1. Dept of Medicine, Ogun State University Teaching Hospital; Sagamu Ogun State. Nigeria

E-Mail Contact - OGUN Shamsideen Abayomi : yomiogun@skannet.com

Parkinson’s disease is a common neurological condition. Environmental, genetic factors and age are important predisposing factors, but there continues to be increasing evidence for a genetic component. Apoptosis and necrosis have been implicated in the loss of the nigral neurons in patients with parkinson ‘s disease. Mitochondrial dysfunction, oxidative stress, the actions of excitotoxins, deficient neurotrophic support and immune mechanisms are contributory. Excessive activity of the subthalamic nucleus has also been found to contribute to the symptoms of parkinsons disease using the neurotransmitter glutamate, blockade of which might provide an effective treatment of parkinson’s disease. Treatment could be preventive, symptomatic or restorative. Neuroprotective agents prevent apoptosis by upregulating apoptosis defence gene and down regulating apoptosis promoting genes. Selegilline (deprenyl) has selective anti apoptotic properties by increasing mitochondrial energy production and reducing generation of free radicals. Free radical scavengers such as atocopherol, high doses of ascorbate, antioxidants such as selenium and ubiquinone, drugs inhibiting glutamate release or receptor interaction such as N- methyl 4 – valine antagonist and aspirin, which down regulate glutamate receptors have been tried without proven benefit. Non-steroidal anti-inflammatory agents and interferon b have also been tried with no documented efficacy. Except for functional neurosurgical procedures, levodopa remains the most effective replacement therapy for parkinson’s disease.

Several new methods of therapy are under development, including the inhibition of dopamine catabolism, synthesis of new dopamine receptor agonists, and manipulation of the function of the subthalamic nucleus. However, as new drugs become available, treatments that influence oxidative phosphorylation and damage due to free radicals, excessive iron deposition, disturbances of calcium homeostasis, cytokines, excitotoxicity, nitric oxide, apoptosis, and the products of causative genes may all be considered in attempts to provide effective neural protection. Fetal nigral implants into the striatum improve symptoms while the transplantation of adrenal medulla tissue to the striatum has been largely abandoned because of its lack of efficacy. Allogenic transplantation of fetal mesencephalon is currently been studied, and initial reports show promising results. Also under study are the intraventricular delivery of the dopaminergic neurotrophic factor (GDNF) and the implantation of foreign cells in semi-permeable polymeric capsules, which obviates the need for potentially harmful immunosuppressive therapy.
In conclusion, the treatment of parkinson’s disease remains enigmatic with high cost of medication and significant morbidity. Till date, surgery has a limited role in the management of parkinson’s patients. In the future however, surgical interventions may incorporate advances in gene therapy and genetransfer is being examined in animal models of parkinsonism. Genes coding for molecules that block apoptosis, scavenge free radicals, enhance the clearance of toxic metabolites, or improve mitochondrial function could also be considered.


Parkinson’s disease otherwise known as ‘’paralysis agitans » or ‘’shaking palsy » was classically described by James Parkinson in 1817 [1]. It is a common neurological disorder that is difficult to treat with enormous cost, substantial morbi – dity and a marked reduction in life expectancy. Mortality is two to five times as high among affected persons as among age-matched controls [2]. James Parkinsons description of “Involuntary tremulous motion with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forward and to pass from a walking to a running pace, the senses and intellect being uninjured” has stood the test of time.

A) Definition

It is a neuro-degenerative disease of insidious onset in middle or late age characterized by slowly progressive akinesia, rigidity, tremor and postural abnormality.

B) Epidemiology

Parkinson’s disease is second only to Alzheimer’s disease with a prevalence of 1 in 10,000. The incidence rises exponentially above the age of 50 years to 1 in 200 [3]. It is rare below the age of 40 and above 65 years. However, about 5 to 10% of patients develop symptoms before the age of 40 years [4]. It affects all social class worldwide but less common amongst the black race and commoner in males with a male:female ratio of 3:2.

C) Aetiology

1) Environmental factors

MPTP (1-methy-4- phenyl-1,2,3,6- tetra hydro pyridine) – a meperidine analogue occasionally used by heroin addicts, has been implicated [5]. It is converted by MAO-B (mono amine oxidase B iso enzyme) to the active neurotoxic metabolite MPP+ (methl phenyl pyridinum) ion and free radicals. This metabolite is concentrated in dopamine neurons where it is bound to neuromelanin and inhibits complex-1 of the mitochondrial respiratory chain [6]. Parkinsonian symptoms could develop within 14 days of exposure to this toxin. If a similar toxin is responsible for the naturally occurring Parkinsons disease, MAO-B inhibitors and free radical scavengers might block the production or action of the toxin, thus slowing the rate of progression of the disease by protecting neurons in the substantia nigra. Other neurotoxic environmental factors include exposure to pesticides (rotenone), herbicides and well water [7,8]. Reduced vitamin E intake has also been implicated in community studies [9].

2) Hereditary factors

The notion that only 5% of parkinsons patients have a positive family history with no concordance between identical twins and between monozygotic and dizygotic twins is no longer true [10]. There continues to be increasing evidence for a genetic component in the predisposition to Parkinson’s disease. Positive family history and age appear to be the most important factors and there is a two to three fold increase in first-degree relatives of patients with parkinson’s disease [11]. Most of the available evidence support an autosomal dominant inheritance with low penetrance and that the cause is possibly multifactorial (environment + genetic predisposition). Parkin gene mutation occurs on the long arm of chromosome 6 and is inherited as autosomal recessive [12]. Mutation of & – synuclein gene occurs on chromosome 4 and is inherited as autosomal dominant while defect on chromosome 2 is inherited as autosomal dominant with low penetrance [13].

3) Viral aetiology

Extensive viral studies in patients with Parkinson’s disease have not been rewarding. No viral agent has been isolated [5]. The fact that all parkinson’s disease were due to encephalitis lethergica has been discredited. Parkinson’s disease has not been transmitted to animals to support an infective aetiology, although it is possible that the animals might not live long enough for parkinsonian features to manifest. The only epidemiological clue to the predisposition to parkinsons disease is that Parkinsons patients smoke less and die less of cancer of the lung [15]. The significance of this observation is however unknown. It has also recently been stated that ingestion of coffee also prevents parkinsons’disease [16].

D) Pathology/Pathophysiology

The basic pathology is cell degeneration and loss of pigmented neurons in the pars compacta of the substantia nigra and locus ceruleus with atrophy and glial scarring. The degenerated pigmented neurons contain Lewy bodies which are intracytoplasmic eosinophilic hyaline inclusions composed of protein filaments (ubiquitin+; &-synuclein), and do not have the electronic microscropic appearance of any known viral or infective agent [17]. They are comparable to the amyloid plaque of Alzehimer’s disease and represent faulty intracellular protein degradation [18]. Lewy bodies are characteristic of parkinson’s disease except in post-encephalitic parkinsons and parken-gene mutants [12].
However, they could be found in 4% of brain without parkinsonian features [18,19] and these are likely cases of subclinical parkinsons as 80% of the zona compacta cells must degenerate before clinical symptoms become apparent.

The pars compacta contains 450,000 dopaminergic neurons. With the loss of dopaminergic neurons at those sites, there is deficiency of dopamine in the basal ganglia, chiefly the striatum (caudate nucleus and putamen) [20]. Furthermore, the enzymes required for dopamine synthesis, DOPA decarboxylase and the rate limiting enzyme tyrosine hydroxylase are reduced. In addition, there is deficiency of neurotropic factors such as glial and brain derived neurotrophic factors [21]. However, neurons in the striatum with dopamine receptors remain intact and are responsible for the therapeutic effects of levodopa. In the parkinsonism unresponsive to levodopa such as that associated with PSP and MSA, striatal neurons are degenerated [20].
Genetic and environmental factors are important in the mechanism of neuronal deaths due to neuronal necrosis or apoptosis. In neuronal necrosis there is disintegration of cell and organelles and subsequent removal by phagocytic and inflammatory response with increased cellular permeability [22]. In apoptosis on the other hand, there is rapid programmed cell death in response to a toxic stimuli. There is chromatin condensation, DNAfragmentation and cell shrinkage, with relative sparing of organelles without inflammatory changes or increased cellular permeability [22].

Among the factors that have been implicated in neuronal degeneration in parkinson’s disease are mitochondrial dysfunction, oxidative stress, the actions of excitotoxins, deficient neurotrophic support and immune mechanisms [23]. HLA-DR positive reactive microglial cells and cytokines such as interleukin 1 (IL-1) and tumor necrosis factor-a play significant role in the pathogenesis of parkinson’s disease. Oxidative stress with excess reactive oxygen species and free radical damage involving one or more unpaired electrons such as hydroxyl ion (OH-), hydrogen peroxide (H202), peroxyl ion, nitric oxide (NO), superoxide ion (O3-) singlet oxygen ion (O- ) react with nucleic acids, proteins and lipids [23]. This metabolic derangement results in generation of toxic byproducts and increased oxidative stress with resultant cellular damage. Furthermore, neuronal excitotoxicity involving glutamate NMDAreceptor results in increased intracellular calcium activation of protease, endonuclease, and phospholipase [24]. Nitric oxide synthase also generates nitric oxide free radicals and release of iron from ferritin. This induces peroxidation and impairs mitochondrial function [23]. There is defect of mitrochondrial energy production resulting in complex-1 deficiency and abnormal calcium handling [6].

In the substantia nigra, the inhibitory neurotransmitter is dopamine; in the neostriatum, the excitatory neurotransmitter is acetylcholine while GABA is inhibitory; in the pallidum the excitatory neurotransmitter is substance Pwhile GABA is the inhibitory neurotransmitter.A fundamental discovery has been that the dopamine deficiency state is associated with increased activity of the excitatory acetylcholine and of the inhibitory GABA which employs GABAergic output nuclei in the basal ganglia, the internal segment of the globus pallidus and the pars reticulata of the the substantia nigra [24]. Furthermore, the subthalamic nucleus excites the internal segment of the globus pallidus and the pars reticulata of the substantia nigra by means of the neurotransmitter glutamate [25]. Excessive activity of the subthalamic nucleus may contribute to the symptoms of parkinsons disease using the neurotransmitter glutamate acting through the D,L, – a amino 3 hydroxy 5 methyl -4- isoxazoleproprionic acid subtype of glutamate receptor [26]. Blockade of this receptor might provide an effective treatment of parkinson’s disease.


In 90% of patients, symptoms set in insidiously at about the age of 55 years, initially on one side but bilateral signs and disability are the rule [2].

1) Tremor : This is usually unilateral at onset, occurs at rest and worsens with emotions and stress, but disappears with action and during sleep. The arms are affected initially with later progression to the head, jaw and feet. It is arrhythmic, 4 to 6 Hz and pill-rolling. It could be absent in up to one quarter of cases of parkinson’s disease [27].

2) Rigidity : most patients complain of stiff muscle. There is plastic resistance (lead pipe rigidity) of the muscles, and in the face of tremors, cogwheel rigidity ensues.

3) Akinesia : There is poverty (hypokinesia) and slowness (bradykinesia) of movement associated with delay in initiating movement (freezing). In addition, there is slowness in executing movement with loss of normal automatic movement such as emotional expression, blinking and arm swing while walking.

4) Postural changes : There is generalized flexion of the limbs, neck and trunk with postural instability causing falls.

According to the WHO, a patient is reported to have definitive parkinsons when 3 of the above 4 symptoms are present, and probable when 2 out of 4 are present. However, if a patient is on treatment, any 2 of the above symptoms qualify for definitive parkinson’s disease [27]. However, parkin gene mutants usually present with atypical early onset, mild or absent tremors and absence of lewi bodies in families.
The face is blank and mask-like with a soft, slurred and monotonous speech. There is defective pronunciation of consonant and lack of variation in speech.
The gait is festinant with loss of arm swings. There is difficulty to start moving (freezing) but once in motion, the pace quickens and the patient is unable to stop with propulsion or retropulsion. The patients are tremulous and untidy, eating and washing become increasingly difficult. Eye movements are usually unaffected and Kayser-fletcher ring may be present in wilson’s disease. Micrographia, blepharoclonus, blepharospasm, drolling salivation, dysphagia and constipation (due to immobility, dietary restriction of fluid and roughage, anticholinergic medications) are common. Urinary frequency and incontinence, excessive sweating and greasy skin (seborrhea) are also found. The deep tendon reflexes and the planter response are normal with normal intellectual and cognitive function. It progresses to difficulty in eating, walking, standing, dressing and eventually patient may become bed and chair bound and may die of other causes. Before the advent of levodopa, death occurs about 9 years after the onset of symptoms. However, with the advent of levodopa, patients may live for up to 30 years in benign parkinsons and for 1 to 2 years in malignant parkinsons with death usually from vascular disease, bronchopneumonia or intercurrent neoplasia [1]. Furthermore, drug treatment may provoke mental disturbances such as depression, toxic confusional state, schizophreniform psychosis and hallucination.

Differential Diagnosis of parkinson’s disease :

1. Post encephalitic parkinsonism : Post encephalitic parkinsonism is now uncommon but was reported after the worldwide epidemics of encephalitis lethergica between 1918 and 1930 (Von economo’s disease) [5]. Affected individuals presented with parkinsonian features acutely or 1 to 2 years after the encephalitis. This is a more benign condition with only 25% of the patients becoming disabled after 20 years. Occulogyric crises occur frequently.

2. Drug-induced parkinsonism : Drug induced parkinsonism: neuroleptic drugs such as resepine which inhibits and depletes dopamine store, phenothiazine which blocks dopamine receptors, butyrophenons, tricyclic antidepressants as well as the antihpertensive methyldopa which is a central DOPA decarboxylase inhibitor, could predispose to parkinsonism. : This remits slowly over weeks or months in 95%
of cases.

3. Other degenerative diseases : Park plus such as progressive supranuclear palsy (PSP) characterized by gaze palsy and preserved vestobulo-occular reflex. The clinical diagnosis of PSP depends on supranuclear paresis of the downward gaze of the eyes, often with paresis of upward gaze (supranuclear vertical opthalmoplegia) as well as lack of response to levodopa. Multiple System atrophy (MSA) consists of olivopontocerebellar and nigrostriatal degeneration, and primary dysautonomia (shy-dragger syndrome). In olivopontocerebellar degeneration, patients may also present with cerebellar ataxia, dysarthria and cerebellar atrophy on CT scan. Autonomic dysfunction with orthostatic hypotension, impaired bladder function, sexual impotence, anhidrosis and a poor or no response to levodopa are prominent features of Shy-dragger syndrome. Frank dementia with diffuse signs of pyramidal tract dysfunction is found in Alzheimer’s disease or cerebrovascular disease (multi infarct dementia). In the Punch drunk syndrome due to a single or repeated severe head injury, and cerebral anoxia due to cardiac arrest or carbon monoxide poisoning, parkinsonism may be prominent features.

4. Parkinsonism could also be apparent in diffuse brain diseases causing generalised cerebral damages and dementia such as Alzheimer’s and multi-infarct dementia, binswanger’s disease, head injury (punch – drunk syndrome), cerebral anoxia and atherosclerotic parkinsons (not a pure parkinsonism because the substantia nigra is strikingly resistant to stroke). Rare causes include Picks disease and Cruetzfelt Jacob disease (CJD) characterized by myoclonus, dementia, pasly, immobility and aphasia. Manganese and carbon monoxide poisoning, wilson’s disease (hepatolentricular degeneration due to caeruloplasmin deficiency and excessive copper deposition), neurosyphilis, cysticercosis and communicating hydrocephalus could also present with parkinsonism like picture [7].

5. Hemi-Parkinsonism could present with unilateral brisk reflexes, upgoing planter response and absent abdominal reflex. This is a very rare condition due to tumor or other focal lesions on the opposite side. Isolated focal lesions of substantia nigra due to trauma, tuberculoma, tumors could cause contralateral hemiparkinsonism [14]. Hemiplegia or hemiparesis must be excluded [14].
6. Benign essential tremors. This is inherited postural tremor without other parkinsonian signs. Alcohol and beta-blockers relieve the tremors.

7. Depression could be confused with early features of parkinsonism.

8. Ankylosing spondylitis due to joint disease also could present as rigidity.


This could be achieved with drugs, surgery or physical therapy. Except for functional neurosurgical procedures, treatment is mainly symptomatic with replacement therapy as parkinson’s disease is a progressive neurodegenerative condition. The treatment can be subdivided into three categories : protective or preventive, symptomatic treatment, and restorative or regenerative treatment.

Drug treatment

a) Neuroprotection:

This protects dopaminergic neurons and prevents or slows the progression of the disease. It prevents apoptosis by upregulating apoptosis defence gene and down regulating apoptosis promoting genes. Apoptosis plays an important role in the immune system and tumor surveillance while mitochondrial dsyfunction increases generation of free radicals. Cyclosporin A inhibits the opening of mitochondrial megapore, which forms the cornerstone of the beginning of apoptotic cell death. Selegilline (deprenyl) has selective anti apoptotic properties. It increases mitochondrial energy production and thus reduces generation of free radicals [28]. It also inhibits monoamine oxidase B isoenzyme (MOABI) irreversibly and prolongs the action of dopamine at the synapse. None of the currently available treatment has proven to slow the progression of Parkinson’s disease [16]. The initial enthusiasm that selegiline delayed the onset of disability was due to amelioration of symptoms [29]. Further studies continue to suggest that selegiline is neuroprotective and recent studies indicate that it blocks apoptosis through a transcriptional effect of its desmethyl derivative that is unrelated to MAO-B inhibition [28]. As new drugs become available, treatments that influence oxidative phosphorylation and damage due to free radicals, excessive iron deposition, disturbances of calcium homeostasis, cytokines, excitotoxicity, nitric oxide, apoptosis, and the products of causative genes may all be considered in attempts to provide effective neural protection [16]. Free radical scavengers such as a-tocopherol (vitamin E) and high doses of ascorbate (vitamin C) were ineffective in slowing the progression of the disease [30]. Antioxidants such as selenium and ubiquinone increase mitochondrial energy production and reduce free radical release [23]. There is no conclusive evidence of their efficacy. Glutamate toxicity causes excitotoxic cell death in neurodegenerative disorders such as Hutinghton’s disease, motor neurone disease and possibly in parkinson’s disease. However, drugs inhibiting glutamate release or receptor interaction such as N- methyl 4 – valine antagonist and aspirin, which down regulate glutamate receptors have been tried without proven benefit [24]. Non-steroidal anti-inflammatory agents and interferon b have also been tried as in multiple sclerosis with no documented efficacy [1]. The role of primary or secondary inflammation in parkinson’s disease remains unknown.

b) Symptomatic treatment : Levodopa

Levodopa remains the most effective replacement therapy for parkinson’s disease [31]. However, levodopa is associated with a number of problems. There has been extensive debate about when to begin levodopa therapy. The controversy relates to the widely held beliefs that levodopa has an important benefit for only five to seven years and that patients thereafter lose their response to the drug; that early use of levodopa results in the earlier development of complications such as motor fluctuations and dyskinesia; and finally, that levodopa may be toxic – possibly because it increases dopamine turnover, with the formation of oxygen free radicals and peroxynitrite, and may thereby speed the progression of Parkinson’s disease [23]. The first belief is patently false. With time, certain symptoms develop that may be resistant to levodopa, but most patients if not all, continue to derive a substantial benefit from levodopa [31]. Furthermore, there is no convincing experimental or clinical data to show that levodopa accelerates the neurodegenerative process, and in fact some studies even suggest a neurotrophic effect [29]. Levodopa increases life expectancy amongst patients with parkinson’s disease and it has recently been shown that survival is significantly reduced if administration of the drug is delayed until greater disability with impaired postural reflexes develops [32]. Therefore, early treatment should be guided by the goal of providing maximal comfort and improved quality of life while limiting reversible but long term side effects [31].

Levodopa crosses the blood brain barrier (BBB) and becomes converted to dopamine in the brain by DOPA decarboxylase. Normally, less than 5% of administered levodopa reaches the brain as it is metabolised by DOPA decarboxylase in the gut wall, liver, kidney and cerebral capillary. Peripheral decarboxylation could be prevented selectively by benzariside (madopar) and cabidopa (sinemet) in combination with levodopa. Such combination therapy reduces peripheral side effects and enhances absorption to brain. The advantages of such combination include a) requirement of 1/5th of plain levodopa for optimal benefit. b) quicker therapeutic response within days and not weeks. c) reduced side effects due to formation of dopamine (a vasoactive amine) outside the brain such as nausea, vomiting, cardiac dysrhytmia and postural hypotension.
The main side effect of combined therapy includes dyskinesia and psychiatric disturbance, which are dose dependent. Levodopa causes abnormal involuntary movements (hyperkinetic choreoathetoid, lurching and jerky movement) in contrast to the hypokinesis of parkinsonism. Most fluctuations occur in approximately 50% of patients after 5 years of levodopa therapy and this increases to 70% among those treatedfor more than 15 years [33].

The “Wearing-off” or “end of dose” deterioration can be defined as a perception of loss of mobility or dexterity, usually taking place gradually over a period of minutes (up to an hour) and usually having a close temporal relation to the timing of anti-parkinsonian medications. The availability of a controlled release medication (Sinemet CR) relieves the “wearing-off ” effect. This “wearing-off” effect can be managed by more frequent doses of standard levodopa, the use of controlled release, the addition of a dopamine agonist, and the use of a drug designed to extend the duration of the response to levodopa by reducing the metabolism of levodopa, dopamine or both [29]. The drugs in the last category include the MAO-B antagonist selegiline and the new cathecol O methyl transferase inhibitors, tolcapone and antacapone. In addition to the approaches just mentioned, hourly intake of a liquid preparation of levodopa or where available, parenteral apomorphine or lisuride given either as needed or by constant infusion, may be extremely effective [32]. “Delayed on” and dose failures may improve in response to agents that promote gastric motility, such as cisapride or duodenal infusion of levodopa, which are delivered directly to the site of absorption in the small bowel [34].

The “On-off” effects are unpredictable and generally sudden occurrences (lasting seconds to minutes) of shifts between “on” and “off” periods that are not apparently related to the timing of anti-parkinsonian medications. Patients may swing from mobility and dyskinesia (on levodopa) to immobility, rest tremor and rigidity (off levodopa) within minutes to one hour. This could become more frequent and abrupt leading to the “on and off” effect or the “yoyo” effect. The dyskinesia includes chorea, athetosis and dystonia, which occur at the time of peak plasma concentration of levodopa. These “off” periods last minutes to hours and do not include transient episodes of “freezing” (also referred to as “motor blocks”), stress induced tremors or the initiation or continuation of a motor act such as walking, which is arrested for a few seconds. These are components of the underlying disease and occur even in the absence of treatment.
The “on-off” phenomenon is due to the rapid onset and terminationof therapeutic effects of levodopa. Two factors contribute, the ingestion of protein and closure of the pyloric valve [32]. Amino acids from digested protein interfere with the facilitated transport of levodopa from gut to blood and from blood to brain. Abstaining from protein during the day may effectively treat the “on-off” effect but patients cared for this way must compensate by ingesting adequate amount of protein at night. Levodopa dissolves in the stomach but enters the blood stream from the jejunum. Closure of the pyloric valve can interfere with absorption, jejunal infusion of levodopa and a carbidopa may therefore be beneficial, athough it is used infrequently [34].
“Peak dose” dyskinesia and “Diphasic” dyskinesia (“beginning of dose” and “end of dose”) dyskinesia are characterized by mixtures of choreathetosis, ballism, dystonia, and alternating movements especially in the legs [34].
Dopamine agonists: Dopamine receptor agonist such as lisuride, bromocriptine and pargolide have less side effects and patients may experience progressive occurrence of parkinsonian disability such as akinesia and postural instability with frequent falls and dementia. Dopamine agonists provide inadequate benefit and usually take longer than levodopa to reach effective doses. They always require supplementary levodopa for supervening disability after varying period of time [29,31]. Typically, patients treated alone with dopamine agonist, do not have fluctuations and dyskinesias until levodopa is added to the regimen to treat the supervening disability. Newer dopamine agonists such as pramipexole, ropinrole, and cabergoline have benefit in untreated individuals. One reason that dopamine agonists infrequently result in fluctuations and dyskinesia may be because of their longer duration of action, which more closely mimics the physiologic tonic release of dopamine from normal nigral neurons, and in contrast to the pulsatile stimulation of receptors caused by intermittent doses of standard levodopa preparation. Furthermore, during the asymptomatic period, the nigral neurons operate harder to overcome the deficient state by increasing the number of receptors for H3 ligand binding. There is also denervation supersensitivity of post synaptic dopamine receptor with increased dopamine turnover and increased pharmacological response to dopamine agonist [20].

Newer therapeutic approaches include [16]

1) Attaching levodopa to metals (copper and zinc), which may increase the dopamine content of the brain.

2) Combination of levodopa with a specific drug that blocks the action of dopamine such as tiapride, oxipe – ronide and domeperidone which do not cross the blood brain barrier can be used as adjuncts in patients sensitive to the emetic effects of levodopa.

3) Manipulation of dopamine synthesis pathways by using tetrahydro biopterin which is a cofactor for tyrosine hydroxylase.

4) Trial of Lithium in patients on long-term levodopa therapy. This acts by lowering the sensitivity of the brain to dopamine.

5) Central noradrenaline replacement using L-threo 3,4 dihydroxy-phenyl serine (L-threo-DOPS) which is useful for managing freezing and akinesia.

6) Monoamine oxidase (MAO) and cathecol-O-methyl transferase (COMT) inhibitors such as Tolcapone, entacapone prevent breakdown of dopamine but are hepatotoxic.

7) Amantadine – an antiviral- previously considered to inhibit dopamine reuptake but now acts primarily an NMDAantagonist.

8) Amphetamine enhances release of dopamine.

9) Adenosine antagonist acts on adenosine receptors on nerves containing GABA and enkephalin. Its stimulation has a negative effect on motor function. Its antagonist such as caffeine increases locomotor activity and therefore coffee could delay the onset of parkinsons disease [16].

c) Restorative, or regenerative or neurorescue treatment :

This rescues neurone at risk and reverses established metabolic abnormality. It halts disease progression, restores normal neuronal function and survival [35,36]. They improve symptoms and early treatment is advocated. There are several functional neurosurgical procedures to this end. Both pallidotomy and deep brain stimulation of the internal segment of the globus pallidus or subthalamic nucleus are associated with reversal of parkinsonism [ 37]. – see surgery below. The decision to treat and the drug of choice is influenced by the stage of the disease according to the scale of “Hoen and Yahr” [29].

Stage I —> unilateral involvement.

Stage II —> bilateral involvement; no postural abnormality: no treatment or only anticholinergic is required.

Stage III —> bilateral involvement; mild postural imbalance – lives independent life.

Stage IV —> bilateral involvement; moderate postural instability requires substantial help.

Stage V —> severe fully developed disease; patient restricted to bed or chair bound.



For mild cases of stages I and II: give anticholinergics such as benzhexol 2 -5 mg tds; benztropin (cogentin); biperidin (akinetin); procyclidine kemardrin; orphenadrine (disipal, norflex) 50mg.
Side effects include peripheral parasympathetic blockade such as dry mouth, blurred vision, constipation, narrow angle glaucoma, urinary retention, toxic confusional state and reduced cognition.
Before the introduction of levodopa in 197, treatment was mainly with anticholinergics. However, Sinemet or Madopar is the drug of choice if levodopa is indicated. The potency and side effects are the same. The pathology of the lesion does not improve because these agents are equivalent of substitution therapy for the nigrostriatal dopamine deficiency. Patients are started on small doses and these are gradually increased over weeks till the maximum tolerated or adequate treatment benefit is obtained.
Use of monoamine inhibitors is contraindicated. Selegiline (deprenyl) and amantadine could be added as adjuncts.


Response to levodopa is poor or nil in a third of patients and this could be due to dopaminergic receptor degeneration, which tends to be progressive. Response is moderate in another third and 2/3rd of those will experience some loss of benefit after 2 to 5 years of treatment. In the remaining 1/3rd, response is dramatic.
Anticholinergics and amantadine could be added to the regimen. Deprenyl prolongs the therapeutic action of levodopa and could delay patients needs for additional treatment by 9 to 12 months. If levodopa and deprenyl fail, bromocriptine could be used because of its long action at a larger dose. The effect is the same with levodopa and they are expensive and have similar range of unwanted effects. Bromocriptine could be started at a dose of 2.5mg tds regime and gradually increased to 20 to 24mg / day.
Generally, there is no justification for “drug holidays” ( i.e the temporary complete withdrawal of levodopa) which may be associated with substantial morbidity, including life threatening symptoms akin to the neuroleptic malignant syndrome [38,39].

Management of specific problems in patients with parkinson’s disease:

Clozapine is widely used for psychiatric disturbance because risperidone worsens the underlying parkinsonism [29]. Toxic confusional state could be due to drug overdosage or intercurrent acute illness such as infection with fever. In depression, MAOI is contraindicated. Irradiation of the parotid gland is useful if there is excessive salivation. Methyldopa inhibits dopa decarboxylase in the brain and its use is discouraged in parkinson’s patients with hypertension. Propranolol is preferable as this also reduces the tremors. Vitamin B6 is a co-enzyme for DOPA decarboxylase and thus increases the metabolism of levodopa peripherally thereby reducing the quantity of levodopa available to cross the blood brain barrier. The combination of plain levodopa with multivitamins was therefore discouraged. However, the newer combination of L-dopa with peripheral DOPA decarboxylase inhibitors obviates this effect and those could be used with multivitamins.

Surgery in parkinson’s disease

This is reserved for disabling, medically refractory problems and small lesions are created mechanically, electrolytically or thermally. In the 50’s and early 60’s, pallidotomy was popular and this reduces contralateral dyskinesia while improving bradykinesia and rigidity [40]. Stereotaxic thalamotomy abolishes tremors and leaves dyskinesia and postural instability [35]. It is advocated when tremor impairs work and is resistant to drugs. Deep brain stimulation to globus pallidum and subthalamic nucleus also improves contralateral symptoms especiallytremors [24].

Fetal nigral implants into the striatum improve symptoms and at postmortem, outgrowths and new synaptic formation from the transplanted tissue were observed [36]. The transplantation of adrenal medulla tissue to the striatum in an attempt to restore the deficient striatal dopaminergic innervation also produces some recovery but the grafts do not survive. The graft secretes nerve growth factors such as brain derived neurotrophic factor and basic fibroblast growth factor. Recovery is sustained because the residual dopmine neurons in the host sprout new terminals. This procedure has been largely abandoned because of its lack of efficacy, which is related at least in part to the poor survival of the implanted adrenal tissue [36]. Allogenic transplantation of fetal mesencephalon is currently been studied, and initial reports show promising results [35]. Another approach currently under study is the intraventricular delivery of the dopaminergic neurotrophic factor (GDNF) [21]. A technique that may be applicable in the future is the implantation of foreign cells in semi-permeable polymeric capsules, thus obviating the need for potentially harmful immunosuppressive therapy [35].
Till date, surgery has a limited role in the management of parkinson’s patients. It has unilateral benefit and we await its long-term sequelae in these patients. The risks of injury to other parts of the brain and death from the procedure are potential complications. In the future, surgical interventions may incorporate advances in gene therapy [41]. Gene transfer is being examined in animal models of parkinsonism. Genes coding for molecules that block apoptosis, scavenge free radicals, enhance the clearance of toxic metabolites, or improve mitochondrial function could also be considered.


Physical treatment is needed because of the wide range of functional and locomotor disability in patients with parkinson’s disease. Physical aids with occupational therapist, physiotherapist and speech therapist are essential. Exercise, provision of high chairs and high toilet seats are necessary in-house modifications for a comfortable living in parkinson’s patients.


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