Another case of human experimentation

One year ago this month, a JFS Special report described the first human experimentation on a fat man who was surgically implanted with electrodes inside his brain and exposed to electrical currents trying to make him lose weight. Fifteen months after the procedure, the man weighed more.

Last week, ABC News Nightline aired the exclusive testimonial from the second person in the United States to under go deep brain stimulation for weight loss. It was one of the clearest examples of media participating in the marketing of medical devices for off-label, non-approved uses.

What viewers didn’t hear was the full story. When it comes to health news, and especially obesity, failing to provide balance has sadly become all too common. But people’s lives should matter more than ratings or profits and the public deserves the rest of the story.

Caloric management of obesity

The ABC News special, A Frontier of Medicine: Brain Surgery for Weight Loss, began by describing a mother of two who saw her weight as her worst problem. Weighing 230 pounds, she had tried every possible way to restrict her caloric intake — including diets, diet pills and bariatric surgery — without long-term success. “I’ve tried them all and [the weight’s] not coming off,” she said. “I really believe it’s got something to do with the brain.”

Viewers didn’t hear that, as a rule, no weight loss intervention has ever been shown to healthfully have long-term success and that virtually everyone regains their weight within five years. That’s because, of course, our body types and sizes are not determined by will power or our diet.

While such beliefs are popular and help to sell a lot of short-term weight loss diets and programs to the public, obesity researchers long ago moved on from dietary factors as having a causal role in true obesity. Obesity is not a disease of overeating, despite the popular condemnation of fat people as being to blame for their size and “noncompliant” with diet and medical management. Fat people as a whole are metabolically just like lean people, except they’re bigger, said Dr. Rudolph L. Leibel, M.D., whose laboratory at Rockefeller University in New York conducted some of the most extensive metabolic research on energy and the biochemistry of fat. Fat and thin people eat no differently to explain the diversity of body types and sizes. A 400-pound nondieting person who is maintaining his/her weight at their natural range is no more a glutton than someone 150 pounds at their set point weight, he said.

As Dr. Jeffrey M. Friedman, M.D., Ph.D., head of the Laboratory of Molecular Genetics at Rockefeller University, explained: “The average human consumes one million or more calories per year, yet weight changes very little in most people.” Research has shown that through diet and exercise, people have a long-term control over their weights within a 10- or 15-pound range, said Dr. Friedman. That’s never going to transform someone into a different body type — make a naturally fat person thin or a genetically lean person obese.

Nor is obesity a mental or behavioral disorder, although the fattest people do experience a disproportionate degree of stigma, even in healthcare and among healthcare professionals. Still, the prejudicial belief that obesity is caused by overeating, an addiction to food or a psychological disorder continues today.

Deep brain stimulation (DBS) is founded on the unsound premise that obesity itself is a disease caused by uncontrolled eating. Dr Julian Bailes, M.D., chairman of West Virginia University’s department of neurosurgery, told ABC News that obesity was a behavioral problem, with something in the brain that makes people unable to control their eating. DBS was called “the best chance” for fat people who fail to lose weight. No evidence was provided to support this claim.

Clearly, the woman in the story had come to believe that overeating was the cause for her weight. After a lifetime of dieting and even bariatric surgery, at the time of her DBS surgery, she weighed about half of her former weight. She interpreted her feelings of hunger as being a disorder and a problem of being unable to control her eating. Instead, she exhibited precisely what the Rockefeller University researchers found when fat people lose a lot of weight or are trying to restrict their eating to maintain a weight below what is natural for them: that while they might look like a naturally thinner person on the outside, by every metabolic and clinical measure, their bodies are starving. They are hungry.

“So what they’re going to do is... insert needles into the part of my brain that controls the food,” the mother in the ABC News story said. Her surgeons drilled about ten centimeters into her brain to the hypothalamus, where they placed a wire that would carry an electrical impulse and make her think she was full. Two pacemaker-type devices were implanted into her chest to control the amount of voltage that is sent to her brain. “Our ideal plan would be to set the electrical setting at just below that threshold of nausea” so she’ll eat less, said her surgeon. As Dr. Bailes said:

This is a frontier of medicine, a frontier of neurosurgery, a frontier of neurological disease, to be able to generate tiny pulses of electricity in these deep nuclei of the brain, and to see what effect they may have on behavior, including in this case the behavior of eating and the issue of uncontrolled appetite...

ABC News viewers weren’t told that all efforts directed towards the hypothalamus for the treatment of obesity in humans have failed, even surgically cutting the hypothalamus. Dr. Andres Lozano, M.D., Ph.D., and colleagues, who had performed the first human experiment of DBS for weight loss, had cited only one study of hypothalamic lesion surgery for the treatment of obesity. It was from 1974. And there is a reason this procedure hasn’t been adopted in the 24 years since then — it didn’t work!

Dr. Lozano explained at the 6th Annual Scientific Meeting of the International Functional Electrical Society Meeting in Cleveland, Ohio, that the use of DBS for eating disorders borders on science fiction. “The control of appetite is tightly regulated by the hypothalamus as clearly established in animal experiments.” So it was believed that neuronal activity could have strong effects on appetite in humans, he said. “It turns out that neurosurgeons have already made this leap by lesioning the hypothalamus in humans to treat obesity,” he said. “Seven patients in Denmark were treated in this fashion and all lost weight in response to coagulation of the lateral hypothalamus. However, over a year after intervention they all regained the weight and the initial effect was lost.”

It was then hoped that DBS might work better than surgery over the long-term because the currents could be turned on and off and sustain the results longer without an accommodation effect. But this hasn’t proven the case, either. Short-term efficacy may not translate to long-term efficacy, even for the effects in Parkinson’s disease patients followed for more than four years, Dr. Lozano’s research found. And, rather than weight loss, Italian researchers reported of weight gain among their Parkinson patients receiving DBS, beyond that explained by the control of movement problems with medication (levodopa).

Never the less, ABC News viewers were told:

Surgeons believe the procedure is effective in treating behavioral problems, such as obsessive compulsive disorder and depression, and now hold hopes about using it to fight obesity. Neurosurgeons from West Virginia University Hospital are leading the way with a Food and Drug Administration approved study of deep brain stimulation for the treatment of obesity.

A search of human clinical trials registered at clinicaltrials.gov, however, finds no DBS trials for obesity or weight loss, as would be required to seek FDA-approval.

Nor is there any clinical research in humans to suggest that DBS holds promise as a treatment for obesity. This was confirmed in a review of the medical literature on DBS for the treatment of obesity published last fall in the Journal of Neurosurgery. Its authors at the University of Pennsylvania School of Medicine said the promise of DBS was in equating obesity to a “refractory neuropsychiatric disorder.”

Even more importantly, there is no evidence that the use of DBS in fat people improves their health or lifespan.

Painting a rosy picture

The ABC News story depicted only the first four weeks for this patient and only one week since the electrical currents had been turned on. “The morning after surgery, Carol was irrepressible,” ABC News reported. She told viewers she was “confident about it” and that her “body feels different.”

I feel like I am more, I'm more satisfied as far as food goes. And & I feel better… When I eat, I get full faster. I just don’t have the cravings like I used to have.

Of course, this isn’t science, nor was it a controlled, double-blind experiment. Subjective feelings are exceedingly easy to manipulate by the placebo effect. She could have been easily made to be convinced that an ear piercing made her feel the same way. A testimonial after one week is not credible evidence for an effective weight loss intervention in anyone’s book. It's a popular marketing technique. Yet, the glowing projections for DBS continued for paragraphs. Dr. Bailes closed the ABC News story by saying they are confident her results will be positive:

This may be the tip of the iceberg…[and] open the door for clever people and brilliant researchers to look at what the other applications could be. I think we can’t foresee some of those now.

ABC News described the lobotomy-reminiscent surgery at length, making it sound like a piece of cake. Readers were told that “since there are no pain receptors in the skull or brain, [she] required only a topical anesthetic wash applied to her scalp.” She said it didn’t hurt and she was awake throughout the surgery. “Almost miraculously, doctors were controlling [her] stomach through her brain,” the public was told.

The risks of the brain surgery and post-op complications from the procedure were minimized. The only mention of possible complications was a single sentence stating: “There are risks associated with the surgery — from infection and hemorrhaging, and in the most extreme cases (less than one percent) paralysis or death.” But Dr. Bailes said “the FDA had been ‘appropriately scrutinizing’ the study.”

As covered last year, most medical sources had depicted DBS cautiously and described a far less rosy picture. “There is approximately a two to three percent chance of brain hemorrhage that may be of no significance, or may cause paralysis, stroke, speech impairment or other major problems,” according to the Cleveland Clinic in Cleveland, Ohio. “This means that for every 100 patients who undergo surgery, two or three will experience a permanent or severe complication.”

Brown University reported additional side effects that included paresthesia or other unusual or unpleasant sensory experiences; disequilibrium; weakness; difficulty in articulating words, caused by impairment of the muscles used in speech; and changes in mood, memory, or cognition.

Dr. Lozano and colleagues reported that even in short-term studies, “device complications were common and necessitated additional surgical procedures in approximately 40 percent of patients.” What's more, and also not mentioned on ABC Nightline, the DBS batteries last between 6 months to 5 years, depending on the dosage, and surgery is required each time the battery needs changing.

At a meeting of the American Neuropsychiatric Association, Dr. Lozano also described a troubling complication observed when stimulation spread to the hypothalamus, which is the target for DBS:

[T]here have been reports of aggressive behavior induced by intraoperative stimulation in the vicinity of the subthalamic nucleus, thought to be related to the spread of the current to the hypothalamus. There have also been acute depression and anxiety induced by stimulation in the vicinity of the substantia nigra pars reticulata; there have also been reports of euphoria and laughter... by stimulation in the subthalamic nucleus. Because the subthalamic nucleus is rather small... it’s quite difficult to only be in the motor territory without having some spillover into the cognitive and limbic territory, so we often, if the current is too high, or if the electrodes are misplaced, get some of these collateral effects.

Mayo Clinic cautioned that “because deep brain stimulation involves brain surgery, the procedure may be especially risky” and the long-term risks are still unknown. The most common side effects and adverse health problems seen with DBS, according to Mayo Clinic, include: bleeding in the brain, infection, delirium, unwanted mood changes, movement disorders, lightheadedness, insomnia, panic attack, speech difficulty, movement problems and even suicide. It advised patients to weigh the pros and cons carefully. If your condition “is incapacitating or life-threatening,” it said, “you may be more willing to face the risks.”

But ABC News made no mention of any of the research to date showing the extensiveness of the complications. Nor did it mention any of the latest studies. Several studies have been published this year describing experiences with DBS, as researchers try to put the risks and benefits into perspective. These studies reported complications that weren’t described on Nightline but are important for anyone trying to make an informed decision about DBS for weight loss.

The largest published, randomized, controlled study of DBS was conducted at seven Veterans Affairs and six university hospitals on a total of 255 patients. This study compared the benefits and risks of DBS compared to the best medical therapy for advanced Parkinson’s Disease during six months of follow-up. The results, published in the January 7, 2009 issue of the Journal of the American Medical Association, found that the DBS group experienced nearly three times the number of serious adverse reactions compared to the medical therapy group: 659 in the DBS patients compared to 236 in the medical therapy group. Most (83 percent) of the serious adverse events were attributed to the device, surgical procedure or stimulation therapy, stated the sponsor, Medtronic, in its press release. Ten percent of the patients developed infections, resulting in the need for the implanted devices to be removed and patients to receive antibiotics. One patient died from a brain hemorrhage within 24 hours of being implanted.

Medtronic also noted: “DBS was associated with small decrements in cognitive test performance at six months. During the six-month follow-up, there were significantly more events (serious and non-serious) for DBS than best medical therapy for gait disturbance, falls, depression, and dystonia” (each side effect was experienced in more than one in ten patients). The study also reported that by the 3-month follow-up, nine patients had withdrawn, mostly due to severe psychological or medical complications, and another three were lost by the 6-month check-up.

In choosing to try any medical procedure, especially an experimental one, higher risks may be accepted in conditions that are extremely severe or life-threatening. Far less risk is acceptable for relatively healthy people. So, “liver toxicity may be acceptable in a drug approved for cancer, but unacceptable in a drug approved for acne,” explained Drs. Adriane Fugh-Berman and Douglas Melnick. A brain infection and second surgery among one in ten elderly patients with advanced Parkinson’s Disease may be acceptable to patients suffering severe disability, but few would consider these risks appropriate for a relatively healthy woman who just wants to lose weight.

To support the use of radical experimental procedures with such high complication rates for weight loss requires exaggerating the deadliness of being fat. “Remember that obesity itself will reduce your life expectancy maybe 20 years,” Dr. Bailes claimed on ABC Nightline. However, equating the risks of being fat with those of 70-year old men with advanced Parkinson’s Disease is not supported in any credible medical literature.

Even the most morbidly obese woman has a longer life expectancy than a normal weight man and, as Dr. Edward Harry Livingston, M.D, at the University of Texas Southwestern, reported, “based on obesity alone, a woman was no more likely to die at a body mass index of 50 (approximately 310 pounds) than at 35.” Even the findings of the Aerobics Center Longitudinal study of over 25,000 men followed for more than ten years, found that the older men get, the more consistent the survival advantage the heavier they are. The main point is that there is considerable evidence to support that fatness isn’t nearly the death sentence that we’re being led to believe.

Off-label promotion?

A Reuter’s article giving advance publicity for the ABC Nightline program said: “Bailes told Reuters that the West Virginia University hospital was the only one in the United States, and the only center he knew of worldwide, using the deep brain stimulation technique specifically on obese patients.”

Neither Reuters or ABC News made any mention of the fact that DBS is not approved by the FDA for use in weight loss.

Medtronic, Inc. says it is the only company with a commercially-available DBS system. It is the primary sponsor of DBS research, both here and in Europe. To date, DBS has been reserved for severe tremors in Parkinson’s disease and other movement disorders that have been unresponsive to other forms of treatment.

Yet within the past year or so, ABC News has aired at least five other features on deep brain stimulation, promoting it for unapproved uses, including obesity, OCD, memory loss, Alzheimer’s and depression:

● Can Deep Brain Stimulation Unlock Lost Memories?

● Procedure Leaves OCD Patient Reborn

● Shocking the Brain Into Happiness

● Lifting the Veil of Depression

● Hope for Alzheimer's? Deep Brain Stimulation

Cleveland Clinic is one of three centers in the U.S. testing Medtronic’s DBS device for mental disorders. Is this another case of marketing as media-supplied news from Cleveland Clinic News Service?

In a recent Public Library of Science Medicine article, Drs. Fugh-Berman and Melnick said that promotion by manufacturers of a drug or medical device for off-label use is usually illegal. Their paper examined the impact on public health with off-label promotion and described techniques companies use to “covertly promote off-label use even where such promotion is illegal.” While off-label use is sometimes unavoidable and in patients’ best interests, their paper concluded that:

Allowing off-label promotion of drugs for untested, unproven benefits maximizes industry profits at the expense of public health. A risk–benefit ratio cannot be assessed without knowing whether benefits exist. Where no benefits exist, no risk is acceptable.

Pharmaceutical marketing has distorted the discourse on off-label uses and encouraged the unmonitored, potentially dangerous use of drugs by patients for whom risks and benefits are unknown. Companies that engage in off-label promotion should be heavily fined and their future marketing practices subject to increased scrutiny by regulatory agencies.

How much might promotional marketing to the public influence regulatory officials or medical practice?

OCD. Last month, on February 19, 2009, Medtronic reported that its Reclaim DBS device, dubbed a “brain pacemaker,” had just been approved by the FDA for obsessive-compulsive patients — a type of anxiety disorder that causes patients to have constant upsetting thoughts, such as fear of germs. [Yes, like Adrian Monk (Tony Shalhoub), the obsessive compulsive detective depicted on TV.]

This became the first time the FDA has ever approved the use of DBS for a psychiatric disorder. It was not approved based on sound clinical trial evidence, however, but under the FDA’s human device exemption policy. This policy allows “life-saving medical devices” to be approved as a humanitarian use device (HUD) without full clinical trials. As the FDA states, to apply for this exemption to market a medical device, a company is “not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose.” Instead, a company need only demonstrate the safety and probable benefit over risks, that there is no other treatment available and that the company could not otherwise afford to bring the device to market.

However, the FDA clarifies, a HUD exemption only approves the marketing of the device, not its use. An HUD may only be used on a person after it’s been given IRB approval. Any HUD device must also state on the label that it’s a humanitarian use device and that the effectiveness of the device for the specific indication has not been demonstrated. (No mention of this fact was made on ABC Nightline.)

As Medtronic stated in its February press release, the FDA based its decision on case reports of 26 patients with severe OCD after one year of using the device. Research on the Medtronic device for the treatment of OCD was conducted at three U.S. medical centers (Cleveland Clinic, University of Florida, Gainesville, and Butler Hospital in Providence, RI).

Published long-term outcome data of DBS for OCD, however, is limited to about 12 patients, with mixed results.

A Medtronic spokesperson said its DBS device is expected to be available for OCD by mid-year, at a cost of about $60,000.

Depression. Medtronic stated that it has been sponsoring research of DBS for other mental disorders, such as depression. In a Medtronic press release, Donald Malone, M.D., psychiatrist at Cleveland Clinic and co-lead investigator of the study said: “This patient population is so severely impacted by their disease that they struggle to engage in social activities or even daily tasks.” The 16-week trial just began recruiting last month. “This clinical trial is an important step forward in evaluating this therapy in a severely depressed patient population where currently available treatments have not provided relief,” said Dr. Malone.

When all the research for a medical intervention originates from a single source, as we learned this past week, special care in examining the research can be valuable. To add a sticky note to DBS research, Medtronic has been especially mired in controversy over recent years, with whistleblower lawsuits, recalls, and investigations of ethical scandals. More than a hundred doctors had been implicated in bogus consulting agreements, sham royalty agreements, accepting lavish trips and kickback schemes to buy and promote its bone graft product, that accounted for nearly 20 percent of the company’s $13.5 billion in revenue in 2007.

The securities class action suit filed against Medtronic also alleges that the positive claims regarding its device were false and misleading, revenues were based on an illegal campaign to encourage off-label uses, and the company failed to disclose that a significant and increasing number of patients were suffering severe medical complications.

That same year, the FDA had issued a Class 1 Recall, its most serious type of recall where “there is a reasonable probability that use of the product will cause serious injury or death,” of Medtronic’s Sprint Fidelis defibrillator wires. By this past Friday, March 13, 2009, Medtronic reported that the number of deaths believed attributed to its faulty defibrillator wires had risen to thirteen.

We may believe we advocate for the best evidence-based medicine that saves lives, restores health and alleviates suffering. But how willing are we to do the hard work of critically examining the research, insisting on that evidence and speaking out when it’s not there?

© 2009 Sandy Szwarc