By David N. Leff

It's now a good 13 years since neuroscientist Curt Freed, at the University of Colorado in Denver, and his neurosurgeon colleague, Robert Breeze, implanted the first fetal dopamine cells into an American Parkinson's disease patient's brain. They followed up over the next few years treating other PD cases, with encouraging results.

So much so that in early 1994 this outlook led the U.S. National Institute of Neurological Disorders and Stroke (NINDS) to invest $9 million to fund a full-court-press clinical trial of the procedure.

Between April 1994 and April 1997, the double-blind, placebo-controlled study enrolled 40 PD candidates for the surgery - 19 men, 21 women. Enrollees were divided between those under and over 60 years of age. The implantation operations began in May 1995 and were completed in January 1998.

Initially, at Columbia University College of Physicians & Surgeons in New York, clinical neurologist Stanley Fahn recorded the patients' defective motor ability on videotape, which reflected the status of dopamine-producing neurons in their brains.

Then they were transferred to Colorado. There, on a strictly randomized basis, half of the 40 - under local anesthesia - had four tiny holes drilled in their skulls, through which needles introduced dopamine-yielding neurons from human fetuses obtained at elective abortion. The remaining 20 underwent sham surgery, in which the holes were drilled in their skulls, but no needles entered.

Now, six years later, the current New England Journal of Medicine (NEJM), dated March 8, 2001, reports the final results of this first-ever controlled human trial of fetal neuron implantation in PD therapy. Its title: "Transplantation of embryonic dopamine neurons for severe Parkinson's disease." The paper's co-senior authors are Columbia's Stanley Fahn and Colorado's Curt Freed.

Neurons Grow Back But Subjective Symptoms Worsen

In fact, of the 20 men and women who actually received the injected neurons, 85 percent, regardless of age, showed growth of the new brain cells, and many had improvement in their symptoms. But paradoxically, patients in the under-60 age group, who underwent only sham operations with no implanted neurons, also self-reported pronounced improvement in their symptoms. In other words, they benefited by the well-known placebo effect.

Not so for the over-60 cohort. Both those on sham placebo and real surgery failed to note improvement, which led to the disconcerting question as to whether the entire fetal neuron strategy is resting on a firm footing.

Virtually the only current clinical therapy for Parkinson's disease is daily medication with levodopa tablets, which provide external replacement of dopamine. However, the beneficial effect of these pills wears off gradually in five to 10 years.

The trial patients recorded their fluctuating symptoms - in diaries and mailed-in reports - early in the morning, before taking their levodopa drugs. This detected the performance of their neuron implants free of confounding medication. "A subjective global rating of clinical improvement or deterioration," the NEJM paper explained, "scored by the patients, was the primary outcome variable. Patients chose phrases ranging from 'parkinsonism markedly worse' through 'no change' to 'parkinsonism markedly improved as compared with before surgery.'"

Among these subjective rating scores 12 months after surgery, only the patients in the younger - under 60 - cohort were upbeat, indicating improvement. Over-60s all turned in negative scores, reporting worsening disease. But when patients - still unaware of treatment group assignment - viewed a preoperative video of themselves, those in both treatment and both age groups changed their scores to positive values.

"While placebo-controlled drug trials have long been the gold standard to test the value of a new drug," Fahn observed, "only a few placebo-controlled surgery trials have been conducted. In Parkinson's disease, about 30 percent of patients feel better after getting a placebo drug. We found that some patients who had placebo surgery did feel their Parkinson's disease had improved."

Two fatal mishaps among the 40 patients made it possible to carry out brain autopsies that actually measured the histologic effects of the implants. One was a 66-year-old woman who died in an automobile accident, when a tree fell across the highway during a storm. Her brain showed degenerating dopamine neurons with Lewy bodies, which are specific to PD. All four of her needle tracks contained large numbers of dopamine neurons.

The other post-mortem case was a 71-year-old man who died of an acute heart attack, unrelated to his surgical implantation three years before. This time lapse revealed that the three-year period had sufficed for nearly complete reinnervation of his putamen, the brain region in which dopamine in PD is most depleted.

A very severe adverse reaction struck five transplanted patients more than one year after surgery. It took the form of uncontrollable, unremitting bodily movements, such as writhing, twisting, flailing, tremor and spasmodic chewing.

"The two patients most impaired by these dyskinesias," Freed recounted, "are the two who had most improved following their transplants. One, a man, was off all drugs and clinically normal in the first year after transplant. The woman had been wheelchair-bound prior to her transplant. The transplant actually led to a remarkable improvement, in which patients were able to discontinue all levodopa, and were much better prior to surgery. Then with the continued growth of the transplant, there was reappearance of dyskinesias, which are present in the absence of levodopa therapy."

Placebo Patients Offered Second Chance

After one year of evaluation and data collection, individual patients learned for the first time which procedure they had received - real or sham. Those who had had the placebo operation were offered the choice of receiving the fetal implants. Fourteen of the sham-surgery patients decided to have the transplants, but as the adverse reactions kicked in, the six remaining patients were advised to hold off until further research had been completed.

Since the double-blind protocol finished, patient follow-up has continued. Evaluation at up to three years in the 19 subjects of the original transplant group showed a 28 percent improvement over baseline - 38 percent among the younger patients, 14 among the older ones.

"We have modified our transplant procedure based on the outcome of this study," Freed concluded, "and in particular we are transplanting less tissue to reduce the chances of excessive effects in these patients." n