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Timothy C. Hain,
MD 
Page last modified:
February 12, 2009
Parkinson's disease (PD) is neurological disorder characterized by bradykinesia, shuffling gait, postural instability, tremor, and loss of automatic movement. It is due to loss of dopamine containing substantia nigra cells. It appears that about 50% of cells need to be lost before symptoms appear. Although Parkinsons can be clearly traced to genetic factors, viruses, stroke or toxins such as pesticides in a few individuals, for the most part the cause of Parkinson's in any particular case is unknown (this is called sporadic PD).
Environmental influences include drinking well water, farming and industrial exposure to heavy metals (e.g. iron, zinc, copper, mercury, magnesium and manganese), alkylated phosphates and organochlorines. Paraquat (a herbicide) has been associated with increased prevalence of Parkinsonism. Several occupations are high risk. Welding is associated with an increased risk vs. the general population of roughly a factor of 10. The prevalence of Parkinsonism is about 1% in wlders between 40-69. Cabinet makers and cleaners are also high risk (Racette et al, 2005).
Cigarette smoking is associated with a decreased incidence. Head trauma increases the risk of Parkinsonism by a ratio ranging from 4.3 to 11 (Bower et al, 2003). The current consensus that Parkinsons might either be caused by an uncommon environmental element combined with high genetic susceptibility or a common environmental element with relatively low susceptibility. Nevertheless, recent work is conflicting suggesting that the genes mentioned above are not associated with sporadic PD (Markopoulo and Langston, 1999).
There is good evidence for genetic factors. A twin study using PET reported greatly increased concordance for dopaminergic dysfunction in monozygotic than dizygotic twins (Piccini et al, 1999). Also, several large pedigrees of autosomal dominantly inherited PD have been reported recently (Polmeropoulos et al. Science 1996:274:1197-1199). A mutation in alpha-synuclein is responsible for this pedigree. Other mutations of synuclein have also been found (Zarantz et al, 2004). Alpha-synuclein includes the non-A-beta component of Alzheimers plaques, is preferentially expressed in dopamine neurons, and is abundant in Lewy bodies (a pathologic marker of Parkinsonism and Lewy body dementia-- Lewy bodies are not increased in PSP). Another kindred has mutations in the "parkin" gene, which manifests as autosomal recessive juvenile Parkinsons (Mizuno Y, 1998). Slow acetylation may also be a predisposing factor in sporadic PD (Bandmann O et al. Lancet 1997:350:1136-1139). Slow acetylation might lead to an impaired ability to handle neurotoxic substances, linking together the genetic and toxic hypotheses.
Parkinson's is uncommon in patients less than 40 years of age. It is found in about 1% of those greater than 50 and 3% of those aged 95 or greater. Every year about 50,000 new cases are diagnosed in the United States. In autopsy studies, Parkinson's is found even more frequently -- about 10% of 70 year olds show evidence of subclinical disease. Prevalence varies greatly throughout the world, ranging from 14/100,000 in China to 328/100,000 in Bombay, India. Asians and African blacks have a lower incidence compared to American blacks and, especially, whites (Lang et al, 1998).
They include resting tremor, unsteady gait. slowness of movement (bradykinesia), rigidity, difficulty initiating movement (akinesia), small handwriting (micrographia). Associated symptoms often include seborrhea, orthostatic hypotension, urinary difficulties, constipation, limb pain, depression, dementia (up to 1/3 patients), smelling disturbances (occurs early).
Ocular symptoms include decreased color discrimination and contrast sensitivity, visual hallucinations, reduced blinking and other problems with eyelid movement, and multistep saccades,(Biousseet al, 2004).
Orthostatic hypotension may occur associated with the disease or as a complication of medication (Goldstein et al, 2000). The orthostatic hypotension is reported to be due to sympathetic denervation (Goldstein et al, 2002). The lesion involves postganglionic catecholaminergic but not cholinergic nerves (Sharabi et al, 2003).
Impaired olfaction (sense of smell preceds clinical parkinsonism by at least 4 years (Ross et al, 2008)
Patients with Parkinsonism have greater mortality, about 2 times,compared to the general population without PD. This is attributed to greater frailty or reduced mobility (Donnan et al, 2000).
Diagnosis is mainly clinical and is based on the clinical findings listed above. There are many conditions which may be mistaken for parkinsonism. Among the most common are side effects of drugs (mainly the major tranquilizers such as haloperidol), strokes involving the basal ganglia, degenerative disorders such as progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration, olivopontocerebellar degeneration, multiple system atrophy, and Huntington's disease.
The pathological hallmark of Parkinson's disease are Lewy bodies, which are intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein has been identified as the main component of Lewy bodies in sporadic Parkinsonism. Lewy bodies are not found in PSP in abnormal numbers, although they are found in Alzheimer's disease. Lewy bodies, in large numbers, can cause dementia. They are also associated with medication intolerance and visual hallucinations.
Nearly all authors agree that treatment with carbidopa-levodopa (Sinemet (TM)) is the single most helpful medication. Levodopa has enabled patients with Parkinsonism to live normal life spans, and greatly ameliorates symptoms in most patients (Ahlskog JE, 1996).
There is presently considerable controversy as to the value of adjunctive agents to levodopa. As a summary, it seems prudent to recommend an approach which incorporates levodopa, direct dopamine agonists, and potential neuroprotective agents such as seligiline. Patients with significant deficits which cannot be adequately treated with drugs may be suitable candidates for surgical approachs. An algorithm for managing parkinsonism published by the American Academy of Neurology can be found here.
Vasoconstrictors for orthostatic hypotension (such as Midodrine) are unlikely to work for orthostatic hypotension in Parkinsons disease because the lesion involves the post-ganglionic sympathetics (Goldstein et al, 2002).
Patients with PD respond to levodopa almost immediately. However, 20 to 50% of patients will develop motor fluctuations or dyskinesias within 5 years of starting levodopa therapy. Response fluctuations consist of a mixture of "wearing-off" phenomenon, "on" dyskinesias (usually choreiform), "Diphasic dyskinesias" (repetitive 3-4 hz movements of the lower limb that occur when the rate of change of dopamine is high), and "off" dystonia (Obeso et al, 2000).
Wearing off can be managed by decreasing the dosing interval, switching to a longer acting product, or by adding or increasing the dose of dopamine agonist. On-off effects are harder to manage. The addition of a direct dopamine agonist or switching to a slow acting dopamine preparation may reduce the frequency of dyskinesias and on/off events. Pramipexole, as initial therapy compared to levodopa, reduces the risk of developing complications by about 55%, but it is not as effective as Levodopa and has some adverse affects (Parkinson Study Group,2000). COMT inhibitors may smooth smooth out the peaks/troughs of dopamine and reduce fluctuation.
Psychiatric adverse effects include psychosis, confusion, agitation, hallucinations and delusions. These can be treated by decreasing dopamine medication, reducing or discontinuing anticholinergics, amantadine or selegiline, or by using clozipine at doses of 6.25 to 50 mg/d (Stern, 1997).
Surgical treatment is presently recommended for those who have failed medical management (see review by Hallet et al, 1999).
Physical therapy is helpful in Parkinsonsm. It maintains muscle tone, flexibility, improves posture and gait. Strangely, this is often called "vestibular rehabilitation therapy".
There are many studies suggesting that the risk of Parkinsonism is modulated by one's environment. Surprisingly, coffee drinking reduces the risk of Parkinsonism (Josefson 2000; Ross et al. 2000). Also, living in a rural area, drinking well water, farming, and exposure to pesticides (Ascherio et al, 2006) may be risk factors for developing PD. Smoking may also be protective in some situations.
Nonsteroidal antiinflammatory agents (such as aspirin or ibuprofen) may protect from Parkinsonism. A recent retrospective study found that 2 or more pills/week of aspirin or NSAID's reduced the odds of PD by roughly 50% in women. There was no effect in men. (Walner et al, 2007). It seems to us that this association is likely a false hope, and a larger, controlled prospective study is needed to evaluate this strong observation.
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