In the fall of 1993, four years after being diagnosed with Parkinson's disease, Terrie Whitling's life had been hijacked by the neurodegenerative disorder. Her symptoms, which included muscle rigidity, uncontrollable tremors, and reduced mental acuity, were so severe that she was forced to retire from her job as a social worker. "I had gone down to the point that I couldn't walk, I couldn't run, I couldn't play tennis, could not shop in a shopping mall without a wheelchair, couldn't drive a car, couldn't cook, and could eat only at certain times," she says. "I had to time out when I talked on the phone, when I ate, when I took a bath, when I washed my hair, every single normal daily function of my life was timed out according to my good periods and my bad periods. I lived by the clock in terms of when I took my medication. I was basically house bound with not much quality of life left and very depressed."
Because her Parkinson's medications were becoming progressively less effective, Whitling was scheduled for a pallidotomy procedure at Emory Hospital. The operation uses a mapping technique pioneered by doctors at Emory in which a microelectrode is used to pinpoint the area of the brain causing the Parkinson patient's symptoms. After the target is located, the malfunctioning portion of the brain is destroyed with a heated probe, creating what the surgeons call a "lesion." The operation requires the patient to be awake, and Whitling remembers the exact moment when the neurosurgeon reached the targeted tissue and destroyed it. "It was a miracle for me, . . ." recalls the forty-year-old Whitling. "At the precise moment that they placed the lesion in me, it was a very dramatic difference. It felt like they had turned the light on or flipped a switch that was off before and suddenly and dramatically it was on.
"It was as though I had been given my Parkinson's medication and it was working well without side effects, but I had not been given my Parkinson's medication. . . . That was a [physical] feeling that I had internally, and there was also an immediate quickening of my mind. It was like I turned on mentally. I was suddenly sharper, clearer, able to articulate in a much more rapid and acute fashion than I could before. Before, I was just very slow, very down or off. So it was a dramatic change physically and mentally for me. It was as though I just woke up."
Whitling was the last of sixteen patients involved in a pilot study performed at Emory Hospital that examined the efficacy of the pallidotomy procedure. According to Mahlon R. DeLong, chairman of the department of neurology in the School of Medicine, "Our preliminary studies showed that pallidotomy provides significant benefit to patients with Parkinson's disease who no longer derive adequate response to anti-Parkinson medications and who suffer from motor fluctuations and drug-induced [muscle impairment and motor fluctuations]."
Using the results from that initial pilot study, a team of physicians and scientists from Emory recently was awarded a $2.5 million grant from the National Institutes of Health (NIH) to conduct clinical trials to test the efficacy of pallidotomy. The study will consist of eighty-four patients with intractable Parkinson's disease who will be followed over a four-year period. Half of the patients will undergo pallidotomy, and the other half will receive drug therapy. According to Shirley Triche, the nurse coordinator for the study, "The goal is to see if there is in fact a change in the patient's motor functions [after a pallidotomy] and to see how long those motor function changes last."
The clinical trials will differ from the pilot study in several key ways. "The clinical trial will rigorously look at outcome over a long period of time," DeLong says. "It will also provide a comparison group that was not built into the pilot study. So it is really much more rigorously controlled. The other difference is that the study will be in patients who will have the advantage of the experience we have acquired in the course of the pilot study and subsequent procedures. We've learned a lot along the way about the size and location of the lesion that appears to be optimal. So we'll be really looking at patients who have had a more optimal lesion."
Parkinson's disease is a perplexing disorder. It causes the brain to lose cells that manufacture the neurotransmitter dopamine, and, for reasons doctors still don't fully understand, the loss of those cells causes other brain cells to be overstimulated. That overstimulation leads to the symptoms of Parkinson's disease.
Pallidotomy is not a new procedure. According to Roy A.E. Bakay, a professor of neurosurgery at Emory who works as the pallidotomy team's surgeon and is a co-investigator in the NIH study, "Pallidotomies have been performed for over forty years. Most neurosurgeons abandoned these procedures thirty years ago because of inconsistent results."
The reinstitution of pallidotomy as a viable treatment for Parkinson's disease grew out of research that DeLong conducted at Johns Hopkins University. (In 1990, DeLong and Jerrold L. Vitek, an assistant professor of neurosurgery at Emory and a co-principal investigator in the NIH study, all came to Emory from Hopkins to pursue their pallidotomy research.) In the September 21, 1990, issue of the journal Science, DeLong co-published an article titled, "Reversal of Experimental Parkinsonism by Lesions of the Subthalamic Nucleus." According to that article, which is credited with kicking off the resurgence of interest in pallidotomy as a Parkinson's treatment, in "monkeys rendered parkinsonian . . . lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor."
Pallidotomy was abandoned as a treatment for Parkinson's disease because the techniques available at that time were not precise enough. Precision is a must in this operation, because "brains are as different as faces," says DeLong. "The location, size, and configuration of different structures varY considerably [among] brains." Previously, doctors used standard atlases of the brain and imaging devices, which DeLong describes as "pretty good, but just not good enough to get you accurately to the target." The mapping procedure DeLong pioneered for pallidotomy has helped increase precision and eliminate that risk.
The mapping, which takes between two and three hours to complete, "consists of lowering a microelectrode to the target area and determining the actual location of the different structures, the target as well as surrounding nuclei and fiber tracts," explains DeLong, who cautions that the patient's optic tract is only a millimeter away from where they place their lesion. "The target is what we call the sensory motor portion of the globus pallidus [an area near the thalamus which lies fifty-eight to sixty-eight millimeters from the surface of the brain]. And that is defined as the part that contains cells that respond to the movement of the different body parts. Those are the ones that when overactive or abnormally discharging cause the symptoms of the disease."
One of the primary ways the doctors use the microelectrode to navigate their way to their target is by sound--the nerve cells in each specific structure of the brain have a very specific firing pattern and frequency. "With the electrode advancing cell by cell," says DeLong, "we listen to see what language they are speaking. And as we go from one structure to another, we are able to detect that change."
To elicit the sounds by which they navigate, doctors will manipulate the patient's limbs as well as have the patient move voluntarily. "That generates input from the sensory nerves to that part of the brain," says DeLong. "So we're looking for responses that are evoked by movement." However, because their target area is so close to the patient's optic tract, that area also has to be precisely located to avoid it. "We want to avoid those visual pathways," he says. "[To do that], we will flash a light [in the patient's eyes] and then we can hear those impulses as they pass by the electrode. . . . [The optic tract] is just a millimeter away from our target--we just want to know where it is."
According to DeLong, pallidotomy is most warranted for patients who have ceased to benefit from Parkinson's medications and have developed severe motor function side effects from their medication. "Probably a quarter to a third of patients after five years or more will experience a waning of response to their medication and will have developed significant complications from the drug itself," he says. "They experience very little quality time and may alternate between being off, that is, in a state where the medication is not working, and being on with side effects and have very little quality on-time. So they are very limited in their independence."
Even though Emory is one of the few places where this procedure is performed, DeLong and his team are currently working to export their expertise. For more than the past two years they have been involved in education and training. "We have had visiting groups at virtually every surgery we've had," he says. "There are a small number of centers now that are starting [to do pallidotomies] using similar techniques."
More than seventy pallidotomies have been performed at Emory Hospital since the first such operation took place there in December 1992. Even with all of those operations, DeLong says the work has yet to become routine because of the way his patients' lives have changed. "It's always an enormously positive thing each time we do the surgery," he says. "It's not something you get used to because the change is so dramatic. These benefits are not trivial; they are usually very profound and impact the patient's quality of life enormously."
Terrie Whitling agrees. "I took a couple of weeks off after the surgery to let my head heal and let the swelling go down around the lesioned area. Then I was walking, running, playing tennis, riding a bike, and driving my car," she says. "I put my wheelchair in the closet. I put my canes, which I had used for five years, in a closet, and I could walk a straight line for the first time in many, many years. I was back doing anything and everything I had ever wanted to do. My appetite had a dramatic and immediate increase. I gained thirty pounds in what seemed like overnight. I had tremendous energy, and I was quite euphoric."
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