Symptoms and Treatment for Early Parkinson's disease

Parkinson's disease (PD) is the second most common neuro-degenerative disorder, after Alzheimer's disease, primarily affecting the elderly people. It is estimated that about 1% of population above the age of 65 years and about 5% above the age of 80 years suffer from PD. It can, therefore, be calculated that in India alone with an estimated population of 100 crore (one billion) by the turn of century, about 70 crore (700 million) people will be above the age of 65 years, of which approximately 70 lac (7 million) will suffer from PD.

After the clinical description of this malady in 1817 by James Parkinson, major breakthrough in the field of PD was the discovery of loss of dopamine in the nigro-striatal pathways by Ehringer and Hornykiewicz.[1] Better understanding of neurochemistry, neurophysiology, pathogenesis, aetiology, genetics and development of experimental models has led to improvement in therapy of PD.

What are the Major Symptoms of the Disease?

Parkinson's disease does not affect everyone the same way. In some people the disease progresses quickly, in others it does not. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and different symptoms are more troublesome.

Tremor. The tremor associated with Parkinson's disease has a characteristic appearance. Typically, the tremor takes the form of a rhythmic back-and-forth motion of the thumb and forefinger at three beats per second. This is sometimes called "pill rolling." Tremor usually begins in a hand, although sometimes a foot or the jaw is affected first. It is most obvious when the hand is at rest or when a person is under stress. In three out of four patients, the tremor may affect only one part or side of the body, especially during the early stages of the disease. Later it may become more general. Tremor is rarely disabling and it usually disappears during sleep or improves with intentional movement.

Rigidity. Rigidity, or a resistance to movement, affects most parkinsonian patients. A major principle of body movement is that all muscles have an opposing muscle. Movement is possible not just because one muscle becomes more active, but because the opposing muscle relaxes. In Parkinson's disease, rigidity comes about when, in response to signals from the brain, the delicate balance of opposing muscles is disturbed. The muscles remain constantly tensed and contracted so that the person aches or feels stiff or weak. The rigidity becomes obvious when another person tries to move the patient's arm, which will move only in ratchet-like or short, jerky movements known as "cogwheel" rigidity.

Bradykinesia. Bradykinesia, or the slowing down and loss of spontaneous and automatic movement, is particularly frustrating because it is unpredictable. One moment the patient can move easily. The next moment he or she may need help. This may well be the most disabling and distressing symptom of the disease because the patient cannot rapidly perform routine movements. Activities once performed quickly and easily -- such as washing or dressing -- may take several hours.

Postural instability. Postural instability, or impaired balance and coordination, causes patients to develop a forward or backward lean and to fall easily. When bumped from the front or when starting to walk, patients with a backward lean have a tendency to step backwards, which is known as retropulsion. Postural instability can cause patients to have a stooped posture in which the head is bowed and the shoulders are drooped.

Treatment for Early Parkinson's Disease:

Parkinson's Disease Study Group of United Kingdom in an open long arm prospective study on 520 patients of early PD compared the effectiveness of levodopa alone and levodopa combined with selegiline. The levedopa alone group showed slightly more disability scores, less peak dose dyskinesia and significantly higher dose of levodopa to achieve motor control after a mean follow up 5.6 years the group as compared to on levodopa with deprenyl. However, an alarming observation noted by these workers was higher mortality among patients who received deprenyl (60% higher) as compared to those who did not receive deprenyl.

There was no relationship of increased mortality in deprenyl treated patients with age and gender of the patient. The difference in mortality in the two groups started after 3 years of treatment. Subsequent studies by same group of workers and group of investigators from Finland demonstrated that selegiline in combination with levodopa, and not the selegiline monotherapy was associated with diminished autonomic response (especially those of sympathetic division) resulting in orthostatic hypotension. However, none of these studies have shown increased incidence of cardiac rhythm disturbance.

Though the mechanism of hypotensive effect of selegiline is unclear, it is postulated that cardiac contractility may be impaired and there may be failure of autonomic system as shown by failure of heart rate and noradrenaline level to rise in response to hypotension. Non selective MAO inhibitors which inactivate both isoenzymes and are not metabolized to amphetamines may be responsible for orthostatic hypotension possibly due to inhibition of tyramine metabolism. It may, therefore, be suggested that selegiline should be used with caution especially in elderly people, with disturbance of cardiac contractility (eg. ischaemic heart disease, cardiac failure). It may be given with caution in young people. If used, it should not be used for more than 2-3 years.

Trihexiphenydyl (THP) is used frequently by Indian neurologists in PD patients, especially those with tremor dominant PD due to easy accessibility and low cost. Though tremor responds favourably to levodopa, the dose needed to achieve this end is very high. For this reason many Indian neurologists prefer THP to very high dose of levodopa. The only limiting factor of THP is its troublesome side effects in some patients. These include blurring of vision, urinary retention (in older men), confusion (older patients) and constipation.

Another frequently forgotten side effect of THP is its ability to slow gastrointestinal movements which may cause retention of levodopa and other antiparkinsonian drugs in the stomach for longer periods of time resulting in `delayed - on', `dose failure' or `no-on'. Therefore, in advanced PD patients when these complications are common THP should be used with caution or may be withdrawn. Under these circumstances domperidone, a peripherally acting D2 antagonist is helpful by promoting gastrointestinal movements and rapidly delivering the drugs into small intestine from where it is absorbed.

In the recent years, there has been a revival in interest in surgical treatment of PD. This was due in part of the emergence of levodopa related motor complications, improvement in surgical techniques, availability of new gadgets and instruments and understanding of pathophysiology of complications of levodopa therapy. Though ablation of ventrointermedius nucleus of thalamus has been used in unilateral tremors in PD patients since a long time, other targets such as internal segment of pallidum (Gpi) has shown promising results in patients with levodopa related dyskinesias.

The drawback of postroventral pallidotomy is that it can not be done bilaterally as it results in severe cognitive impairment. Subthalamic neucleus (STN), another target important in the pathogenesis of PD has been in the focus as a promising site, both for lesioning and deep brain stimulation. Lesioning of STN was produced by Muthane et al in PD patients with good results. Many neuro-surgeons will shy from producing a lesion in STN due to disabling complications though. Currently interest is generated in stimulating various targets in the brain. These targets have been identified as ventro-intermedius nucleus of thalamus (for tremors), Gpi (for dyskinesia, bradykinesia and rigidity) and STN for all the symptoms of PD. It is conjectured that STN stimulation may have some neuroprotective action.

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The procedure requires placement of electrodes at the identified target in an awake patient after carefully calculating the co-ordinates and noting the response to stimulation of pulse generator. The pulse generator, which is of the size of usual cardiac pace-maker, is implanted below the clavicle. Though the short term results are encouraging, results of long term effects have yet to come. The procedure is expensive and careful selection of patients is needed before subjecting them to this mode of therapy. A new concept in surgical therapy is transplantation of genetically engineered cells or viral vectors capable of producing DA or enhancing the activity of enzymes involved in its synthesis in certain areas of brain. This approach is still in experimental stage.

In conclusion, levodopa with peripheral dopa-decarboxylase inhibitor (DCI) is the gold standard in the treatment of Parkinson's disease. The toxic effect of levodopa has not been proved conclusively. Since the best effect of levodopa therapy is confined to 5-8 years, all patients must receive the benefit of levodopa therapy especially early on in the course of treatment. The only exception is patients younger than 60 years who should be initially started on DA agonists and levodopa be supplemented when DA agonists do not provide adequate control. In the early disease, especially in younger patients (<60 years) DA agonists, amantadine and selegiline could be used due to their possible neuroprotective dopa sparing action.

While using selegiline the precautions as already alluded to should be followed keeping in mind to restrict its use for 2-3 years. As the disease advances and these drugs are not able to provide adequate control of symptoms to the patient, levodopa with DCI should be added. In elderly patients in whom levodopa with DCI is started from the beginning the dose should be increased slowly with at least 2 weeks in between increments. If needed DA agonist may be added if disability increases after some years. Tremor dominant young PD patients may do well with THP, but when bradykinesia and rigidity become prominent levodopa with DCI may be added. Care should be taken in prescribing THP in elderly and advanced PD patients.