189 PARKINSON’S DISEASE
Harrison’s Manual of Medicine
Parkinsonism consists of tremor, rigidity, bradykinesia, and characteristic abnormalities of gait and posture; may occur with many disorders. Parkinson’s disease (PD) is idiopathic parkinsonism without evidence of more widespread neurologic involvement. Onset between 40 and 70 years with insidious progression. Tremor (“pill rolling” of hands) at rest (4–6 Hz); worsens with stress. A faster (7–8 Hz) “action tremor” may also occur when the hands are held against gravity. Presentation with tremor confined to one limb or side of body is common. Other findings: rigidity (“cogwheeling”—increased ratchet-like resistance to passive limb movements), bradykinesia (slowness of voluntary movements), fixed expressionless face (facial masking) with reduced frequency of blinking, hypophonic voice, drooling, impaired rapid alternating movements, micrographia (small handwriting), reduced arm swing while walking, flexed “stooped” posture with walking, shuffling gait, difficulty initiating or stopping walking, en-bloc turning (multiple small steps required to turn), retropulsion (tendency to fall backwards). In advanced PD—intellectual deterioration, aspiration pneumonia, and bedsores (due to immobility) common. Normal muscular strength, deep tendon reflexes, and sensory exam. Diagnosis based upon history and examination; neuroimaging, EEG, and CSF studies usually normal for age.
Degeneration of pigmented pars compacta neurons of the substantia nigra in the midbrain resulting in lack of dopaminergic input to striatum; accumulation of eosinophilic intraneural inclusion granules (Lewy bodies). Cause of cell death is unknown, but it may result from generation of free radicals and oxidative stress, perhaps by oxidation of dopamine itself. Rare forms of parkinsonism are due to mutations in a-synuclein or parkin genes.
Features of parkinsonism may occur with: depression (paucity of vocal inflection and facial movement); essential tremor (high-frequency tremor with limbs held against gravity; head tremor common; improves with alcohol intake); normal-pressure hydrocephalus (apraxic gait, urinary incontinence, dementia); Wilson’s disease (early age of onset, Kayser-Fleischer rings, low serum copper, low ceruloplasmin); Huntington’s disease (positive family history, chorea, dementia); multiple system atrophy (parkinsonism, impaired autonomic function, or pyramidal or cerebellar or lower motor neuron signs); other neurodegenerative diseases (progressive supranuclear palsy, olivopontocerebellar atrophy, cortical-basal ganglionic degeneration, striatonigral degeneration, diffuse Lewy body disease, Creutzfeldt-Jakob disease, Alzheimer’s disease).
It is not always possible to exclude other causes of parkinsonism prior to initiating treatment for PD. Primary goal of treatment is to restore function (i.e., reduce disabling tremor). A summary of commonly used drugs for PD is listed in Table 189-1; an algorithmic approach to overall management is shown in Fig. 189-1. Amantadine is useful for mild symptoms and acts by potentiating release of endogenous dopamine. Tremor responds best to anticholinergic drugs (trihexyphenidyl, benztropine). Early use of dopamine agonist drugs alone (bromocriptine, pergolide, pramipexole) may delay the emergence of late side effects associated with chronic Sinemet use.
Table 189-1 Drugs Used in Parkinson’s Disease
FIGURE 189-1. Algorithm for the management of patients with Parkinson’s disease.
Sinemet is most helpful for bradykinesia. Sinemet consists of levodopa, the metabolic precurser of dopamine, combined with an extracerebral inhibitor of dopa decarboxylase. The combination maximizes entry of levodopa into the brain. A common initial dose is 25/100 PO tid. Late complications: (1) end-dose phenomenon—deterioration shortly before next dose; and (2) on-off phenomenon—abrupt, transient fluctuations in function without warning or obvious relationship to dosing. On-off may be partially controlled by reducing dosing intervals, restricting dietary protein, and administering levodopa 1 h prior to meals. Response fluctuations to oral levodopa may be reduced by frequent dosing, continuous gastric infusion, or parenteral administration. Controlled-release Sinemet may reduce dosing frequency. Pramipexole may be used with Sinemet to reduce Sinemet dose and drug-response fluctuations. Selegiline, an inhibitor of monoamine oxidase B, may reduce oxidative damage and slow disease progression; the usual dose is 5 mg twice daily. Selective inhibitors of catechol-O-methyltransferase (COMT) such as tolcapone (100 mg tid) or entacapone (200 mg with each Sinemet dose) may enhance the benefits of levodopa therapy.
In refractory cases, unilateral pallidotomy may be effective in relieving signs of PD on the contralateral side. Long-term efficacy is still being defined. Deep brain stimulation of the globus pallidus or subthalamic nucleus has a lower morbidity than pallidotomy and appears to improve clinical status. Adrenal medullary transplants may benefit individuals < 50 years. Transplantation of fetal midbrain cells remains experimental.
For a more detailed discussion, see Aminoff MJ: Parkinson’s Disease and Other Extrapyramidal Disorders, Chap. 363, p. 2399, in HPIM-15.