Medicine: Brainstorm for Parkinson’s
It’s a disabling disease, but Hadassah physicians have developed a deep-brain stimulation technique that ameliorates Parkinson’s symptoms.
Larisa Korvan is hoping desperately that Hadassah neurosurgeon Zvi Israel will add her to his waiting list. Although the procedure for which she hopes to qualify is only a few years old, although its cost is not covered by her health insurance, and although it will require her spending at least eight waking hours lying rock-still while surgeons drill her skull and reach into her brain, she wants this as much as she has ever wanted anything. “My Parkinson’s symptoms were beginning while I was still in Ukraine,” she says. “But it wasn’t until after we moved to Israel 12 years ago that they became bad enough for me to take notice.”
Steady progression of the disease has now frozen Korvan’s face into the typical, expressionless mask of Parkinson’s disease. It has made her muscles rigid, her balance poor and all but taken away her fine-motor control. She suffers constant tremors and increasing difficulty in walking.
While medication controlled the symptoms of this chronic movement disorder for several years, their side effects have become almost as debilitating as the illness itself.
“I’m only in my sixties,” she says. “I have children and grandchildren to live for. This new procedure is my only solution.”
A decade ago, as Korvan’s illness was taking hold, this solution did not exist for her or for millions of others (about a million and a half in the United States; about two per thousand in Israel) afflicted by the crippling, progressive neurodegenerative disorder. Its development owes much to the work of Israeli physiologist Dr. Hagai Bergman of the Hebrew University–Hadassah Medical School, a member of the team that would be involved in Korvan’s treatment. It was Dr. Bergman, probing the subthalamic nucleus, an area deep in the brain only millimeters in diameter, who discovered it to be overactive in Parkinson’s disease and that when inactivated, all major symptoms are ameliorated.
“Neurosurgeons have been searching for surgical solutions to Parkinson’s for a hundred years,” says Dr. Israel, of the neurosurgery department at the Hadassah–Hebrew University Medical Center at Ein Karem. “Parkinson’s surgery, however, hit a long hiatus in 1967 with the appearance of L-dopa. L-dopa is a very successful medication but it, too, has side effects and ultimately loses its effectiveness.”
In 1982, a chance occurrence set in motion a shift back to surgery, but in a new form that has already restored to thousands of Parkinson’s victims their quality of life. In that year, California emergency rooms were suddenly seeing young patients suffering an acute and irreversible syndrome that resembled Parkinson’s. It turned out all were drug users who had bought from a batch in which a certain chemical had been mixed. The chemical was isolated and used to create, for the first time, a laboratory model of Parkinson’s. Investigation could now begin in earnest.
Among the researchers was Dr. Bergman, then in the United States doing postdoctoral study. Working with monkeys, he ablated or burned away the overactive subthalamic nucleus and strikingly reduced their Parkinson’s symptoms. In 1993, ablation was replaced by the less risky procedure of delivering electrical stimuli to the subthalamic nucleus via implanted electrodes.
The Food and Drug Administration approved this technique in 2001, and the three years since have seen an exponential growth in this therapy worldwide.
In summer 2001, Dr. Israel returned to Israel following a two-year fellowship at the Oregon Health and Sciences University in Portland. Armed mainly with determination—no additional budget was available—he set about creating a deep-brain stimulation program that has made Hadassah Israel’s leading functional neurosurgery center.
“I started by building a multidisciplinary team,” Dr. Israel explains. “It comprises myself, three neurologists, a neuropsychologist, a physiotherapist and Dr. Bergman. It’s a team that has proven very productive in both research and clinical work.”
His next step was acquiring the equipment. A $180,000 grant from the Nash Family Foundation bought microrecording equipment. The navigation computer, which the team uses to locate the subthalamic nucleus, however, dates from 1997. “To calculate programming coordinates and design a treatment plan should take 10 minutes,” Dr. Israel says. “It often takes up to two hours because of this dated hardware. We need $130,000 to replace it.”
In January 2003, the team performed its first deep-brain stimulation. Like the 15 performed since then, this treatment, which still is too new to have more than a 10-year follow-up, was a complete success. “Neurologists tend to be very conservative,” says Dr. Israel, “but we’re receiving referrals from all Israel’s major neurology centers, as well as referrals from abroad.”
The number of applicants increased in spring 2004, when Israel Television showed one of Dr. Israel’s Parkinson’s patients prior to surgery and again two weeks afterward. The dramatic improvement generated over a hundred inquiries a day for the week following the broadcast—Larisa Korvan’s among them.
“This treatment isn’t appropriate for all patients,” says Dr. Israel. “We must be careful in our selection. Depression, dementia or other illnesses will exclude some. Age may exclude others, although we try not to make it a limiting factor.”
None of this applies to Korvan. If her wish is realized, she will be admitted to Hadassah the day before the procedure and her medication will be halted. At 6:30 the next morning she will go to the operating room, where a three-dimensional frame will be fitted around the outside of her head. Her brain will be scanned and the image obtained combined with an earlier MRI.
“We use this to program our path to the subthalamic nucleus,” Dr. Israel explains. “Because all of us have differently shaped heads, the location of this tiny spot differs slightly in each of us. We must reach it with great precision to avoid damaging other brain structures and to achieve the best results.”
By about 9 o’clock, Dr. Israel will drill a small hole through the patient’s anesthetized skull just above the hairline, getting the angle down to the deep brain exactly right.
Once the channel is opened, he will insert about three inches of silicone-covered wire the thickness of a paper clip, four tiny electrodes at its end, and advance it gently down to the subthalamic nucleus. To check if it is accurately placed, he will ask Korvan to move and speak, so he can judge reactions and whether the tremors and rigidity decrease.
Next will come what Dr. Israel calls “the plumbing.” With one end of the silicone wire in place, the other, emerging from the skull, will be slipped under Korvan’s skin and trained down the side of her head and neck to her upper chest. There it will be connected to its electrical generator, also implanted under the skin.
It will be about seven hours since Dr. Israel drilled the hole. The patient will be taken to intensive care for overnight observation.
“The initial effect of inserting the electrodes is to stun the overactive subthalamic nucleus cells, and the patient is thus often dramatically better,” Dr. Israel says. “Within a week or two, however, the cells begin recovering, and its time for the generator to be programmed.”
Placing a hand-held electrical device over the generator in the patient’s chest, Dr. Israel can fine-tune the electrical pulses it delivers deep into the brain. “I can make any one of the four electrodes or any combination of them produce stimuli of different strengths,” he says. “It can take up to a couple of months to get the correct balance. During this time, medication has to be very carefully balanced. Eventually, some patients do so well they come off medication altogether. Those who can’t usually need about 50 percent less than before, which means the side effects dramatically subside.”
Hadassah’s deep-brain stimulation program is one worth investing in, says Dr. Israel, both for the relief it brings to patients and because it is one of few worldwide that intimately combines with a research arm. Microrecordings of each procedure are passed on to Dr. Bergman’s lab. Research funds, however, are modest, and the cost of surgery—$26,000 compared to about $100,000 in the United States—is not covered by Israel’s strapped health funds, despite clear evidence that it becomes cost-effective within two and a half years.
Futuristic as deep-brain stimulation is, the longer-term future therapy for Parkinson’s and other neurological disorders is likely to be in a different realm altogether—that of stem cells.
“Parkinson’s disease results from degeneration of dopamine-producing nerve cells in the brain,” says senior Hadassah neurologist Dr. Tamir Ben-Hur. “Dopamine stimulates and fine-tunes the motor system in the brain that controls the muscles. When its production is depleted, the motor system nerves can no longer control movement and coordination. Parkinson’s patients have lost more than 50 percent of their dopamine-producing cells by the time symptoms appear.”
Dr. Ben-Hur is working with Dr. Benjamin Reubinoff to create cells that secrete dopamine and then implant them in the appropriate area of the brain. “We don’t have to invent the wheel,” he says. “There are encouraging results worldwide in transplanting fetal tissue to help Parkinson’s patients. But with material from up to eight pregnancy terminations needed per patient, fetal tissue is ruled out for both logistical and ethical considerations. We must cultivate an alternate source of dopaminergic cells for transplant.”
Researchers worldwide are working on growing such cells from stem-cell lines. Drs. Ben-Hur and Reubinoff are building on work in which they successfully implanted into the brains of newborn mice laboratory-grown nerve cells derived from human embryonic stem cells. Recently, they implanted dopamine-creating cells grown from these stem cells into the brains of Parkinsonian rats and became first in the world to report some clinical effect from these transplanted cells.
“There’s still a long way to go,” says Dr. Ben-Hur. “We must learn how to improve the yield of dopaminergic cells in culture and improve their delivery and survival in the brain after transplant.”
Here, perhaps, is where the two approaches to treating Parkinson’s disease are to meet: Hadassah’s neurologists will create the cells that secrete dopamine safely and efficiently, and its neurosurgeons will implant them deep into the human brain with the pinpoint precision required.
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