Hope lies in slowing the rate of progression

Professor Stanley Fahn, H. Houston Merritt Professor of Neurology at Columbia University, and Director, Centre for Parkinson's Disease and Movement Disorders, Columbia-Presbyterian Medical Centre, has done pioneering work in some lesser-known subspecialities of movement disorders such as dystonia and Huntington's disease. He is also the founding member and the first president of the Movement Disorder Society, besides being president of the American Academy of Neurology. The awards he has received include the American Academy of Neurology award for excellence in research and the A.B. Baker award for outstanding teaching. He is on the advisory board of several international committees on movement disorders.

Recently, he was in Chennai to receive the Lifetime Achievement Award from the Neurosciences India group, on which occasion he also delivered the 22nd T.S. Srinivasan Endowment Lecture.

Professor Fahn spoke to Asha Krishnakumar on movement disorders, the role of the environment, genetic factors, the status of research on Parkinson's disease, and the future for patients with movement disorders. Excerpts:

Why do the dopamine-producing cells die?

There are several theories. One is that along with dopamine, other monoamin cells also die. Every time the cells metabolise, hydrogen peroxide is formed which has to be got rid of quickly as it reacts with other parts of the cell to form free radicals, which attack the protein, the cell membrane, the DNA and eventually kill cells.

Researchers are trying different approaches to get rid of the hydrogen peroxide and slow the progression of the disease. They are trying drugs that block protein aggregation and so on. None of the treatments can slow the disease. We can only treat the symptoms.

How much does the environment impact the onset of the disease?

Studies on twins gave us some clues. Only in those cases where one twin has Parkinson's disease before the age of 50 did the other twin get it too. The later onset of Parkinson's disease is more due to environment than genes. But many feel that where one twin had early onset of Parkinson's disease, the other twin may not have been infected as they did not live long. Thus the current thinking is that both genes and environment are important.

Have there been epidemiological studies on Parkinson's disease? What is the incidence of the disease?

There are a number of epidemiological studies. Parkinson's is the second most common neuro degenerative disease, after Alzheimer's. The highest prevalence rate is probably in the U.S. - 200 per 100,000. According to studies by Professor H. Wadia in Mumbai, the prevalence rate of Parkinson's disease among Parsis settled in Mumbai is 363 per 100,000. So, some genetic factor is responsible for the high prevalence of the disease among Parsis. In the U.S. there are over 60,000 new cases a year.

The prevalence rate among men is higher than women at 3:2. Some theories are floating around such as estrogen acts as a protective measure for women or that men eat more meat and get more iron, which accumulates and triggers the disease and so on. But no one knows for sure.

The prevalence rate is higher in older age groups. But though women live longer than men, they have lower prevalence rates.

Are diagnostic techniques well-developed?

Parkinson's is still diagnosed clinically. The family history of the patients and physical examination can almost always diagnose Parkinson's correctly.

Can Parkinson's disease be cured? What are the different treatment methods?

The treatment was discovered over a century ago. Some plants and herbs were used to treat some of the symptoms. In the 1950s, many of these compounds were synthesised chemically and became the standard treatment. It was more or less discovered by accident in France. But in the 1960s some scientists discovered that dopamine deficiency in animals can mimic Parkinson's. This led to the understanding that dopamine deficiency in the brain caused Parkinson's disease. Brain autopsy showed that most symptoms were related to dopamine deficiency. Then it became known that this was happening because dopamine-producing cells were dying in the brain's Substantia nigra region. The picture then became clear.

It was also learnt that a dopamine replacement therapy could reverse Parkinson's disease conditions. Levodopa did wonders - patients' stiffness and tremors vanished, they could walk, talk and do their chores better. Levodopa is the immediate precursor to dopamine.

Then why do we not use dopamine instead of Levodopa?

Levodopa is used because dopamine does not cross the blood-brain barrier. But Levodopa has amino acid and hence is an active transport system. It can cross the blood-brain barrier and enter the brain where it can be converted into dopamine. This is still the best-perfected and the most powerful treatment for Parkinson's disease.

In the 1960s, George Cotzias, who discovered Levodopa, worked out how to get it into the brain without causing many side-effects. Some drugs (such as Carbidopa) have been developed to be taken with Levodopa to tide over some of its problems. A combination of the two drugs, called Sinemet, is prescribed extensively for Parkinson's disease. Such drugs as Agonists that behave like dopamine have also been developed. Recently, a group of drugs called Comt was prescribed with Levodopa to prolong the latter's action and to decrease some of its side-effects. But Levo-dopa still remains the standard and the most powerful treatment for Parkinson's disease.

Can Levodopa be administered to all patients suffering from Parkinson's disease?

Not all patients can take Levodopa because of its side-effects. The next most powerful group of drugs is called dopamine Aganus which acts directly on dopamine receptors. Dopamine Aganus drugs are milder than Levodopa. Unfortunately, they have their own side-effects - swelling in the ankle, drowsiness and so on. Mostly patients start with these weaker drugs and when the symptoms worsen and they need to take powerful drugs they are put on Levodopa.

Levodopa revolutionised treatment as it got wheelchair-bound patients on their feet. However, many patients developed complications and the drug had to be stopped as they became dyskineseous (having abnormal involuntary movements). That is a very common problem in Levodopa therapy. The trick is to get the dosage right. The longer the patients are on Levodopa, the more sensitive the receptors get and over-react. It is difficult to treat such patients.

Another big problem with Levodopa is that it has a very short half-life - it does not stay very long. Initially the patient does well and it does not matter when you take Levodopa. But after some years complications develop and the frequency of drug use has to be increased.

New drugs have been developed to extend the period of effective use of Levodopa. Various combinations of drugs are also administered. It is an art treating patients with complicated Parkin-son's disease.

What is the state-of-art of research in the diagnostics, pharmacology and treatment of Parkinson's disease?

Genetic research is fairly dominant as it gives clues to the genesis of the disease. As the extended use of Levodopa leads to complications, drug companies are working on methods to overcome its common side-effects.

The most exciting research is on slowing the rate of progression of the disease. There are as yet no positive clues to slowing down its progression. But hope lies in this area of research.

When there will be a cure, one is not sure. People are speculating on cell transplants, gene therapy and so on. But already embryonic dopamine cells have been implanted onto the brains of patients. The results were published a year ago. We have shown that these cells from the foetus can grow and survive in the brain and make dopamine reducing the need for Levodopa. But it does not work in older patients. Also, people might end up with too many dopamine-making cells and hence producing too much dopa. So they end up being dyskinesious (hyperactive). So, we concluded that unless we know how to control the cells, cell transplants should not be done.

The same is true with stem cells. The idea with stem cells is that they can be converted to dopamine cells by growing them in a test-tube. The important thing is to know how to control the cells so that they do not grow tumorous, get cancerous or not make too much dopamine. Research is on in this area.

Another potential area of stem cell research is to grow other cells besides dopamine-producing cells such as neuro-tropins. This could probably be an answer to Parkinson's disease.

So, what is the hope for Parkinson's disease patients right now? It is still a symptomatic treatment method that is followed.

Every year we make advances. Thirty years ago we did not have Levodopa. Now we have it. We have other drugs that overcome Levodopa's side-effects. Surgery can treat some of the side-effects. The hope is in the studies which are on to slow the progress of the disease. We are not there as yet.