Dissecting Parkinson's

A major workshop on Parkinson's disease offers insights into the nature of the disease, the medical challenges involved and the state-of-play of research advances.

AN international workshop on "Parkinson's disease and other movement disorders" was held in Chennai in mid-February. Hosted by the T.S. Srinivasan Department of Clinical Neurology and Research (at the Public Health Centre) and the Madras Institute of Neurology (at the Madras Medical College), the workshop brought together over 300 Indian and international delegates - neurologists, clinicians, neuro-physicians, geneticists, imaging experts, surgeons, neuro-psychiatrists, paediatricians, and radiologists - to discuss the incidence of Parkinson's disease, its manifestations, methods of treatment and key research findings. Its sponsors included the Movement Disorders Society (the umbrella organisation of all movement disorder groups the world over), the Institute of Neurology, London, and the Wellcome Trust, United Kingdom.

Parkinson's disease, which was first described in "An Essay on the Shaking Palsy" in 1817 by a London physician James Parkinson, has probably existed for thousands of years. Its symptoms and treatment methods find mention in the texts of Ayurveda, the system of ancient Indian medicine, and in the first Chinese medical text, Nei Jing, some 2,500 years old.

According to Stanley Fahn, who is Professor of Neurology, Columbia University, United States, and Director, Centre for Parkinson's Disease, Columbia-Presbyterian Medical Centre, "Since the 1960s, when Dr. George Cotzias administered the miracle drug Levodopa on patients, dramatically changing their lives, no breakthrough has been made in treating the disease. Though the world over many facets of the disease - pharmacology, genetics, surgery and transplantation - are being researched, the cause of Parkinson's disease still remains elusive".

Parkinson's disease is a progressive neurological disorder caused by the degeneration of nerve cells (neurons) in the region of the brain that controls movements. The destruction of neurons leads to a shortage of the brain-signalling chemical or neurotransmitters called dopamine, responsible for the pigmentation of neurons (a normal outcome of metabolism that begins after birth and is completed at the age of 18) in the mid-brain or the Substantia nigra. Pathological studies indicate that the loss of the pigmented nerve cells, of which there are some 4,000 in the Substantia nigra, causes Parkinson's disease. Also, when dopamine starts depleting, various other areas in the brain such as the thalamus, Globus pallidus and the subthalamic nucleus start to malfunction. Since these areas send signals to other parts of the brain, malfunctions in these small areas lead to widespread brain dysfunction.

In the normal course, at least 2,000 neurons in the Substantia nigra are lost every year. But when a person loses 40 per cent of the neurons (160,000) in the Substantia nigra, symptoms of the disease develop. Sometimes the rate of loss of neurons accelerates. According to Professor Fahn, accelerated loss of cells remains a mystery. The sudden loss could be due to a genetic defect, because of an internally-produced chemical (a naturally occurring free radical), or because of contact with an external chemical (a toxin that breaches the cell defences).

Although the exact cause of Parkinson's disease is not known, the current thinking is that both genetic and environmental factors might be responsible. While genes like the alpha-synuclein and Parkin can trigger Parkinson's disease on their own, for a majority of patients, without a family history of the occurence of Parkinson's disease, it might be one gene that is susceptible to some toxic element in the environment that might cause Parkinson's disease.

Available treatment methods can only treat the symptoms. The first symptom of Parkinson's disease is usually tremor of the limb which spreads gradually from one side to the other, especially when the body is at rest. Other symptoms include slow movement (bradykinesia), inability to move (akinesia), rigidity of limbs, shuffling gait and stooped posture. Affected people often show reduced facial expression and speak softly. There may be other symptoms such as depression, dementia, sleep disturbances, personality change, speech impairment and sexual dysfunction.

The symptoms appear first around the age of 60, though in 15 per cent of the cases they occur before the age of 50. It is estimated that one in every 100 persons over the age of 60 is affected by Parkinson's disease. Most people who develop symptoms of primary Parkinson's disease are said to have "idiopathic Parkinson's disease", as its causes are unknown. Secondary Parkinson's disease, or Parkinsonism, occurs not because of loss of pigmented neurons but because the melanin cells or pigmented neurons in the Substantia nigra are affected due to a viral attack or trauma. Affected people develop the symptoms of Parkinson's disease, but the symptoms disappear as the infection wanes or when the trauma-induced problems are corrected. Japanese encephalitis, a viral infection, is known to cause Parkinsonism. In India, drug-induced Parkinsonism is common.

According to Professor Andres Lozano of the Department of Surgery, Toronto Western Hospital, Canada, Parkinson's disease is treated mainly by replacing the missing dopamine. Today, the best drug available is Levodopa, the miracle drug developed in the 1960s that got patients out of wheel-chairs. But it is effective only for a few years. After some years of therapy, not only does the drug become less effective but it causes side-effects such as involuntary movement, or dyskinesia. Then options such as surgery are considered.

There are three types of surgery: ablative or destructive, which involves locating, targeting and then destroying a clearly defined area of the brain, deep brain stimulation where a probe or an electrode is implanted into a clearly-defined abnormal brain region such as Globus pallidus, thalamus or subthalamic nucleus, and transplantation or restorative (implanting dopamine-producing cells into the striatum).

Surgery was employed to treat tremors a century ago but it ceased to be a useful option after Levadopa arrived in the 1960s. With developments in diagnostic techniques and following problems caused by the extended use of Levodopa, surgery was revived in the 1970s. This was aided by developments in imaging techniques leading to a better understanding of the targets, and improvements in surgical methods.

Surgery is effective in treating tremors (reduction to an extent of 80 per cent), rigidity and akinesia (60 per cent), gait and postural disturbances (50 per cent) and dyskinesia. Surgery can reduce and even eliminate the use of drugs.

But, according to Dr. Lozano, surgery could lead to psychiatric disturbances, urinary problems, sexual dysfunction, and difficulties in swallowing and speech. Also, the deep-brain stimulator, which is put inside the targeted area with counter current to stop brain cells from degenerating, costs Rs.4 lakhs and it could get infected.

Molecular approaches to surgery such as infusing drugs that protect neurons from dying or implanting genes that help produce more dopamine are in various stages of development. Transplantation is another possibility - using stem cells exogenously or from patient's own tissues, to repopulate dead cells and reconnect defective circuits in the brain.

According to Professor N.H. Wadia, Director, Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, studies show that the prevalence of Parkinson's disease is the lowest among Nigerians, followed by Chinese, Japanese, Afro-Americans and Indians. The prevalence rate is higher in Western countries. For example, the incidence of the disease among Italians is 11 times higher than among the Chinese. The prevalence of Parkinson's disease varies across communities too. For instance, in India, the incidence of the disease is higher among Parsis.

In India, the crude age-adjusted prevalence rate of Parkinson's disease per 100,000 population is 14 in northern India, 27 in the south and 16 in the east, while it is 363 for Parsis in Mumbai. The rate is 100 to 200 in the U.K.

According to Uday Mutane, Assistant Professor, Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, who analysed neurons in 84 brains from brain banks in London and Bangalore, the loss of pigmented melanin cells in the Substantia nigra is 40 per cent lesser among Indians. The reasons are not clear.

Dr. Maduri Bihari from Delhi found from a study of 377 Parkinson's disease patients that several factors such as family history, drinking of well water for a long time, vegetarian diet, rural residence, exposure to herbicides and insecticides and excessive alcohol intake increased the risk of acquiring Parkinson's disease. These results need to be corroborated with more studies.

A NIMHANS study concentrated on the ethnic roots of Parkinson's disease. In India, Anglo-Indians are found to be less prone to the disease. While 19.5 per cent of Indians at large have Parkinson's disease, only 4 per cent of Anglo-Indians are affected.

According to Professor Jean Aicardi, a paediatrician attached to Hospital Robert Bebre, Paris, while children are generally not affected by Parkinson's disease, some 4 per cent of children are affected by a movement disorder called tic, an involuntary movement of muscle. It is mostly benign and disappears with age.

According to Dr. E. S. Krishnamoorthy, Assistant Director, (Research), National Neuroscience Institute, Singapore, treating movement disorders is expensive, This is particularly true in the case of newer treatment methods such as the Botolinum stimulation injection. India, he said, has the scientific base to develop Botolinum injections that can bring down the treatment costs significantly. "The future of treatment lies in pharmacogenomics that links drug treatment to the response of genes," he says.

Professor Kailash Bhatia from the Institute of Neurology, London, conducted a workshop on Botulinum treatment methods with patients with dystonia, writer's cramp and so on.

The Chennai workshop concentrated on epidemiological studies, which offered clues and insights into the risk factors involved in Parkinson's disease and other movement disorders; genetic studies - computational models, gene-based research and treatment; newer drugs to treat not only movement disorders but also cognitive disorders such as memory loss and depression arising as side-effects from taking traditional drugs that are dopa-based, or MAO inhibitors; and surgical techniques and management including stimulation of certain areas in the brain and transplantation.

The Chennai workshop brought out the need for India to set up national registers and do a number of multi-population epidemiological studies with nested controls, particularly as the country is diverse in environment, culture, diet and ethnicity.