Parkinson’s Disease: In the Future, You Won’t Take a Pill for That

Doctor at conference

Neurophysiologist Aristide Merola, MD, PhD, has joined the Gardner Family Center for Parkinson’s Disease and Movement Disorders. Photo by Cindy Starr.

Therapies for Parkinson’s disease are advancing as you read this sentence, and Aristide Merola, MD, PhD, has arrived on our shores to help ensure that patients in the Cincinnati region have access to the very best.

Merola, a neurophysiologist and Parkinson’s expert, was recruited to the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders from the University of Turin in Italy, where his research focused on advanced surgical therapies for Parkinson’s disease. He brings to Cincinnati a physiologist’s understanding of deep brain stimulation (DBS) surgery and the infusion therapies that have been used in Europe for several years but are new to the United States.

“I’m interested in developing what we call advanced therapies,” Merola says. “These are likely to become the therapies of the future because they will provide stable dopaminergic support, resulting in a physiological rebalance of brain areas that are impaired in Parkinson’s disease. In 20 years, there will be no more tablets.”

Parkinson’s disease, a disease of motion, is caused by the loss of dopamine-producing cells in the brain. Patients in the early stages of Parkinson’s are treated with levodopa replacement in tablet form. The medication relieves symptoms for a few hours before wearing off. Over time, patients may find themselves alternating uncomfortably between “off” periods with symptoms of stiffness, tremors and shuffling gait, and “on” periods accompanied by dyskinesias, the wiggly, dance-like movements that are a complication of levodopa.

“A patient with Parkinson’s disease receives levodopa in up to 10 tablets a day,” Merola says. “There may be a big dose followed by nothing every four hours.”

Therapy without interruption

More effective is therapy by infusion, as in a drop-by-drop stream of levodopa. Alternatively, the functionality of the substantia nigra, the region where dopamine is physiologically produced and released, can be normalized with a steady electrical stimulus delivered by tiny wires that reach deep into the brain.

“Treatment of Parkinson’s disease will be greatly improved by these therapies,” Merola says. “I believe in anything that delivers constant therapy. Think of it as a river. The infusion is constant. This is the way to normalize the brain.”

Alberto Espay, MD, MSc, director of the Gardner Center, led Cincinnati’s portion of the pioneering study of levodopa infusion. This therapy, approved by the Food and Drug Administration (FDA) last year and marketed as Duopa, is delivered through a tiny catheter surgically implanted in the duodenum. The Michael J. Fox Foundation reports that “continuous levodopa infusion can result in reductions of more than 50 percent in time spent in the ‘off’ state and time spent with severe dyskinesias.”

Two new infusion therapies, now in the experimental phase, will be delivered through subcutaneous catheters in the abdomen. One therapy is a form of levodopa, marketed as DopaFuse; the other is apomorphine, a dopamine agonist marketed as Apokyn®. Apomorphine is derived from morphine but it does not contain morphine and does not bind to opioid receptors. Espay is leading the Cincinnati portion of both studies involving subcutaneous infusion of levodopa and apomorphine.

Innovations in deep brain stimulation

Innovations are also occurring in DBS surgery, which is performed at the Gardner Center by George Mandybur, MD, a neurosurgeon and director of the UC Neurorestorative Program. Although DBS was approved by the FDA nearly 20 years ago, many patients have balked at the requirement that they be awake during surgery. DBS has been done this way so that doctors, who are targeting an area the size of a jelly bean, could make sure they have the electrodes in the right spot. Doctors – and patients – listen to the brain cells’ electrical activity while the surgeon threads the tiny electrode wires toward the subthalamic nucleus.

“This area is small, like an olive,” Merola says. “It is not simple to target this area exactly. The first time I saw it done I was amazed.”

The thought of someone threading wires into your head while you’re awake can also cause dread.

“It is very stressful for patients to undergo brain surgery while they are awake,” Merola says. “I feel great admiration for these patients. Having DBS surgery while asleep like every other surgery is practical and an ideal to strive for. It means that every patient could have DBS without having to endure what may be a psychologically difficult experience.”

Patients can be asleep during DBS surgery

That change is underway at elite centers around the world, including the Gardner Center. Mandybur has performed 10 asleep DBS surgeries in Cincinnati to date. Because an intraoperative MRI is required, the Gardner Center cases have taken place at Cincinnati Children’s Hospital Medical Center.

Other technological improvements involve the stimulators themselves — the pacemaker-like devices that are implanted under the collar bone and that deliver electrical pulses to the brain.  “The stimulator is programmed for every single patient,” Merola says. “The potential for programming innovations is very broad. We are currently exploring the possibility of using a different frequency of stimulation for a subset of Parkinson’s patients who have difficulty walking.”

Candidates for DBS surgery are carefully evaluated and selected during team meetings involving Mandybur, Merola, several neurologists, two neuropsychologists and a nurse practitioner. Not all patients are candidates for DBS surgery; in some cases, surgery would not be effective because the disease process has advanced to include cognitive impairment or other complications that increase post-surgical risk.

“People who do DBS surgery are like the pilot of an airplane,” Merola says. “Everything has to be perfect before taking off. I myself would like to have a pilot who is very careful. If you are performing DBS, you want it to be safe.”

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