African Journal of Neurological Sciences, Vol. 21, No. 1, 2002, pp. 30-36
PARKINSON'S DISEASE - A REVIEW.
Shamsideen Abayomi OGUN, B.Sc (Hons);M.B.ch.B;(Ife);Cert.Neurol.(Lond); F.W.A.C.P.(Int.
Med.)
Correspondence: S.A. Ogun, Senior lecturer/Consultant physician/neurologist,
Dept of Medicine, Ogun State University, Teaching Hospital; Sagamu., Ogun State.
Nigeria. Te l: 00234-90-407006; E- mail: yomiogun@skannet.com
Code Number: ns02008
SUMMARY :
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 a-tocopherol, 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 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.
INTRODUCTION
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
morbidity 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.
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.
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.
Aetiology
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].
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].
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].
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, DNA fragmentation 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-α 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
NMDA receptor 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 P while
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, - α
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.
CLINICAL FEATURES
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 :
Post encephalitic parkinsonism: Post encephalitic parkinsonism is now
uncommon but was reported after the world-wide 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.
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.
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.
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].
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].
Benign essential tremors. This is inherited postural tremor without other parkinsonian
signs. Alcohol and beta-blockers relieve the tremors.
Depression could be confused with early features of parkinsonism.
Ankylosing spondylitis due to joint disease also could present as rigidity.
TREATMENT
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 α-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 treated for 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 termination of 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]
a) Attaching levodopa to metals (copper and zinc), which may increase the
dopamine content of the brain.
b) Combination of levodopa with a specific drug that blocks the action of
dopamine such as tiapride, oxiperonide and domeperidone which do not cross
the blood brain barrier can be used as adjuncts in patients sensitive to the
emetic effects of levodopa.
c) Manipulation of dopamine synthesis pathways by using tetrahydro biopterin
which is a cofactor for tyrosine hydroxylase.
d) Trial of Lithium in patients on long-term levodopa therapy. This acts
by lowering the sensitivity of the brain to dopamine
e) Central noradrenaline replacement using L-threo 3,4 dihydroxy-phenyl serine
(L-threo-DOPS) which is useful for managing freezing and akinesia.
f) Monoamine oxidase (MAO) and cathecol-O-methyl transferase (COMT) inhibitors
such as Tolcapone, entacapone prevent breakdown of dopamine but are hepatotoxic.
g) Amantadine - an antiviral- previously considered to inhibit dopamine reuptake
but now acts primarily an NMDA antagonist.
h) Amphetamine enhances release of dopamine.
i) 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.
Physics
INITIATION OF DRUG TREATMENT
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.
MAINTANANCE
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 [409]. 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
especially tremors [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
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.
REFERENCES
[1]8 Abi, Burger, Parkinsons' disease due to pesticide BMJ 2000: 32: 1175
[2]22 Beal, M.F. Aging energy and oxidative stress in neurodegenerative diseases.
Ann Neurol 1995; 38: 357-66.
[3]3 Bennett, D.A., Beckett, L.A., Murray, A.M. Prevalence of Parkinsonian
signs and associated mortality in a community population of older people. N
Engl J Med 1996; 334: 71-6.
[4]41 Chase, T.N. A gene for Parkinson disease. Arch Neurol 1997; 54:1156-7.
[5]25 Davis, K.D., Taub, E., Houle, S., Globus pallidus stimulation activates
the cortical motor system during alleviation of parkinsonian symptoms. Nat Med
1997, 3: 671-4.
[6]32 Djaldeti, R., Baron, J., Ziv, I., Melamed, E.Gastric emptying in Parks
dx: patients with and without response fluctuations. Neurology 1996; 46:1051-4.
[7]29 Fahn, S. Management of Parkinson's diseases at different stages of the
illness.
[8]31Fahn, S. Is levodopa toxic? Neurology 1996; 47 (3):5184-5195.
[9]17 Gai, W.P., Blessing, W.W., Blumbergs, P.C. Ubiquitin positive degenerating
neurites in the brainstem in parkinson's d Brain 1995; 118:1447-59.
[10]18 Gibb, W.R.G., Less, A.J. The relevance of the Lewy body to the pathogenesis
of idiopathicParkinson's disease. J. Neurol Neurosurg Psychiatry 1988; 51: 745
- 52.
[11]14 Giladi, N., Burke, R.E., Kostic, V. Hemiparkinsonism hemiatrophy syndrome:
clinical and neuroradiologic features.Neurology 1990; 40: 1731-4.
[12]4 Golbe, L.I. Young-onset Parkinson's disease: a clinical review. Neurology
1991; 41: 168-73.
[13]5 Golbe, L.I. Genetics of Parkinson's disease. In:Ellenberg JH, Koller
WC, Langston KW. Eds. Etiology of Parkinson's disease. New York: Marcel Dekker,1995:
115-40.
[14]19 Jendroska, K., Olasode, B.J., Daniel, S.E.Incidental Lewy body disease
in black Africans. Lancet 1994; 344:882-3.
[15]23 Jenner, P., Olanow, C.W. Oxidative stress and the pathogenesis of parkinson's
disease. Neurology 1996; 47 (l 3):5161 - 5170.
[16]40 Jennifer, Fine., Jan Duff, Robert Chew, Willam, Hutchisan. Andren Long
term follow-up of unilateral pallidotomy in advanced park dx. N. E. J. M. 2000;
342: 1708-14.
[17]12 Kitada, T., Asakawa, S. Hattori, N. Mutations in the parkin gene cause
autosomal recessive juvenile parkinsonism. Nature 1998; 392:605-8.
[18]26 Krack, P., Pollak, P., Limousin, P., Benazzouz, A., Perret, J.E., Benabid,
A . L. Abnormal involuntary movements induced by subthalamic nucleus stimulation
in Parkinson patients. Mov Disord 1996; 11:231-5.
[19]39 Kuno, S., Mizuta, E., Yamasaki, S. Neuroleptic malignant syndrome in
parkisonian patients: risk factors. Eur. Neurol. 1997; 38:56-9.
[20]21 Lapchak, P.A., Miller, P.J., Jiao, S.S., Araujo, D.M., Hilt, D., Collins,
F. Biology of glial cell line derived Neurotrophic factor (GDNF): implications
for the use of GDNF to treat Parkinson's disease. Neurodegeneration 1996; 5:
197-205.
[21]1 Lees, A.J.Parkinson's disease and other involuntary disorders Medical
education (international) 1983; 1516 - 1521.
[22]9 Limousin, P. Parkinson study group. Impact of depreynl and tocopherol
treatment on Parkinson's disease in DATATOP patients requiring levodopa. Ann
Neurol 1996; 39: 37 - 45.
[23]24 Limousin, P., Greene, J., Pollak, P., Rothwell, J., Benabid, A.L., Frackowiak,
R. Challenges in cerebral activity pattern due to subthalamic nucleus or internal
pallidum stimulation in Parkinson's disease. Ann Neurol 1997;42:283-91.
[24]2 Marsden, C.D.Involuntary movement disorders.Medicine 1978;1075 - 1078.
[25]20 Marsden, C.D.The pathophysiology of movement disorders. Neurology Clinics
1984; 2: 435 - 459.
[26]38 Mayeux, R., Stern, Y., Mulvey, K., Cote, L.Reappraisal of temporary
levodopa withdrawal in Parkinson's dx.N Engl J Med 1985; 313:724-8.
[27]15 Morens, D.M., Grandinetti, A., Reed, D., White, L.R., Ross, G.W. Cigarette
smoking and protection from Parkinson's disease: false association or etiologic
clue? Neurology 1995; 45; 1041-51
[28]28 Mytilineou, C., Radcliffe, P.M., Olanow, C.W. L-(-)-desmethylsegiline,
a metabolite of selegiline [L-(-)-deprenyl], protects mesencephaliic dopamine
neurons from excitotoxicity in vitro. J Neurochem 1997; 68:434-6.
[29]35 Obeso, A., Guridi, J., Obeso, J.A., Delong, M., Surgery for Parkinson's
disease. J Neurol Neurosurg Psychiatry 1997; 62:2-8.
[30]36 Olanow, C.M., Kordower, J.H., Freeman, T.B.Fetal nigral transplantation
as a therapy for Parkinson's disease. Trends Neurosci 1996; 19: 102-9.
[31]30 Parkinson Study Group. Effects of tocopherol and deprenyl on the progression
of disability in early Parkinson's disease. N Engl J. Med 1993; 328:176-83.
[32]13 Polymeropoulos, M.H., Lavedan, Leroy, E., Mutation in the &-synuclein
gene identified in families with Parkinson's disease. Science 1997; 276:2045-7.
[33]16 Richardson, P.J., Kase, H., Jenner, P.G. Adenosine A2A receptor antagonists
as new agents for the treatment of Parkinson's disease. Trends Pharmacol. Sci.
1997; 18:338-44.
[34]33 Riley, D.E., Lang, A.E. The spectrum of levodopa-related fluctuations
in Parkinson's disease. Neurology 1993; 43: 1459-64.
[35]34 Sage, J.I., Sinsalla, P.K., McHale, D.M., Heikkila, R.E., Duvoisin,
R.C. Clinical experience with duodenal infusions of Ldopa for the treatment
of motor fluctuations in Parkinson's disease: Adv Neurol 1990; 53:383-6.
[36]37 Samuel, M., Ceballos, Baumann, A.O., Turjanski, N. Pallidotomy in Park.
dx increases supple. motor area and prefrontal activation during performance
of volitional movments on H2 15O PET study. Brain 1997; 120:1301-13.
[37]6 Scharpira, A.H., Gu, M., Taanman, J.W. Tabrizi, S., Seaton, T,. Cleeter,
M Mitrochondria in the aetiology and pathogenesis of Parkinson's disease. Ann
Neurol 1998: 44(1): 589-98.
[38]7 Semchuck, K.M., Love, E.J., Lee, R.G.Parkinson's disease and exposure
to agricultural work and pesticide chemicals.Neurology 1992; 42: 1328-35.
[39]27 Sid Gilman. Advances in Neurology; Parkinsons disease. N. E. J. M. 1992;
326 (1613 - 1615)
[40]11 Tanner, C.M., Ottman, R. Ellenberg, J.H. Parkinson's disease (PD) concordance
in elderly male monozygotic (MZ) and dizygotic (DZ) twins. Neurology 1997; 48:
A333, abstract.
[41]10 Ward, C.D., Duvoisin, R.C., Ince, S,j Nutt JD, Eldridge R, Calne DB.
Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology
1983; 33:815-24.
Copyright 2002 - African Journal of Neurological Sciences