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Year : 1999  |  Volume : 47  |  Issue : 4  |  Page : 259-62

Treatment of Parkinson's disease : fighting the surging enemy.


Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Correspondence Address:
Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.



How to cite this article:
Behari M. Treatment of Parkinson's disease : fighting the surging enemy. Neurol India 1999;47:259


How to cite this URL:
Behari M. Treatment of Parkinson's disease : fighting the surging enemy. Neurol India [serial online] 1999 [cited 2020 May 25];47:259. Available from: http://www.neurologyindia.com/text.asp?1999/47/4/259/1594



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. This is a staggering Figure. 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.

The basic mechanism(s) responsible for apoptosis (programmed cell-death) in PD still alludes us. Certain environmental factors and molecular mechanisms which may be responsible for the disease and its progression are unfolding themselves. The observation that smoking is seen in significantly lower number of PD patients suggests that smoking may have protective action in some way for the development of PD.[2],[3] This observation was earlier believed to be due to natural selection, whereby smokers were thought to die earlier than non-smokers due to occurrence of fatal diseases like coronary artery disease, cerebrovascular disease and lung cancer. A group of researchers has now shown that cigarette smoke contains a mono-amine oxidase-B (MAO-B) inhibitor which may protect nigral neurons.[4] Research on several environmental and endogenous toxins has identified some of the factors which may cause PD. Mitochondrial respiratory failure and oxidative stress appear to play important roles in the pathogenesis and progression of PD. Progress in the area of genetics has identified a subgroup of PD patients in whom the disease is inherited as an autosomal dominant trait and is associated with missense mutation of alpha-synclein gene.[5] Another subgroup of PD patients have been identified with deletion mutation in a novel protein `Parkin' gene in whom the disease runs as autosomal recessive trait with early onset PD.[6] Though these mutations are identified in a large number of patients tested, these are not present universally.[7],[8],[9],[10] It seems, therefore, that idiopathic Parkinson's disease with nigral Lewy body as we identify it now, may consist of several subsets of `Parkinsonisms'.

Better understanding of neurochemistry and neuropharmacology has resulted in improved drug delivery systems, newer treatment strategies including newer dopamine (DA) agonists, mono-amine oxidase inhibitors, catechol-O-methyl transferase inhibitors and development of several neurosurgical procedures, namely, neural transplant, ablative and stimulation techniques.

Levodopa still remains the gold standard of treatment of PD. However, long term treatment with levodopa is associated with response fluctuations, dyskinesias and psychiatric disturbances. Though, several studies have implicated prolonged use of levodopa to the development of dyskinesias and motor fluctuations in PD, the issue of neurotoxicity of levodopa is not settled due to lack of conclusive evidence in experimental and clinical studies.[11] The risk factors for development of these complications include age at onset of illness, duration of disease, levodopa dose, and duration of levodopa therapy.[12],[13] The exact cause of these complications is not known. It is suggested that impaired dopaminergic metabolism and/or receptor sensitivity, decreased presynaptic DA storage, decreased capacity to buffer fluctuations of DA plasma concentrations, diminished brain DA pool, postsynaptic down regulation of striatal D2 receptors and reduction of plasma half life of DA may all be responsible for levodopa associated complications. The reason for this is believed to be pulsatile, intermittent exogenous levodopa stimulation in a chronically denervated nigrostriatal dopaminergic system.[14] However, use of continuous administration of levodopa by drip infusion does not prevent development of severe dyskinesia.[15] On similar principle, sustained release levodopa formulations have been used in de-novo PD patients and the results compared with standard levodopa in a double blind manner. The five year study did not show any difference in the incidence of motor fluctuations between the two groups of patients.[16]

DA agonists have been used in the treatment of PD since the mid 1970s. Both ergot derived DA agonists such as bromocriptine, lisuride, pergolide and cabergoline and nonergot derivatives such as pramipexole, piribedil and ropinirole are powerful D2 receptor stimulators. They can be used as monotherapy or as add on in `early' or `late' PD patients in combination with levodopa. Many of these agents are now available to the Indian patients. Apart from reducing rigidity and bradykinesia they are also useful in rest tremors.[17] The efficacy, safety and tolerability of these new agents are now proved in large randomised controlled, double blind, multicentre studies.[18] Apart from symptomatic relief, many studies have shown neuroprotective action of DA agonists believed to be due to the suppression of release of endogenous DA. Bromocriptine has been shown to possess hydroxyl radical scavenging property.[19] Similarly, pramipexole has been shown to have neuroprotective action both in vitro and in vivo studies in animals. These actions include DA autoreceptor agonist properties, antioxidant properties, ability to block the mitochondrial permeability transition pore and ability to stimulate release of trophic factors.[20],[21] Clinical studies have shown that PD patients receiving only DA agonists (usually bromocriptine) therapy initially and later started on concomitant levodopa therapy showed low incidence of adverse reactions.[22] Early DA agonists monotherapy provides adequate control of PD symptoms for about one year after which there is need to add levodopa. Only a small proportion (approximately 10%) obtain good benefit for 4-5 years.These studies have shown that substitution of >25% of levodopa by bromocriptine gives good symptomatic effect along with low incidence of motor fluctuations and dyskinesia.[23],[24] A study by pergolide monotherapy study group has shown that pergolide monotherapy is efficacious and well tolerated as first line treatment in early stage PD patients in a 3 month randomized controlled study.[25] These clinical findings suggest that treatment of PD should be initiated with DA agonists and levodopa should be prescribed only when DA agonists no longer provide satisfactory control of PD symptoms. A large number of studies are available using DA agonists as add on therapy either in `early' or `late' PD patients which suggest its levodopa sparing effect and reducing the early incidence of levodopa related motor response fluctuations. The dose equivalents amongst various available DA agonsits is difficult to know but has been estimated as 30mg of bromocriptine, 15mg of ropinirole, 4.5mg of pramipexole and 3.0mg of pergolide.[26]

Ability of pre-treatment with selegeline, a MAO-B inhibitor to protect rodents from toxic effects of 1 methyl 1,2,3,6, tetra hydropyridine (MPTP) was considered to be due to neuro-protective action of selegiline.[27] Also MAO is a major enzyme in the metabolism of DA in the brain. Therefore, a logical approach is to inhibit MAO in an attempt to conserve endogenous DA. Another factor considered important in the worsening of PD is formation of free radicals consequent upon metabolism of endogenous and exogenous DA. It was hence considered logical to inhibit MAO-B selectively with selegiline in an attempt to reduce turn-over of DA allowing endogenous dopamine to stay in the brain for longer period, reduce formation of free radicals and mop up any free radicals that are formed.[28] The DATATOP study recruited 800 early PD patients. Initial results showed that selegiline delayed onset of disability requiring therapy with levodopa by slowing progression of the disease. It is now thought that this initial effect of selegiline was the effect of its dopa sparing action, its amphetamine metabolites, clinically unsuspected antidepressant effect or by an increase in phenylethyl-amine levels.[29] The follow up of DATATOP study also suggested that the initial effect of selegiline was not sustained.[30],[31]

Neuroprotection is the ability of an agent to slow the rate of progression of neuronal cell death resulting in slower progression of clinical symptoms and less disability. Selegiline is a candidate for a neuroprotective agent in PD. Experimental study has shown extension of life span of rodents treated with selegiline by 50%.[32] Mechanism of neuroprotective action of deprenyl is not clear, but may consist of several actions such as prevention of conversion of a protoxin to a toxin or change the progression of PD. There are two divergent views on the protective effect of selegiline in PD. Workers in USA are of the opinion that deprenyl treated patients deteriorate much slowly as compared to placebo treated patients.[33] Tatton et al in their study demonstrated that deprenyl limits MPTP induced nigral damage and reduces PC12 cell apoptosis in doses that do not inhibit MAO-B.[34] They propose that deprenyl rescues nigral neurons by inducing selective changes in transcription with new protein synthesis and alteration in gene expression. In another study Wu et al showed reduction in nigral damage and free radical formation by deprenyl in doses that did not inhibit MAO-B.[35] These studies suggest that deprenyl may favourably influence the rate of neuronal damage through mechanisms not dependent on MAO-B inhibition.

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.[36] 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.[37],[38] 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.[39] 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. 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.[40],[41] 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.

The debate on incidence of motor complications in controlled release levodopa with DCI is not yet settled. A single long term (5 year) randomized study has shown no difference in these complications between controlled release and standard levodopa with DCI. Theoretically, however, it sounds to reason that controlled release formulation should result in lower incidence of motor complications due to sustained levels of DA in brain. It may therefore, be prudent to prescribe controlled release formulation to younger patients.

It can be summed up by saying that we are still in the process of understanding many aspects of PD and there is no treatment plan which can be considered as the best for all patients. The therapeutic plan for each patient has to be individualized and it requires not only the science of medicine but also the art of medicine to achieve optimum results.

 

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