research budget — would be devoted to research on CCSVI.
This allocation was remarkable considering that many of the people who study and treat M.S. regard the theory as bunk. Dr. Robert Fox, medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, says he sympathizes with patients pushing CCSVI research but thinks it offers false hope. “People without a scientific background,” he says, “often view all scientific papers with equal weight. Well, scientists don’t. I don’t know of a more prominent example where there’s been such profound pressure, driven by a nonmedical and nonscientific — though rightfully very self-motivated — constituency on what specific treatments should be explored with weak scientific basis.”
All seven of the studies the society is sponsoring are attempts to verify Zamboni’s discovery, which would entail finding CCSVI in a significantly greater percentage of people with M.S. than in healthy control subjects or in patients with other neurological disorders. Zamboni’s studies were small, and because he knew which subjects had M.S. and which did not, even he cautioned that “bias could be playing an important role” in his work. So far, evidence backing up his CCSVI theory has been scant: the largest study to date, led by Dr. Robert Zivandinov at the State University at Buffalo, found it at a higher rate in patients with M.S. (56 percent) than in healthy controls (23 percent) but also at a higher rate in patients with other neurological disorders, which some interpreted to mean that even if CCSVI were a significant abnormality, it is not M.S.-specific. Moreover, finding CCSVI at all is problematic. Researchers conducting studies in Israel, Italy, the Netherlands and Germany found no abnormal blood flow in M.S. subjects they examined. Whether a patient is said to have CCSVI can depend on a number of extremely variable factors, like the settings on the ultrasound machine, whether the patient is sitting up or lying down and what volume of blood flow the investigator pegs as “normal.” (Zamboni recently recommended a standard protocol.)
Many mainstream M.S. researchers share the opinion put forward by Florian Doepp of the Department of Neurology at Charité Hospital in Berlin after reviewing studies of CCSVI and M.S.: “I conclude there is no evidence for CCSVI in multiple sclerosis and no evidence to support” the surgical treatment for it.
Zamboni’s hypothesis contradicted substantial evidence supporting the autoimmune hypothesis, including the fact that more than 50 genes have been identified as associated with M.S., and every one involves the immune system and the most successful drugs against M.S. work on the immune system. Moreover, patients with Parkinson’s disease have abnormally high iron levels in their brains but don’t develop M.S., undercutting Zamboni’s idea that an iron backup in the brain leads to the disease.
Earlier this month, The Journal of Vascular and Interventional Radiology published a study concluding that using the CCSVI surgery in patients with M.S. “appears to be a safe procedure resulting in significant clinical improvement.” But the study did not rely on randomized or blinded data to protect against observer bias and the placebo effect. I showed the paper to J. A. Reekers, a Dutch professor of interventional radiology, the medical specialty that performs the treatment. “The scientific value of this paper is zero,” he told me. “M.S. complaints are very much related to external psychological factors.”
The author of the paper was Dr. David Hubbard, a neurologist who became interested in CCSVI after his son, Devin, found out he had M.S. in 2009. “Look, if not for my son I’d be on the other side of this,” Hubbard says. He knows that the only way purists of evidence-based medicine will be satisfied is a trial in which some people get the actual angioplasty and others undergo a sham operation. Such a trial would be expensive, but pressure from M.S. patients has made it possible: two such studies are now under way.
M.S. is a vexing disease: it progresses unpredictably both across and within patients, making a treatment’s effectiveness difficult to assess. Elena Zamboni and Adam Gottschalk still take Copaxone, so it is hard to know if it’s the vein-opening surgery or the drug keeping relapses at bay. But Devin hasn’t taken any of the disease-modifying M.S. drugs for years, Hubbard says, and not only has he had no relapses since the surgery, but his latest M.R.I. showed he has fewer brain lesions.
Hubbard is working with Zamboni and others to form an explanation for why constricted neck veins would lead to M.S. that would address the doubts of neurologists like Chris Gottschalk. Central to their model is that “poor flow” is at the root of the damage M.S. does to myelin, an insulation layer critical to the functioning of the nervous system. In M.S., Hubbard theorizes, “the brain is not having as complete blood flow as it should,” allowing iron to build up and damage the myelin.
David Jones, who teaches the history of medicine at Harvard, sees a longstanding narrative of disease and illness in this hypothesis. “The notion of obstructed flow is one of the most ancient and persistent beliefs in medicine,” he says. “Throughout history, from the Greeks with the four humors to the 19th century, the belief was that when flow obstructs, tissue will putrefy. It’s a theory deep inside the logic of medicine.” Even though theories of putrefaction have been abandoned, Jones says, theories of obstructed flow persist. It’s an idea that makes intuitive sense to people.
For centuries, doctors saw the restoration of flow as proof that a treatment worked. A cathartic given to a patient with a stomachache, Jones says, provided “powerful, visible evidence” of what was assumed to be the treatment’s success. Flow that is obstructed in places that can’t be seen with the naked eye, like the veins, can now be seen in pictures. CCSVI doctors and patients speak of the ability to see restricted and restored flow on M.R.V.’s — an M.R.I. on the veins — as proof that CCSVI is real and the surgical treatment effective. Jeff Beal posted on This Is MS that when he learned about CCSVI, “on some gut level, it just seemed so darn plausible.”
When I asked Chris Gottschalk about the treatment and about his own brother’s faith in it, he told me, “It’s one of the saddest and most outrageous stories of scientific misconduct.” That doctors are performing CCSVI surgery, he said, is “just that much more extraordinary, because the hype has been so enormous and because of the serious risk.” Chris thinks that any benefit Adam feels is probably a placebo effect. Nonetheless, Chris said with resignation, “what can I say to him but ‘I’m happy to hear that you’re feeling better’?”
Dr. Michael Arata has performed the neck-vein surgery on about 1,200 patients, including Adam Gottschalk, since early 2009. Arata and his partners at Synergy Health Concepts in Costa Mesa, Calif., used to focus on patients with varicose veins and similar chronic venous disease, but now they advertise on Facebook and travel to CCSVI conferences, and the Zamboni procedure is all they do.
Speaking in his office late last year, Arata brushed aside mainstream scientific criticism: “I’m not treating M.S.,” he said. “I disagree with anyone who says this is an M.S. treatment. If you think it is, you should be in a clinical trial. There’s nothing that I’ve seen to help me predict who or what will improve” in terms of M.S., “whereas with CCSVI, I feel very comfortable telling patients, ‘Yes, you will see improvements in your sleep, you will see improvements in your energy.’ I can’t say that with any M.S. symptom.” Of course, sleep disorders and fatigue are common M.S. symptoms. Moreover, CCSVI’s very existence as a condition originated only in the context of M.S., a point underscored by the five Synergy patients I interviewed, all of whom said they had M.S.
Arata said the Zamboni procedure resembles those he does on other vein disorders. The F.D.A. calls such practices off-label; once an intervention has been approved in one part of the body, doctors can perform it elsewhere in the anatomy. “All the treatments I’ve done my entire career have been pretty much based on the same thing,” Arata said. “We’re not a specialty that has these huge numbers of cases that we generate randomized control trials and everything’s evidence-based. And having a couple of catastrophic events also doesn’t deter me.” He added: “Radio-frequency ablation of tumors had small studies, no randomization, driven by patients. There were a couple of deaths early on; it’s now mainstream. Early on the critics were oncological surgeons, and guess what? They’re now doing it.”
Dr. Michael Haupts, a CCSVI doubter who heads neurology at Augustahospital M.S. Clinic in Germany, agrees with Arata — up to a point. “Lots of procedures and operations get evidence-based only after a while, and maybe some you can never prove in evidence,” Haupts told me. But, he said, treatment for a chronic and incurable disease like M.S., which can be survived for many years, has a high bar for safety and effectiveness. Even Zamboni agrees with this sentiment. “With this big attention in social networks, it has generated a black market with speculation, with not properly performed procedures,” he says. “It’s unethical to offer a treatment when it’s in an experimental phase.”
In May, the F.D.A. issued a warning about the CCSVI procedure, underscoring that “there is no reliable evidence from controlled clinical trials that this procedure is effective” and that “the criteria used to diagnose CCSVI has not been adequately established.” The agency went further, “alerting people with M.S. to the risks of serious injuries and death associated with procedures to treat” CCSVI. At least one person has died shortly after the procedure, and there are reports of paralysis, blood clots and nerve damage in the brain, hemorrhaging and emergency surgery after a stent came loose and headed to the heart (stents are normally placed in the arteries, which carry blood away from the heart). Dake and Stanford Hospitals and Clinics are being sued by two patients claiming injury from CCSVI operations. (Stanford says the claims are without merit.)
This summer, after the F.D.A. warning came out, Arata e-mailed me with a change of view, attaching a paper he wrote and submitted to The American Venous Forum. He had “come to the conclusion that what we are treating is autonomic dysfunction,” he said. The paper included a list of symptoms of autonomic dysfunction that closely track many symptoms of M.S. It’s unusual for a doctor to reach a conclusion that a condition for which he already treated more than 1,000 people is not what he thought he was treating them for.
The surgery may be doing something for Arata’s patients, but it’s hard to say exactly what. “We know every time you do something on a hopeless person — inject, cut something, even stimulate with electricity — you will change his or her endogenous being and hormonal state and will have biological effects,” Haupts, the German neurologist, says. “If I would operate on people’s veins, I’m quite sure I’d have effects. Yet I know those effects will disappear and will not be really clear.”
That was essentially the message of a study of 462 patients presented this month at the major annual conference of European M.S. researchers and clinicians. Objective measures of disability showed there was no change after the surgery, and more than a fifth of the patients had relapses, some more than once. Yet more than half of all patients said their symptoms had improved. Researchers from the Italian Society of Neurology attributed the results to “high expectation.” CCSVI supporters took to the Web, criticizing the study; one Facebook post said it amounted to “huffing and puffing” and noted the scientists’ disclosures of relationships with pharmaceutical manufacturers. Whatever is happening to the patients, it seems to be temporary: many CCSVI patients return for a second (or even a third) operation several months after their initial procedures. Jeff Beal, who is one of these, says it’s “pretty common [to] need a tuneup or two.”
When I was in Arata’s office a year ago, I met Jack Karnes, a 53-year-old from the Seattle area, who had undergone the vein-clearing operation the previous day. Karnes uses a wheelchair and can barely speak as a result of M.S. He was elated that when his brother and caregiver, Randall, helped him out of bed that morning, his foot was able to move in a way it hadn’t in years. He demonstrated his newfound ability to touch the tips of his thumb and forefinger. “We’ll get you playing that guitar again in no time, Jackie,” Randall told him. “He used to be a hell of a guitar player.”
“Godsend,” Jack kept repeating. “Godsend.”
On the morning after his 42nd birthday, about five months after his surgery, Adam Gottschalk was sitting in his living room in Tampa. His father, Pete, had stopped by to help his son fabricate a mold for his perfume business, and he mentioned someone he used to know who has M.S. and is now being treated by his elder son. “Chris is his doctor?” Adam said, setting up his punch line. “Poor guy.”
The night before, Adam and his girlfriend drove into Tampa to meet his father and some extended family members to celebrate Adam’s birthday at a jazz club and restaurant. (Chris had to attend a conference that weekend.) After college, Adam was a D.J. on a radio program called “Post 69,” which played modern jazz, so there was some discussion about where in the club to dine — in the back room with the traditional jazz trio or in the front, where the louder, electric band would be playing. A compromise was reached: the group would eat in the quieter spot, then migrate after dinner.
Pete told me he can’t see any difference in Adam’s condition since the procedure. “He says he sleeps better and is more clearheaded, but those are things I can’t see. There’s no improvement in his mobility or his speech. I talk with his girlfriend, and she says the same thing. But I don’t say anything to him about it. He needs to feel like it was a beneficial experience.”
After dinner, the band broke into some classic funk as the Gottschalk family watched and listened. Adam’s sister, Leila, urged him to dance with his girlfriend. He put down his cane, took Mary’s hand and walked out onto the floor.
29 ottobre 2012