Parkinson's Disease

Timothy C. Hain, MD

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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).

Typical symptoms

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).

Differential Diagnosis

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.

Conventional Treatment

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.

Drug Treatment