Clinical Manifestations

The Parkinson's-Reversing Breakthrough

Medication for Parkinson Disease

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The cardinal features of Parkinson's disease are resting tremor, bradykinesia, rigidity, and postural instability. The resting tremor usually is 4 to 6 cycles per second and is present at rest and decreases with

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Figure VIII. 102.1. Scheme illustrating the mechanism of MPTP toxicity at nigral dopamine neurons in primates. MPTP, which is lipophilic, enters the brain where it is transformed into MPP+ by monoamine oxidase B located in glial cells or in serotonergic neurons. MPP+ is taken up into the dopaminergic (DA) neurons, where it accumulates, by dopamine reuptake mechanisms. The binding of MPP+ to neuromelanin might assist in the accumulation of MPP+, or might contribute to its toxicity. MPP+ within the neurons is assumed not to undergo redox cycling to reproduce free radical species but, rather, to be actively accumulated by mitochondria, where it inerferes with mitochondrial energy metabolism, leading to cell death. The precise mechanism of MPP+ toxicity remains unknown. The sequence of events leading to MPTP toxicity can, in theory, be inhibited at a number of points: (1) Selective monoamine oxidase B inhibitors (MAOI B) such as deprenyl inhibit the conversion of MPTP to MPP+; (2) dopamine reuptake blockers such as nomifensine inhibit the entry and accumulation of MPP+ into dopaminergic neurons; (3) chloroquine might inhibit the binding of MPP+ to neuromelanin and thus limit its toxicity for protective substances such as antioxidants (e.g., alpha-tocopherol); or substances such as acetyl-L-carnitine that protect mitochondria from toxic insults might inhibit the toxic mechanism of MPP+; (4,5) other substances as yet unknown might inhibit the production of free radicals or boost energy metabolism. (From Joseph Jankovic and Eduardo Tolosa, eds. 1988. Parkinson's disease and movement disorders. Baltimore, Maryland: Urban and Schwarzenberg, by permission of the publisher.)

action. The tremor usually starts in the upper extremity on one side and then spreads to the lower extremity on the same side. Upper and lower extremities are usually time-locked, with the lower extremity a half cycle behind the upper extremity. Once the tremor has spread to one side of the body, the opposite upper extremity is usually involved, and then the opposite lower extremity. Postural tremor is also present in the majority of Parkinson's patients, and postural tremor is usually slightly faster than the resting tremor. Bradykinesia, which literally means "slow movement," is not the same as hypokinesia, meaning "decreased movement," or akinesia, "no movement." All of these movement disorders can be part of Parkinson's disease. The bradykinesia shows up as a delay in the execution and initiation of voluntary movement, and also there is difficulty arresting the movement once it has been started. Akinesia is simply an extreme state of immobility, and some Parkinson's patients, particularly before treatment with levodopa became available, eventually ended their days totally rigid and immobilized. Rigidity is resistance to passive stretch of muscle, and the patients with parkinsonism have a characteristic stiffness of the muscles of the body. This stiffness can be brought out by passive rotation of the wrist or flexion-extension at the forearm. It is also present in the truncal muscles and can be examined by placing one's hands on the dorsal aspect of the patient's back muscles and having the patient flex and extend the body at the waist. The rigidity that is characteristic of parkinsonism is the rigidity that usually gives way in little catches and, hence, has been called cogwheel rigidity. The most disabling of the cardinal features of parkinsonism is the postural instability. This one symptom alone accounts for most of the falls that occur in this disease. The instability results in loss of balance with propulsion and retropulsion, and such patients are unable to anticipate a change in their posture and thereby correct for the change, and thus they often follow their center of gravity as they fall to the ground. Little postural corrections that are normally made automatically cannot be done, and this is the major motor defect in the disease. Other clinical features of parkinsonism include masked facies and decreased blinking, increased saliva production called sialorrhea, hyperhidrosis (profuse sweating) or oily skin, a low-pitched monotonous voice, stooped posture, scoliosis, decreased upward gaze, a tendency toward low blood pressure, micrographia, and a shuffling and small-stepped gait.

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