Timothy C. Hain,
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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 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.
Cigarette smoking is associated with a decreased incidence. The current consensus
that Parkinsons might either be caused by an uncommon toxin combined with high
genetic susceptibility or a common toxin 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.
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.
Incidence and Prevalence
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). 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). 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
Haldol), 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.
- Levodopa, mainly in the form of a combination product containing carbidopa
and levodopa (Sinemet and Sinemet CR), is the mainstay of treatment and is
the most effective agent (Ahlskog, 1996; Koller, 2000). Carbidopa is a peripheral
decarboxylase inhibitor which prevents side effects and lowers the overall
dosage requirement. The starting dose of Sinemet is one 25/100 tablet prior
to each meal. Usual maintenance dose is 25/250 QID. Dyskinesias may result
from overdose and also are commonly seen after prolonged (e.g. years) use.
Direct acting dopamine agonists may have less of this side effect (see below).
Visual hallucinations often seen with overdose. Orthostatic hypotension may
respond to increased carbidopa. About 15% of patients do not respond to Levodopa.
Dopamine is metabolized to potentially toxic free radicals and some feel that
direct-acting dopamine agonists should be used early to supplement dopamine
- Amantadine (Symmetrel) is a mild agent thought to work by blocking
the reuptake of dopamine into presynaptic neurons. Dosing is 200 to 300 mg
daily. Amantadine is particularly helpful in patients with predominant tremor.
Side effects include ankle swelling and red blotches (livedo reticularis).
- Anticholinergics such as Artane or Cogentin are also helpful in managing
tremor and rigidity but not helpful with bradykinesia. Anticholinergic agents
use is limited by adverse effects (confusion, dry mouth, blurred vision, urinary
retention) which are particularly severe in older individuals.
- Direct acting dopamine agonists include bromocriptine (Parlodel), pergolide
(Permax), ropinirole (Requip) and pramipexole (Mirapex). These agents cost
substantially more than levodopa (Sinemet), with controversial additional
benefits (Ahlskog 1996). New with this group is concern about
which dopamine receptor (D1, D2 or D3) is being stimulated. Both D1 and D2
agonists exert antiparkinson effects. Pergolide stimulates both the D1 and
D2 receptors. Mirapex (pramipexole) and Requip (ropinirole) are the newest
of these agents. Both are somewhat selective for dopamine receptors with highest
affinity for the D2 receptor and also activity at the D3 receptor. Starting
dose for Mirapex is 0.125 mg TID, vs .25 TID for ropinirole. Ropinirole may
have less dyskinesia side effects as does L-dopa (Rascol et al, 2000). Direct
dopamine agonists in general are more likely to produce adverse neuropsychiatric
side effects than levodopa such as confusion (Stern, 1997). Also dopamine
agonists, whether direct or not, may commonly induce hypotension, abdominal
bloating, fatigue, sedation, nausea and vomiting, constipation, dry mouth,
hallucinations and nasal stuffiness, probably because they act both peripherally
and centrally. Unlike levodopa, direct dopamine agonists do not undergo conversion
to dopamine and thus do not produce potentially toxic metabolites. In rodents,
pergolide slows the age-related loss of nigral neurons induced by 6-hydroxydopamine.
It is also theorized that early use of direct dopamine agonists might protect
against the development of late complications of dopamine, such as the "on-off"
- Selegiline (Deprenyl, Eldepryl) MAO-B inhibitor. Taken in a low dose, 5
mg BID or 5 mg QD. Initially it was thought to reduce progression of Parkinsonism.
This idea is now not well accepted but it still may be a reasonable adjunctive
medication (Stern, 1997). A recent study has documented that Seligiline delays
need for use of levodopa, roughly by 3 months (Palhagen et al, 1998). Selegiline
may reduce free radical production and may also rescue damaged neurons through
activation of trophic mechanisms.
- COMT inhibitors. Catechol-O-methyltranferase is an enzyme that degrades
levodopa and inhibitors can reduce the rate of degradation. Entacapone (not
yet available) is a peripherally acting COMT inhibitor, which may be used
to reduce peripheral metabolism (Parkinson Study Group, 1997). Tasmar, or
tolcapone, approved by the FDA in 6/1997, is presently available. A small
percentage of patients develop abnormal liver function on this tolcapone and
before starting the drug, physicians must obtain written informed consent
and check liver function tests every 2 weeks. Entacapone does not have any
known hepatotoxicity. COMT inhibitors are reviewed in a supplement edited
by Olanow and Obesco, 2000 (see below for details).
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).
- Unilateral thalamotomy -- can be used to reduce tremor. Consider for patient
with unilateral tremor not responding to medication. Improvement fades with
time. Bilateral procedures are not advised.
- Unilateral Pallidotomy is an effective technique for reducing contralateral
levodopa induced dyskinesias.
- Unilateral deep brain stimulation of the thalamus for tremor may also
be of benefit for tremor. These types of procedures carry a risk of infection
of hardware failure. Subthalamic stimulation is presently available only
as a research procedure (Limousin et al, 1998)
- Neural transplantation is no longer felt to be effective treatment.
- Gamma knife -- thallamotomy or pallidotomy can be performed with focussed
radiation. Very preliminary reports suggest that this treatment is effective
in controlling tremor in most patients (Shumway-Cook, 1997). Long term risks
of this procedure are unclear.
Physical therapy is helpful in Parkinsonsm. It maintains muscle tone, flexibility,
improves posture and gait.
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 may be risk factors for developing
PD. Smoking may also be protective in some situations.
Other sources of information:
The American Parkinson's Disease Association (800-223-9776) is a good source
of information for patients.
- Ahlskog JE. Treatment of early Parkinson's disease: are complicated strategies
justified ? Mayo Clinic Proc 1996;71:659-670
- Bandmann O et al. Lancet 1997:350:1136-1139
- Donnan and others. Seligiline and mortality in subjects with Parkinson's
disease. A longitudinal community study. Neurology 2000:55:1785-1789
- Goldstein DS and others. Cardiac sympathetic denervation in Parkinson disease.
Ann Intern Med 2000:133:338-347
- Goldstein DS et al. Orthostatic hypotension from sympathetic denervation
in Parkinson's disease. Neurology 2002:58:1247-55
- Guttman M, and others. C11RI-32 Pet studies of the dopamine transporter
..., Neurology 1997;48:1578-1583
- Hallett M. Litvan I, taskforce on surgery for Parkinson's disease. Evaluation
of surgery for Parkinson's Disease. Neurology 1999;53:1910-1921
- Josefson, D. (2000). "Coffee may lower risk of Parkinson's disease." Bmj
- Koller WC. Levodopa in the treatment of Parkinson's disease. Neurology 2000:55(Suppl
- Lang AE, Lozano AM. Medical Progress: Parkinson's disease. Parts 1 and 2.
- Limousin P, et al. Electrical stimulation of the subthalmic nucleus in advanced
Parkinson's Disease. NEJM 1998:339:1105-1111.
- Markopoulou K, Langston JW. Candidate genes and Parkinson's disease: Where
to next ? Neurology 1999, 53, 1382-1383
- Mizuno Y. Nature, 1998:393:605-608
- Obeso JA and others. The evolution and origin of motor complications in
Parkinson's disease. Neuroogy 2000:55(Suppl 4), S13-S20
- Olanow CW, Obesco JA (editors). The role of COMT inhibitors in the treatment
of Parkinson's disease. 2000. Supplement to Neurology, 5, #11, Supplement
- Parkinson Study Group. Entacapone improves motor fluctuations in levodopa
treated Parkinson's disease patients. Ann Neurol 1997;42;747-755
- Parkinson Study Group. Pramipexole vs. Levodopa as initial treatment for
Parkinson Disease. JAMA 2000:284, 1931-1938
- Palhagen S and others. Seligiline delays the oset of disability in de novo
parkinsonian patients. Neurology 1998:51:520-525
- Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks D. The role of inheritance
in sporadic parkinson's disease: ... Ann Neurol 1999:45:577-582
- Rascol O, and others. A five-year study of the incidence of dyskinesia in
patients with early parkinson's disease who were treated with ropinirole or
levodopa. N. Eng J. Med 2000:342:1484-91
- Ross, G. W., et al. (2000). "Association of coffee and caffeine intake with
the risk of Parkinson disease." Jama 283(20): 2674-9.
- Shumway-Cook A. Functional outcomes following gamma kinfe radiosurgery in
Parkinson's disease. Northwest Neuroscience Institute Journal, 1997, 4, 1-3.
Note: This article has not undergone peer review.
- Stern MB. The changing standard of care in Parkinson's disease. Neurology
1997:49 (Suppl 1), S1.