A carefully controlled study [There exist studies that are not carefully controlled ??? DCW] that tried to treat Parkinson's disease by implanting cells from aborted fetuses into patients' brains not only failed to show an overall benefit but also revealed a disastrous side effect, scientists report. In about 15 percent of patients, the cells apparently grew too well, churning out so much of a chemical that controls movement that the patients writhed and jerked uncontrollably.
The researchers say that while some patients have similar effects from taking too high a dose of their Parkinson's drug, in this case the drugs did not cause the symptoms and there is no way to remove or deactivate the transplanted cells.
On the researchers' advice, six patients who enrolled in the study but who had not yet had the implantation operation have decided to forgo it.
The results, reported today in The New England Journal of Medicine, are a severe blow to what has been considered a highly promising avenue of research for treating Parkinson's disease, Alzheimer's disease and other neurological ailments.
The study indicates that the simple solution of injecting fetal cells into a patient's brain may not be enough to treat complex diseases involving nerve cells and connections that are poorly understood.
Some say it is time to go back to the laboratory and to animals before doing any more operations on humans.
The findings may also fuel the debate over whether it is appropriate to use tissue from aborted fetuses to treat diseases. Despite their disappointment, some researchers said they hoped that the results would not bring fetal cell research to an abrupt halt.
The research has been controversial because the fetal cells were obtained from abortion clinics.
"This is still our one great hope for a cure," said Dr. J. William Langston, who is scientific director and chief executive officer at The Parkinson's Institute in Sunnyvale, Calif.
Parkinson's disease occurs when cells of the substantia nigra region in the base of the brain die, for unknown reasons. The hope was that fetal substantia nigra cells might take over for them. But, the study showed, in older patients the operation had no benefit and in some younger patients, the transplants brought on nightmarish side effects.
Although the paper depicts the patients with the side effects in impassive clinical terms, doctors who have seen them paint a very different picture. Dr. Paul E. Greene, a neurologist at the Columbia University College of Physicians and Surgeons and a researcher in the study, said the uncontrollable movements some patients suffered were "absolutely devastating."
"They chew constantly, their fingers go up and down, their wrists flex and distend," Dr. Greene said. And the patients writhe and twist, jerk their heads, fling their arms about. "It was tragic, catastrophic," he said. "It's a real nightmare. And we can't selectively turn it off."
One man was so badly affected that he could no longer eat and had to use a feeding tube, Dr. Greene said. In another, the condition came and went unpredictably throughout the day, and when it occurred, the man's speech was unintelligible.
For now, Dr. Greene said, his position is clear: `No more fetal transplants. We are absolutely and adamantly convinced that this should be considered for research only. And whether it should be research in people is an open question."
Dr. Gerald D. Fischbach, who was director of the National Institute of Neurological Disorders and Stroke, which sponsored the study, said that while the operation had been promoted by some neurosurgeons as miraculous, this was the first time it was rigorously evaluated. [!!!!!]
It used sham surgery as a comparison, a controversial and rarely used strategy but one that researchers felt was necessary to understand the true effects of the operation. Dr. Fischbach, who is now dean of the faculty of medicine at the Columbia University College of Physicians and Surgeons, was the director of the institute only at the end of the study. "Ad hoc reports of spectacular results can always occur," Dr. Fischbach said. "But if you do these studies systematically, this is the result you get."
The surgery, he added, "is not the final solution that people would have hoped going into it." [!!!]
In the study, researchers, led by Dr. Curt R. Freed of the University of Colorado Health Sciences Center in Denver and Dr. Stanley Fahn of the Columbia University College of Physicians and Surgeons, recruited 40 patients, ages 34 to 75, who had had Parkinson's disease for an average of 14 years. The patients were randomly assigned to have substantia nigra cells from four fetuses implanted in their brains or to have sham surgery, for comparison.The surgery took place in Colorado and the patients were evaluated in New York.
The fetal cell surgery involved drilling four small holes in the patient's forehead and then inserting long needles through the holes into the brain and injecting fetal cells. The sham surgery involved drilling the holes but not injecting needles into the brain. After a year, the patients were told whether they had the fetal cell surgery and, if not, they were offered it if they wanted it.
The study's primary measure of success was whether the patients themselves noticed that they were better, as determined by a survey that they mailed in a year later but before they knew whether they had had fetal cell implants or a sham operation. The study found no difference between the two groups — neither those who had had the fetal cell operation nor those who had had the sham surgery noticed an improvement in their symptoms.
Other tests, like neurologists' assessments of the patients while they were taking their medication and the patients' assessments of their condition in diaries they kept also showed no effect of the surgery.
And there was no difference between the two groups in the doses of drugs needed to control the disease.
The one glimmer of hope came from assessments by neurologists before the patients had had their first dose of medication in the morning. By that measure, the 10 patients under age 60 who had had the fetal cell implants seemed better than those who had had sham surgery, with less rigidity, although their tremor was just as bad.
Dr. Freed hailed that result, saying, "It was a clear-cut improvement."
And, he added, the fetal cells survived in most patients' brains. "I would be disappointed if people used a strict clinical trial approach," Dr. Freed said. "This study is about multiple phenomena."
Others were less enthusiastic, pointing out that finding subgroups after the fact who may have benefited suggests a hypothesis for future studies, not evidence of an effect. "We try to teach everybody that you have to identify beforehand what's the primary outcome," said Dr. William Weiner, the director of the Maryland Parkinson's Disease and Movement Disorder Center and a professor of neurology at the University of Maryland School of Medicine in Baltimore, referring to the measure of success determined before the study began.
"In this case, they picked a subjective assessment by the patients themselves, which I think is a very good one." And so, Dr. Weiner said, when the patients noticed no improvement, "the study was negative."
In addition, Dr. Langston said, even if a subsequent study confirmed that the surgery had an effect on the condition in younger patients before they took their medicine in the morning, and even if there was a way of preventing the terrible side effect, the operation would still hardly be a breakthrough. Parkinson's disease is almost always a disease of the elderly, he noted, adding that well under 10 percent of patients who would be candidates for the surgery are younger than 60.
The wiggling and writhing movements first emerged a year after the operation, showing up in five of the younger patients who had at first appeared to benefit from fetal cell surgery — three who had the operation in the initial phase of the study and two who had it a year later, when they learned that they had originally had a sham surgery.
While doctors sometimes see such effects in Parkinson's patients, it is caused by giving too much of drugs that act like dopamine in the brain. And it can be controlled by reducing the drugs. In this case, however, drugs were not the culprit. Even when doctors took away the drugs, the symptoms persisted.
The fetal implant study had been controversial from the start, both because it included sham surgery and because it used fetal tissue from abortions.
But many Parkinson's disease experts said it had to be done because doctors were already offering the surgery to patients, and charging them for it, at costs of $40,000 or more, with no evidence that they were helping them. [!!!!!]
Yet patients, facing a disease in which brain cells slowly and inexorably die and in which even the drugs that once controlled their symptoms of tremor and rigidity would inevitably fail, took their chances with the operation, thinking they had little to lose. Dr. Freed said he was the first in the United States to offer the treatment, starting in 1988 with a 52-year- old man, who is still alive although, of course, he also still has Parkinson's disease.
Dr. Freed continued to offer it to paying patients while he was treating those who were part of the federal study and whose procedures were paid for by the study. He said he considered these other operations research because he experimented with different amounts and placements of fetal cells. He has given fetal cell implants to 27 patients, he said, with the most recent operation last October.
Dr. Freed said his group was now implanting less fetal tissue and putting the tissue in a different area of the brain, hoping [At least his heart's in the right place. God knows where his head is. DCW] to avoid the devastating side effects. But, he said it would be a mistake to stop doing the surgery altogether.[!!!]
"To say that you can't do or shouldn't do human research because the research has uncertain outcome, I think would be a bad decision," Dr. Freed said.
Meanwhile, a second federally financed study of the operation is winding to a close, and some researchers say it is time to go back to animal studies and learn more about the complex roles of the brain cells involved in Parkinson's disease.
Dr. Weiner said that if a patient came to him today seeking advice, he would say: "The bottom line for patients is that human fetal cell transplants are not currently the best way to go. If you are willing to pay for them, you can still have them done. But my advice is you ought not to do this."