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Parkinson disease
Parkinson disease is a progressive brain disorder characterized by the loss of
neurons in an area of the midbrain known as the substantia nigra. These neurons use dopamine as a neurotransmitter and project their axons to the thalamus and the caudate and putamen areas of the basal ganglia. Parkinsonism refers to any disease that alters dopaminergic pathways connecting the substantia nigra to the basal ganglia. The striatal system is involved in voluntary muscle movement; it consists of the substantia nigra, caudate, putamen, globus pallidus, subthalamus, and thalamus. Dopamine is the principal neurotransmitter in the nigrostriatal tract connecting the substantia nigra with the caudate and putamen. Parkinsonism is a clinical syndrome of rigidity, bradykinesia, resting tremor, and postural instability (loss of postural reflexes).
Epidimiology Estimated prevalence: 500,0001 million patients in United States o Incidence: 40,00060,000 new cases per year in USA. o Affects up to 0.3% of general population, but 13% of those >65 y/o. PD is largely a disease of older adults: only 510% of patients have symptoms before 40 y/o (young-onset PD). Occurs between 45 and 65 years of age: o Distribution is equal in men and women. o Most cases are sporadic, but some cases are familial. Average age of onset is 60 years. Most cases are due to Parkinson's disease, an idiopathic disorder with a prevalence of about 1-2 per 1000. In the first half of the last century, parkinsonism was a common sequela of von Economo's encephalitis. Pathogenesis: Many theories on cell death but no firm conclusions: Apoptosis, mitochondrial dysfunction, oxidative stress, excitotoxicity, deficient neurotrophic support, immune mechanisms are linked to the pathogenesis of PD In Parkinson's disease, there is selective degeneration of monoamine-containing cell populations in the brainstem and basal ganglia, particularly of pigmented dopaminergic neurons of the substantia nigra and locus ceruleus with decreased neuromelanin-containing neurons. In addition, scattered/affected neurons in basal ganglia, brainstem, spinal cord, and sympathetic ganglia contain large homogenous eosinophilic, cytoplasmic inclusion bodies (Lewy bodies) which possess neurofilament, ubiquitin, and crystalline immunoreactivity Alterations in mitochondrial complex I activity appear to play an important role in the pathogenesis of Parkinson's disease The reasons why dopaminergic neurons appear selectively vulnerable to complex I inhibition are not clear;some evidence suggests that dopamine can promote neurotoxicity. Addition of exogenous dopamine is toxic to neurons in culture which undergoes auto-oxidation to generate reactive oxygen species. Thus, dopamine within dopaminergic neurons may provide a source of reactive oxygen species, which, when coupled with reduced complex I function, may promote cell death.
Causes: Idiopathic parkinsonism Parkinsons disease (PD) Secondary parkinsonism Drug induced o Neuroleptics o Antiemetics o Reserpine o Tetrabenazine o Lithium o Flunarizine o Cinnarizine o Diltiazem Hydrocephalus Hypoxia Toxins o MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) o CO o Manganese o Cyanide o Methanol Infections o Fungal o Acquired immunodeficiency syndrome o Subacute sclerosing panencephalitis o Postencephalitic parkinsonism o Creutzfeldt-Jakob disease Metabolic o Hypo-/hypercalcemia o Chronic hepatocerebral degeneration o Wilsons disease Paraneoplastic parkinsonism Psychogenic Trauma Tumor Vascular Parkinson-plus syndromes Multiple system atrophy o Striatonigral degeneration o Shy- Drager syndrome o Olivopontocerebellar atrophy Progressive supranuclear palsy Corticobasal ganglionic degeneration Progressive pallidal atrophy Lytico-Bodig Heredodegenerative disease Alzheimers disease Dementia with Lewy bodies Picks disease Huntingtons disease Machado-Josephs disease Hallervorden-Spatz disease Lubag (X-linked dystonia-parkinsonism)
Genetic factors: Autosomal dominant (AD) and autosomal recessive (AR) patterns of inheritance have been identified.
1. Park 1: chromosome 4q21-23: o Alanine-53-threonine mutation in the -synuclein gene. o Autosomal dominant (AD). o Earlier disease onset (mean, age 45 years). o Faster progression. o Some with fluent aphasia. 2. Park 2: chromososme 6q25.2-27:
o The parkin gene. o Autosomal recessive (AR). o Relatively young-onset parkinsonism. o Early dystonia. o Symmetric involvement. o Good levodopa response. o Absence of Lewy bodies at autopsy.
3. Park 3: chromosome 2p13: o Autosomal dominant (AD) but with 40% penetrance. o All from northern Germany and southern Denmark. o Nigral degeneration and Lewy bodies at autopsy. o Dementia may be more common 4. Park 4: chromosome 4p14-16.3: o Autosomal dominant (AD). o From a family known as the Iowa kindred. o Also younger age of onset (mean, 34 years). o Rapid clinical course. o Early-onset dementia. o Equivocal response to levodopa. o Some family members with only postural tremor resembling essential tremor. o Autopsy shows Lewy bodies in the nigra and hippocampus. 5. Park 5: mutation in ubiquitin carboxy-terminal hydrolase L1 on chromosome 4: o Autosomal dominant (AD). o Young-onset progressive parkinsonism. 6. Park 6: chromosome 1p35-36: o Autosomal recessive (AR). o Early-onset parkinsonism. o Slow progression. o Marked response to levodopa. o Gene not yet identified. 7. Park 7: chromosome 1p3: o Early Autosomal recessive (AR) parkinsonism. o Slow progression. o With levodopa responsiveness. o Mostly from the Netherlands.
Clinical Manifestations
Resting tremor: causes "pill rolling" between thumb and index fingers and
illegible writing o Parkinsonian tremor is characteristically slow, of medium to coarse amplitude (3-7 Hz); present at rest; increased by emotion, fatigue, stress, and anxiety; absent in sleep; and decreased by volitional activity. o It typically affects the distal appendicular muscles, leading to: Flexion-extension movements of the metacarpophalangeal and interphalangeal joints of the fingers and thumb Adduction-abduction movements of the thumbs (pill rolling) Pronation-supination movements of the wrists. It often begins unilaterally in the hand and may be present initially only in the thumb or a single finger. o The tremor then typically spreads to the ipsilateral lower extremity (hemiparkinsonism) before involving the opposite half of the body. o In addition to resting tremor, an action tremor (7-12 Hz) may be seen. o Tremor of the protruded tongue is not uncommon, whereas tremors of the head, lips, and jaw are less frequent.
Diagnostic Tools:
Treatment (Early Stage): Treatment of Parkinson disease has become a specialized endeavor, with the continuing development of new medications and treatments. Patients with early Parkinson may not require treatment with medication until they experience difficulty functioning. Selective monoamine oxidase inhibitors, selegiline and rasagiline, may be neuroprotective. These have been used as first-line agents in early Parkinson disease. Once difficulty arising from a chair, walking, or using the limbs becomes a problem, medication aimed at improving these functions is indicated.
o Despite this, many physicians delay the use of levodopa until later in the o o o o o o o o o
course with the hope that the long-term side effects of this medication can be reduced or delayed. The effect may be dramatic when administered early in disease. Used alone, large doses are needed for effect, and the peripheral effect causes nausea and orthostatic hypotension. When combined with a dopa-decarboxylase inhibitor (carbidopa), the peripheral effects are minimized, and the dose may be reduced as more of the dopa reaches the brain to be converted to dopamine. Combination medication is available as a short-acting or long-acting preparation. The short-acting medication is available as 10/100, 25/100, and 25/250, with the first number referring to the milligrams of carbidopa and the second number referring to the milligrams of levodopa. A long-acting (CR) form is available as 25/100 or 50/200 mg, but does not confer a significant added benefit. Levodopa/carbidopa 25/100, 3 to 4 times a day is the usual starting dose. The most common side effect of levodopa therapy is nausea. Early motor fluctuations, dyskinesia, and on-off phenomena are common problems encountered with levodopa/carbidopa as parkinsonism progresses. Dystonia, agitation, hallucinations, and sleep disorders also may occur, particularly in patients with dementia. Providing levodopa/carbidopa 30 minutes before meals and limiting protein intake during the day may improve absorption and efficacy of levodopa/carbidopa.
Advantages of Levodopa: o Most efficacious antiparkinsonian drug o Immediate therapeutic benefits (within 1 week) o Easily titrated o Reduces mortality o Lower cost Disadvantages of Levodopa: o No effect on disease course, o No effect on nondopaminergic symptoms, such as dysautonomia, cognitive disturbances, and postural instability, motor fluctuations and dyskinesia develop over time (especially in younger patients, those with more severe disease and those requiring higher doses).
Drug Ergot derived Yes Bromocriptine Yes Pergolide No Pramipexole No Ropinirole Yes Cabergoline +, least receptor affinity. +++, greatest receptor affinity.
D1 +
D2 ++ ++ ++ ++ ++
D3/D4 + ++ +++ + +
Half-life (hrs) 3 27 12 4 65
Lesion surgery o Thalamotomy most effective for parkinsonian and essential tremor o Pallidotomyimproves bradykinesia, tremor, rigidity, dyskinesia in PD
Advantages:
o Inability to do bilateral lesions without increased risk of dementia o Swallowing dysfunction, etc. o Side effects could be permanent
o Minimal to no cell destruction, o Ability to perform deep brain stimulation on both sides o Adjust the stimulation settings as the disease progresses
Disadvantages:
o More expensive o Requires technical expertise o Could be prone to hardware malfunctions (kinks, lead fractures) or infections
The ideal surgical candidate:
o o o o o o
Clear PD diagnosis with unequivocal and sustained levodopa response Relatively young Nondemented Nondepressed Nonanxious Emotionally and physically stable.
Complications: