Parkinson’s Disease Treatment : Mexican Doctor Unfazed by Surgery Controversy

Dr. Ignacio Navarro Madrazo shows few signs that he has been showered by fame for most of the past 18 months--or that he has been under fire for the last month.

He still takes time to shake hands and chat with patients on a Friday morning as he makes his way to a cramped office on the sixth floor of the Specialties Hospital at La Raza Medical Center here, and he still greets visitors cordially, albeit somewhat shyly.

Only a new personal computer, a videotape monitor and a mammoth stack of entreaties from desperate victims of Parkinson’s disease hint at how his life has changed since he announced a new treatment for the disease a year and a half ago.

He reported then that by implanting tissues from the adrenal gland into the brain he had wrought near-miraculous improvements in the ability of patients to walk, speak and otherwise control their bodies. The tissues secrete a hormone, dopamine, that is involved in the control of muscular activity.

Such dramatic results prompted other neurosurgeons throughout the world to do the operation themselves, and more than 200 brain grafts have now been performed, half of them in the U.S.

But in recent months, some physicians have begun questioning the value of the surgery and--implicitly--the credibility of Madrazo’s claims for it. At a contentious meeting in Chicago last month, critics charged that the results of the surgery were frequently less dramatic than Madrazo had claimed, and that some patients got worse after the surgery.

“The disparity between what we see in American patients and what we have been told about the Mexican patients is substantial,” said Dr. Harold Klawans, a neurologist at Rush Medical College in Chicago who organized the meeting.

Four of Madrazo’s patients have died since their surgery--two perhaps as a result of the surgery. Perhaps most damning evidence against the surgery is the fact that in autopsies of those patients, the grafted cells were found to be dead. Further evidence of the controversy emerged last week when the British medical journal The Lancet urged a moratorium on the surgery until the long-term effects have been studied.

Other Results Told

Two weeks after the Chicago meeting, which was widely reported in the news media as refuting the success of the procedure, U.S. neurosurgeons reported results on 43 of their patients at a meeting in Toronto. Madrazo has also made available more information about the first 30 patients on whom he has operated.

This data, combined with Times interviews of nine patients, provides the most comprehensive picture of the Parkinson’s surgery yet available.

These results indicate that the surgery is not the panacea for Parkinson’s that it first seemed to be, but that it does seem to provide at least some benefits for the majority of the patients who undergo it.

The brain grafts produced remarkable improvements in seven of the American patients and one-third of the Mexican patients, enabling the severely crippled to become nearly fully functional. In another one-third of the Mexican patients and 31 of the American patients, the improvement was more modest: Tremors and stiffness were reduced and mobility was increased.

Failures Also Noted

But the remainder of the patients received little or no benefit from the surgery and some, in fact, got worse.

Furthermore, Madrazo and other neurosurgeons have concluded that the interaction of the grafted cells with the recipient’s brain is much more complicated than they had originally thought. The most important role of the cells may be to produce growth factors or other chemicals, he said, suggesting that even if the grafted cells do die, the procedure is still beneficial.

This has generated optimism among some researchers because it suggests the eventual availability of alternatives to the current procedure--ranging from the use of fetal cells to the use of growth factors and other chemicals isolated from genetically engineered cells.

“We clearly feel that there is something to this operation, a kernel of real potential,” said Dr. Abraham Lieberman, a neurosurgeon at the New York University Medical Center. “But it obviously needs refinement so it will be useful to more patients.”

Madrazo agrees. “I am not married with the (current procedure),” he said. “Fetal cell transplants are obviously the technique of the future, and we may find something even better. We have a long way to go.”

Parkinson’s disease, which afflicts as many as 1.5 million Americans, most of them over the age of 50, is characterized by severe tremors, rigidity of the limbs, slow movements and stooped posture. About 30% of the victims also suffer dementia, an impairment of mental functions.

Its cause is unknown, but deterioration of brain cells causes a decreased production of dopamine. Parkinson’s can be controlled in the early stages with a drug called L-dopa, which increases the brain’s supply of dopamine. As the disease becomes more severe, however, patients receive less benefit from the drug.

The adrenal glands--two walnut-sized organs that sit atop the kidneys--also secrete dopamine, but the hormone cannot reach the brain because of a blood-brain barrier that prevents many potentially harmful substances in the blood from reaching the brain’s delicate tissues. (L-Dopa can pass through the barrier and is converted to dopamine in the brain.)

Pioneered the Procedure

Madrazo pioneered the technique of removing one of the adrenal glands and grafting the dopamine-secreting tissues into the brain. There, scientists believed, the cells would continue to secrete the hormone and lead to improvements in muscular activity.

In some cases, the results have been spectacular.

“We’re not talking about amelioration of a few symptoms or a little bit of the problem,” said Dr. Kemp Clark, a neurosurgeon at the University of Texas Health Sciences Center in Dallas who has done the operation five times and is planning another 10. “When it works, it is absolutely phenomenal.”

Clark cites the case of 38-year-old Dan Covey, a transplanted Californian who is now a supervisor at the water company in the Dallas suburb of Plano. Before Clark operated on him last July, Covey had been forced to quit his job because his stiffness made walking very difficult; he could no longer drive or feed himself because of the violence of his tremors.

His memory also faded, and he needed a tape recorder to remind himself of what he had done during the day.

Within three months after the operation, Covey was back at work, driving his car again and eating in public without embarrassing his family. Now, he runs three miles every day.

“It’s like being freed from a jail,” said 43-year-old Elvira Ramirez Montes, an archivist in Mexico City who experienced similar improvement after she was operated on 10 months ago by Madrazo.

Many, but not all, of the most spectacular improvements have occurred among younger patients, but researchers still have no way to predict who will benefit most.

A larger number of graft recipients have shown a more modest improvement.

“Parkinson’s is often a cyclic disease in which the patients are ‘off’ (severely impaired) or ‘on’ (less impaired),” said Dr. C. Warren Olanow, a neurosurgeon at the University of South Florida in Tampa who has operated on six patients.

In his patients, he said, “The ‘on’ periods remained relatively the same, but the ‘off’ periods were improved. The patients were less, bad less often. That is not a trivial benefit, especially if it persists.”

One such patient is 43-year-old Dickye Baggett, who was operated on by Dr. George S. Allen of Vanderbilt University in Nashville in April, 1987--the first time the surgery was performed in the U.S.

Baggett was only moderately impaired by her disease: She had tremors on her right side, her right foot dragged when she walked, and she had difficulty writing, although she was able to perform in her job as an office clerk.

Happy With Results

Now, she said, “I take less medicine, my foot doesn’t drag and my tremors are less severe. . . . I’m quite happy with the results and I would do it again in a minute.”

So would 40-year-old Donald Berns, a Presbyterian minister in La Canada who was operated on by Allen last July. “It was not an instant cure, but it was very helpful,” he said. He is still taking the same amount of L-dopa as before, but he can work longer each day, his handwriting has improved, and he is able to play tennis again. “When I went out to play tennis three months after the operation, it was like my body seemed to be working again for the first time in six or seven years.”

“We are unquestionably seeing changes after the surgery,” said Dr. Michael Apuzzo of USC, who performed his seventh and eighth transplants earlier this month. “Based on the cases we have done, we feel we should press on.”

“We’re just looking for a benefit,” said Dr. Donald Becker of UCLA, who has done two operations and plans four more. “It’s inappropriate to demand that it produce spectacular results.”

Reason for Controversy

But some patients have not benefited at all from the surgery, and this seems to be the nub of the controversy surrounding Madrazo. Some U.S. physicians said in interviews that Madrazo claimed all his patients had improved when, in fact, some had not improved.

Neurologists at Loma Linda University have examined three transplant recipients who did not improve or who got worse, said Dr. Donald Peterson, a neurologist at Loma Linda. One, operated on in Mexico City, had an epileptic seizure--probably caused by the operation, Peterson said--and died of a heart attack.

Another “fellow who had it at USC said he was better,” Peterson said, “but those who observed him didn’t see much improvement. . . . The (third) one from Kansas got a lot worse and is bedridden. I question whether any of the three got any benefit.”

Dr. William J. Weiner, a neurologist at the University of Miami, cautions against accepting the claims of improvement from patients or their families. He cites one of his patients who went to Mexico City and died from an infection after his pancreas was nicked during the removal of the adrenal gland.

“The thing that was interesting was that when my nurse talked to his wife (after he died), the wife said, ‘Well, tell Dr. Weiner that his Parkinson’s was better before he died.’ When they invest emotionally and economically in that decision to have extensive surgery, they have a tremendous interest in things being better. They lose their objectivity about the outcome.”

Publicity Avoided

Many U.S. neurosurgeons, in fact, prefer that their patients not talk to the press for just that reason.

But Madrazo, with perhaps a touch of disingenuousness, argued that the controversy is primarily “semantic. I have never claimed that all my patients have improved. What I did say was that, in all my patients, the evolution of their disease had changed.” In other words, some had not improved, but had stopped getting worse.

But even that concession does not please everybody.

One neurosurgeon, who asked that his name not be used, argued: “He is in serious jeopardy of losing his credibility, not by the fact we didn’t reproduce his results--because we did--but because he reported some patients as being improved when they weren’t. If his results aren’t as good as he hoped, no one will go crazy as long as he reports them correctly.”

Like many others, Madrazo no longer believes that the grafted cells simply provide dopamine. Instead, he said, it now seems likely that the cells secrete some kind of growth factor or other substance that, in effect, re-energizes the patient’s own brain cells and improves their function. This benefit persists even if the grafted cells die, he said.

This further suggests that the younger the transplanted cells, the better, a hypothesis that is supported by experiments which suggest that adrenal glands from young animals are more effective than those from older animals, and that tissues from fetuses are best of all.

This approach has the additional advantage that surgery to remove the adrenal gland--which is riskier than the brain surgery--is not required, a definite advantage in older patients who are already ill.

Need for Drugs

Counterbalancing that benefit somewhat is the need to use immune-suppressing drugs to prevent rejection of the fetal tissues. Many ethical problems are also associated with the use of fetal cells because such cells would come from aborted fetuses. Their use, critics argue, would encourage abortions and might stimulate the sale of fetuses.

Madrazo last September implanted brain cells from a spontaneously aborted fetus into one Parkinson’s victim and adrenal cells from the same fetus into a second patient--the first time either procedure had been performed. He said both patients have shown at least a 90% improvement in their symptoms.

Leonor Cruz Bello, 35, received the fetal adrenal tissue. Her disease was not severe before the operation, she said, “but I feared that I would develop worse problems that would prevent the operation later.” She said she had stiffness in her right side, walked with difficulty and with a pronounced list to one side, and couldn’t prepare her own food.

“Now life is normal,” she said. She has a slight amount of tremor and still tires easily climbing stairs, but she is able to cook and take care of her children. Most of her improvement has come in the last three months, she said, and she continues to get better.

Surgery Abroad

Fetal tissues have subsequently been implanted in two patients in Sweden, two in Britain, and four in Cuba, although no results have been announced yet. Madrazo would like to do more himself, but he is in an awkward position: Abortions, the source of most fetal tissues, are illegal in Catholic Mexico.

He is now alerting obstetric/gynecological clinics throughout Mexico City to his need for spontaneously aborted fetuses and is offering to make surgical residents available to harvest tissues. But he is not optimistic: The fetus must be less than 13 weeks old and the abortion must have been caused by problems with the mother rather than the fetus. And in any case, most early spontaneous abortions occur at home.

Neurosurgeons at the University of Wisconsin are also considering the use of adrenal glands from cadavers.

Meanwhile, Madrazo, 44, leads a hectic life. His biggest problem, he said, is that no one else on his surgical team speaks English, so he must do all the traveling to report results and demonstrate the procedure.

He travels out of the country twice a week, on average, primarily to the U.S., Europe, and South America, and he is planning trips to China and Japan.

Despite the controversy about some of the patients, many researchers concede that Madrazo’s efforts have been invaluable to the study of Parkinson’s. “Madrazo spurred everybody to do much more,” said NYU’s Lieberman. “He really sparked a tremendous amount of research effort throughout the U.S. and the world.”

And Madrazo does not seem overly concerned about the controversy. “I am really confident in my data,” he said. “It will speak for itself.”