VCP3042; 1st August 2008 [email_address] Slightly more Caucasians and males Like Alzheimer’s disease, the incidence of PD is lower in smokers Death – medical complications 12-15 years or 1-3 years… variable Mutations in Alpha synuclein and Parkin genes May be induced by drugs or toxins (e.g. MPTP), and major tranquillizers cause extrapyramidal side effects, e.g. neuroleptics; manganese and CO produce extrapyramidal effects Exposure to pesticides increased risk for developing PD by 70% (Ascherio et al., 2006). Neuromelanin; oxidation of DA Increased Fe2+ in SN, decreased transferrin = increased oxidation Increased lipid peroxidation
VCP3042; 1st August 2008 [email_address] Start low and go slow! Education, physical and speech therapy, dietary modifications In Australia, l-dopa is not available without peripheral DDC inhibitors Anti-cholinergics will worsen dementia M receptor antagonists, e.g. benzatropine; modest effect, only used at the beginning to delay l-dopa; better for tremor D-dopa not converted to dopamine in vivo, and causes granulocytopaenia
VCP3042; 1st August 2008 [email_address] L-dopa effectiveness gradually declines as time progresses (2-5 years) (may rely on presence of functional dopaminergic neurones) Converted and metabolised in gut and in plasma by DDC, MAO, COMT Carbidopa and benserazide inhibit aromatic L-amino acid decarboxylase , which converts L-DOPA into , which cannot cross the BBB. Awakenings. It tells the true story of British neurologist Oliver Sacks, fictionalized as American Malcolm Sayer and portrayed by Robin Williams who, in 1969, discovers beneficial effects of the then-new drug L-Dopa. He administered it to catatonic patients who survived the 1917-1928 epidemic of encephalitis lethargica. Encephalitis lethargica or von Economo disease is an atypical form of encephalitis. Also known as &quot;sleepy sickness&quot; or as &quot;sleeping sickness&quot; (though different from the sleeping sickness transmitted by the tsetse fly), it was first described by the neurologist Constantin von Economo in 1917. The disease attacks the brain, leaving some victims in a statue-like condition, speechless and motionless. Between 1915 and 1926, an epidemic of encephalitis lethargica spread around the world; no recurrence of the epidemic has since been reported, though isolated cases continue to occur.
VCP3042; 1st August 2008 [email_address] Diminished window between wanted effect – reduced rigidity – and unwanted effect – dyskinesia (involuntary writhing) On-off effect – fluctuat es from being symptom free to having full blown symptoms Implementation of drug holidays is controversial
VCP3042; 1st August 2008 [email_address] Peripheral dopa decarboxylase inhibitors p enetrate only weakly into CNS, therefore stop conversion in periphery only; reduce dose by ¼ or a 1/5 th , reduce dopamine-induced emesis Inhibitors of dopamine degradation in the CNS by MAO, s elective for MAO B (CNS – lacks peripheral side effects); may retard progression of disease (protecting against free-radical induced neurotoxicity and apoptosis) Inhibitors of dopamine degradation in the periphery by COMT, e.g. entacepone (peripheral only); tolcapone is able to penetrate the CNS When you have a peripheral decarboxylase inhibitor this shifts the metabolism of L-dopa to the COMT pathway; COMT converts L-dopa to 3-O-methyldopa, compete with L-dopa to cross the BBB (may also contribute to the development of motor dysfunctions) Increase the amount of L-dopa available to cross the blood brain barrier Antagonists of peripheral dopamine receptors (reduce side effects)
VCP3042; 1st August 2008 [email_address] Redressing the balance between dopaminergic and cholinergic neurons appears to be some compensation for the overall deficit in dopamine function
Amantadine – less effective; better for bradykinesia and rigidity; some patients develop tachyphylaxis – drug holiday
Bromocriptine: D2 receptor agonist, mild D1 receptor antagonist Pergolide: D1/D2 receptor agonist, more potent and longer acting
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