Neurotransmitter - June 1995

Pallidotomy for Parkinson's Disease

I have been evaluating a 36 year old man with severe Parkinson's disease who in January underwent a neurosurgical procedure, pallidotomy, to relieve symptoms of his disease. He recently wrote down this summary to explain how he felt 3 months after the surgery. "Can not verbalize how much better I am now. I can now function semi-normally as an afflicted person, without constantly worrying what my body will do next to embarrass and humiliate me. Think about it. Wherever you go, whatever you do, your body will betray you. Everyday tasks like shaving and saying good morning become hurdles too high to overcome.

Now those tasks are infinitely easier and the body responds, if not normally, at least within a livable range. I still have quite a long way to go because I was down so damn low. At least now I figure I have a chance."

The symptoms of Parkinson's disease are caused by the loss of nerve cells in a part of the brain called the substantia nigra that is about the size of your thumb nail. This small part of the brain makes a chemical, dopamine, that is been vital to normal movement. Without dopamine, Parkinson's disease patients' movements become very slow (sometimes slowing to the point of being unable to move), their muscles become rigid, they develop a tremor and their balance is impaired so that they fall frequently.

Twenty-five years ago an effective drug for Parkinson's disease was introduced. This was levodopa which is converted in the brain to dopamine. Treatment with levodopa relieved all the symptoms of the disease and doctors thought that the disease was cured. Unfortunately, time has revealed that this is not the case. Patients only get good relief of symptoms for five to ten years. Then the patients become extremely sensitive to the drug so that after they take it the patients get abnormal, extra movements called dyskinesias which may themselves be disabling and when the drug wears off the patients get symptoms of Parkinson's disease that are worse than if they had taken no medicine at all.

This is precisely what had happened to the patient. He developed Parkinson's disease at age 25 and had gotten a wonderful response from levodopa for eight years. However, for the past three years he had fluctuated between being incapacitated by his disease and being incapacitated by side effects of the medicine. Desperate, he came to Dr. G Reese Cosgrove of the Neurosurgery service and I seeking a recently revived operation known as a pallidotomy.

Pallidotomy was a popular operation for Parkinson's disease 50 years ago when its chief proponent was a Swedish neurosurgeon, Lars Leksell. At the time patients with Parkinson's disease were so desperate that they allowed surgeons to, essentially randomly, destroy various parts of the brain hoping for some relief. Pallidotomy, destruction of the part of the brain called the globus pallidus, was one of many operations that were tried. It was quite often successful at helping the rigidity and slowness of the patients but was largely replaced as an operation in the 1950's by thalamotomy, destruction of the thalamus, because thalamotomy was better at relieving tremor. When levodopa was introduced, both operations ceased to be performed.

Two things have combined to bring about a rebirth of interest in pallidotomies. The first is that advances in our understanding of anatomy and physiology led to the prediction that one of the consequences of dopamine cell loss in Parkinson's disease is that nerve cells in the internal segment of the globus pallidus become overactive (See figure). This prediction has been confirmed in studies of monkeys who have been made parkinsonian. Destroying the internal globus pallidus in these monkeys made their parkinsonian symptoms better leading researchers to predict that the same operation should work in humans with Parkinson's disease. At the same time that these animal experiments were being carried out, a student of Leksell, L. Laitenen, decided to revive the operation that Leksell had been performing 50 years ago. He found that the operation was very useful for Parkinson's disease patients whose medicines caused incapacitating dyskinesias.

There are two different ways of performing the operation. In both the patient is awake, has a rigid frame attached to his head for guiding the electrodes to the internal globus pallidus, deep inside the brain, and has CT and MRI scans to determine exactly were the internal globus pallidus is. A hole is then drilled in the skull after local anesthesia has been given and an electrode is pushed into the brain to the spot where calculations from the CT and MRI scans predict that the internal globus pallidus should be. In one type of operation pioneered by Mahlon DeLong and Roy Bakay at Emory University the electrode is used to record the activity of the nerve cells in the brain. The electrical activity of internal globus pallidus nerve cells is very rapid bursts of firing. The electrode is pushed into the brain a number of times, taking 4 to 5 hours, to determine exactly where the internal globus pallidus is. A heating electrode is then pushed into the internal globus pallidus and the heat is used to cook (destroy) it. The other type of operation is that pioneered by Leksell, revived by Laitenen and used at Massachusetts General. Instead of a recording electrode being pushed into the brain, a combined stimulating and heating electrode is used. When the predicted location of the internal globus pallidus is reached, a tiny electrical current is sent through the electrode. This inactivates but does not destroy the area of brain around the electrode's tip. If the patient's symptoms get better and if there are no side effects, it is assumed that the electrode is in the internal globus pallidus and the heat is turned on to destroy it. The entire operation takes about an hour from the time the hole is drilled. If all goes well, the patients go home two days later with much decreased symptoms of the disease and with reduced levodopa side effects. Of the 18 patients who have received pallidotomies at MGH in the past 2 years, two thirds have had major benefit from their surgeries. The others have either not had the typical feature of marked fluctuation between severe symptoms of the disease and severe drug induced side effects or have not had perfect placement of their pallidotomies.

The results of this operation have raised one significant issue for neuroscientists. Current theory predicts that the operation ought to make the levodopa induced dyskinesias worse rather than better, but dyskinesias are the feature of the illness that respond best to the operation. As a clinician I am pleased that dyskinesias respond so well; as a scientist I am hopeful that this operation will lead us to a new understanding of how the brain works.

Figure Legend: The effect of dopamine on nerve cell activity of the basal ganglia. Dopamine neurons of the substantia nigra pars compacta (N) ordinarily stimulate (arrow head at the end of connections) the Substance P/GABAergic striatal neurons that inhibit (dot at the end of connections)the neurons of the internal globus pallidus (I) via the direct striatal output pathway. At the same time dopamine inhibits the striatal neurons of the indirect output pathway that would otherwise disinhibit the subthalamic nucleus (S) and internal globus pallidus by inhibiting the external globus pallidus (E). Both actions of dopamine result in inhibition of the tonically active internal pallidum. Loss of the dopamine neurons in Parkinson's disease results in over activity of medial pallidal neurons.

John B. Penney