The discovery that methyl-phenyl-tetrahydropyridine (MPTP; A contaminant in methylenedioxymethamphetamine ("ecstasy“)) caused severe parkinsonism in young drug users suggests that the idiopathic disease might be due to an environmental toxin.
Viral infections (encephalitis lethargica)
No strong genetic factors, but genetic influence may be greater than previously thought. Genetic mutations 1-2%; alpha-synuclein gene, Parkin gene, Ubiquitin gene mutations.
Protective factors-Both smoking and coffee drinking have been associated with a lower risk for PD.
Paul Marie Louis Pierre Richer (1849-1933) was a French anatomist, physiologist, sculptor and anatomical artist. Paul Richer was an assistant to Jean-Martin Charcot at the Salpêtrière. In 1880, Jean-Marie Charcot completed a full clinical description of Parkinson's Disease. The symptoms were depicted by Paul Richer in drawings and a statuette of people with Parkinson's Disease. Along with a photograph, these are the first known depictions of Parkinson's Disease
Additional information to read later Clinical features:
There are a number of abnormalities on neurological examination:
Muscle strength / reflexes remain normal, plantar responses are flexor.
There is a paucity of facial expression (hypomimia) & the blink reflex may be exaggerated & fail to habituate (glabellar tap sign).
Eye movements are normal to standard clinical testing, provided allowance is made for the normal limitation of upward gaze with age.
Sensation is normal & intellectual abilities are not affected initially.
As the disease progresses, 1/3 develop cognitive impairment.
PD commonly associated with other features; loss of smell, depression, dementia, autonomic dysfunction, sleep disturbance- due to involvement of other non-dopaminergic structures as disease progresses.
L-3,4-hydroxyphenylalaninine (L-DOPA) a precursor of dopamine. Although the number of dopamine-releasing terminals in the striatum is diminished in Parkinson's disease, remaining neurons can be driven to produce more dopamine by administering its precursor, L-DOPA. D-DOPA is not active as a pro-drug.
Well absorbed from gut, but > 90% is decarboxylated to dopamine peripherally in GIT& blood vessels & only a small proportion reaches the brain (dopamine does not readily cross BBB). Therefore combined with peripheral decarboxylase inhibitor that does not cross the blood-brain barrier along with L-DOPA . 2 peripheral decarboxylase inhibitors, carbidopa & benserazide, are available as combination preparations with levodopa, as Sinemet & Madopar, respectively.
Acute effects (tend to disappear over first few weeks):
The peripheral conversion of levodopa is responsible for the high incidence of side-effects if used alone.
Nausea and anorexia, hypotension, psychological effects (confusion, insomnia, euphoria, inappropriate behaviours, nightmares, hallucinosis, psychosis) Reduced by the use of a peripheral dopamine antagonist as domperidone.
Slowly developing unwanted effects, motor fluctuations.
Late deterioration despite levodopa occurs after 3-5 years in 1/3-1/2. manifests as fluctuation in response; of 2 types:
End-of-dose deterioration due to progression of the disease& loss of capacity to store dopamine, often can be improved by dividing the levodopa into smaller but more frequent doses, or by converting to a slow-release preparation
‘ On-off' phenomenon: More complex fluctuations present as sudden, unpredictable changes in response, in which periods of severe parkinsonism alternate with dyskinesia&agitation,is difficult to treat, but sometimes SC apomorphine (a dopamine agonist) are helpful to 'rescue' the patient rapidly.
Slowly developing unwanted effects, motor fluctuations.
Develop in most patients after 3-5years on L-dopa, esp if young, high dose
Involuntary movements, sp orofacial dyskinesias, limb &axial dystonias,occasionally depression, hallucinations& delusions. Involuntary movements (dyskinesia), can be violent; may occur as a peak-dose phenomenon, or as a biphasic phenomenon (during build-up & wearing-off phases). Management is difficult, but again involves modifying the way levodopa is administered (reduce dose) to obtain constant levels in the brain & use of alternatives, particularly dopamine agonists. Thought to be related to the short phamacological T1/2 of L-dopa causing pulsatile stimulation of the striatum and eventual disordered basal ganglia output.
Dopamine dysregulation syndrome (DDS) dysfunction of the reward system, characterized by self-control problems such as addiction to medication, gambling, or hypersexuality.
Now aim to prolong the pharmacological dopaminergic stimulation of the striatum to limit the development of motor fluctuations
In younger patients, preference is given to neuroprotective and L-DOPA sparing therapies.
L-DOPA should only be started to help overcome significant disability. In young (<65) aim to avoid L-DOPA for as long as possible (although all patients eventually need it) and tend to use long-acting (t1/2 8+hrs) dopamine agonists initially.
Peripheral COMT inhibitors, e.g. entacapone
MAO B inhibitors, e.g. selegiline; may retard progression of disease
While the mechanism of action of amantadine in the treatment of PD is not known, it is believed to release brain dopamine from nerve endings making it more available to activate dopaminergic receptors.
This has a mild, usually short-lived effect on bradykinesia, but may be used early in the disease before more potent treatment is needed.
The dose is 100 mg 8- or 12-hourly.
Side-effects include nausea, dizziness (lightheadedness) and insomnia, livedo reticularis (a mottled reticulated vascular pattern that appears like a lace-like purplish discoloration of the lower extremities), peripheral oedema, confusion, seizures.
Selegiline and rasagiline belong to a class of drugs called monoamine oxidase inhibitors (MAOIs). They slow the breakdown of dopamine in the brain. They have a fairly mild anti-Parkinsonian effect in their own right .
There has been some doubt as to its safety, but this is also controversial and the subject of ongoing research.
The usual dose is 5-10 mg in the morning.
Selegiline has an amphetamine-like metabolite (by-product). This means it can cause insomnia and hallucinations in some people.
In the periphery MAO A breaks down dietary tyramine (found in cheeses, smoked meats, fish, red wine, etc.) – if you also block MAOA, will get tachycardia, hypertension, vomiting, headache)
Entacapone prevents COMT from metabolizing L-DOPA into 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the periphery, which does not easily cross the blood brain barrier (BBB). Pharmacologically, entacapone is somewhat similar to carbidopa or benserazide .
Entacapone (200 mg with each dose of levodoa) prolongs the effects of each dose & reduces motor fluctuations when used with levodopa.
This allows the levodopa dose to be reduced & given less frequently.
More easily administered drugs include bromocriptine (D2 receptor agonist, mild D1 receptor antagonist); pergolide (D1/D2 receptor agonist, more potent and longer acting)
These drugs are less powerful than levodopa in controlling features of parkinsonism, but they are much less likely to cause dose fluctuations or dyskinesia, though they will certainly exacerbate the latter once these have developed. Side-effects include nausea, vomiting, confusion and hallucinations.
Orally administered; The dose of bromocriptine is 1 mg initially, increased to 2.5 mg 8-hourly, up to 30 mg/day.
Pergolide dose starts at 50 μg, increased to 250 μg 8-hourly, possibly to 3000 μg/day.
Dopamine agonists derived from ergot (e.g. pergolide / cabergoline) have recently been associated with the development of cardiac fibrosis -fibrotic reactions/ thickening of heart valves, so most are screened with echo, chest X-ray / renal function tests before commencing therapy&every 6 months
Apomorphine given alone causes marked vomiting & has to be administered parenterally.
The vomiting can be overcome by the concomitant use of the anti-sickness drug domperidone, & parenteral administration achieved through continuous subcutaneous infusion from a portable pump, or direct injection as needed.
This requires considerable nursing support but, if used correctly, can be very useful.
Additional information to read later: Alternative treatment approaches
Stereotactic thalamotomy can be used to treat tremor, though this is needed relatively infrequently because of the medical treatments available.
Other stereotactic lesions are currently undergoing evaluation, in particular pallidotomy to help in the management of drug-induced dyskinesia.
Implantation of dopamine rich fragments of brain
into the striatum
Implantation of stem cells
Midbrain neurones transplanted into the striatum
Immortalised neuronal precursor cells
Patients at all stages of Parkinson's disease benefit from physiotherapy, which helps reduce rigidity& corrects abnormal posture.
Speech therapy may help in cases where dysarthria & dysphonia interfere with communication.
Transfection of tyrosine hydroxylase gene into the brain