There exists a group of people who live the final years of their lives in glass boxes. They are perfectly capable of seeing outside, but incapable of reaching out to the world around them. Their emotions can not be shown through facial expression, and as their condition continues, speech also becomes difficult or even impossible. These people are men and women of all races and geographical areas, constituting one percent of the world’s population over 50 years old. Parkinson disease is their affliction. Although Parkinsonism has been around almost as long as recorded history, there is yet to be found a cause or a cure. Medications tame the symptoms and prolong life, but are incapable of reversing the disease progression.. Diagnosis relies exclusively upon clinical signs and symptoms, because almost all laboratory and radiography tests are normal in the Parkinson patient. For this reason early diagnosis is very difficult. The fact that early signs of Parkinsonism can easily be overlooked as normal aging, further complicates diagnosis. Therefore, primary care physicians of the middle-aged and elderly population must be extremely sensitive to patients’ outward appearance and changes in movement ability.

Most signs and symptoms of Parkinson disease correspond to one of three motor deficiencies: bradykinesia, akinesia, tremor, and rigidity. The first two qualities are usually present before tremor, but often attributed to aging by the patient and even the physician, and thus the disease is rarely diagnosed until tremor becomes evident much later. An average of 80% of the nigrostriatal neurons may have already degenerated by the time Parkinsonism is diagnosed, which complicates treatment (Fitzgerald, 130). Bradykinesia, or slowness of movement, and akinesia, difficulty in initiating movement, cause a wide range of clinical signs and symptoms affecting every aspect of daily living. They are implicated in the great effort needed by patients to change position, walk, write, focus gaze, swallow, blink, and speak. "In fact, the patient with Parkinson disease is under constant stress to voluntarily perform actions that normally come naturally and involuntarily" (Rowland, 529). Even normal facial expressions are effected as a result of brady- and akinesia, being "reduced in amplitude, slow in developing, and unduly protracted" (Walton, 328), causing patients to look abnormally blank or stern.

Many Parkinson patients feel they have a decrease in muscle strength. Ironically, it has been found that muscle strength remains about normal. The sensation of weakness they feel can usually be attributed to muscle rigidity, which is present in almost all cases, but tends to appear later in the disease than bradykinesia and akinesia. Rigidity is defined as "resistance to passive movement" (Rowland, 528). The rigidity starts immediately with the passive movement, is continuous throughout (Adams, 938), and is accompanied by an increased muscle tone. Together they contribute to decreased range of motion and a change in body posture, characterized by flexion of the trunk, drooped shoulders, and bent elbows. "The center of gravity appears to be displaced forward, leading to the patient’s inability to stand erect without toppling (Rowland, 528).

Probably the most visible symptom of Parkinson disease is tremor, usually beginning after bradykinesia and before rigidity. It is frequently the presenting symptom, because it is irritating to the patient and "carries with it undesirable connotations about the emotional stability of the individual" (Rowland, 528). The tremor is of the resting type, normally evidenced by the thumb and fingers moving against each other a few times each second as the hands sit in the lap (Adams, 938). Initially the tremor can be controlled voluntarily, but the tremor worsens and occurs at the distal joints of the arms, legs and at the mandible. The tremor is usually reduced during active movement and disappears during sleep (Walton 328).

The difficulty Parkinson patients show in walking is a nice example of integrating many of the individual problems seen in the disease. The patients may stand still for a period of time before taking a step as if they must command their feet to move, or require a little push, reflecting the akinesia. Once they are walking, their feet shuffle in slow, short steps due to the bradykinesia and muscle rigidity (Walton, 328), and they experience great difficulty stopping due to their altered center of gravity. These patients also walk with little to not accompanying arm swing (Adams, 939).

Individuals with Parkinson disease also suffer a variety of symptoms which are unrelated to the motor system. Depression is the most common of these, occurring in up to 90% of patients (Walton, 329). The other non-motor symptoms are still surrounded in controversy. For example, the incidence of dementia is considerably higher among Parkinson patients than the unaffected population of the same age, but many Parkinson patients, 68%+, show no signs of dementia. Cerebral imaging of Parkinson patients show lesions in white matter which are absent in other Parkinson patients (Adams, 939). Some literature suggests two separate strains of Parkinson disease, one form with dementia and another showing no dementia (Rowland, 530).

Parkinson disease causes what appears to be autonomic dysfunction also. A very common autonomic complication of Parkinson disease is gastrointestinal dysfunction, most notably esophageal dysfunction and constipation. Both symptoms are normally well controlled by changes in eating habits possibly accompanied by a laxative, but more research needs to be devoted to investigating possible involvement of the vagus nerve and its dorsal nucleus (Korczyn, 1990). Another common and often dangerous problem relating to the autonomic nervous system is hypotension. Parkinson patients have a low resting blood pressure due to poor baroreceptor mechanisms, giving rise to the danger of orthostatic syncope upon standing (Rowland, 530). However, outside of these symptoms, it is difficult to be sure if other autonomic symptoms are primary autonomic dysfunction’s or secondary to the decreased motor abilities and their associated problems. It has been noted, for instance, that Parkinson patients tend to drool from excess saliva, sweat more, and experience seborrhea. These symptoms may be direct autonomic dysfunction’s, but they are probably better explained by the decreased ability to swallow, uncontrolled movement, and difficulty in regularly washing, respectively (Adams, 939). It is therefore difficult to assess which symptoms are primary and which are secondary to others.

The hallmark neurological deficit of individuals suffering from Parkinson disease is the degeneration of pigmented nerve cells in the substantia nigra. To this degeneration is attributed most of the symptomology seen. The substantia nigra is located in the midbrain and projects to and from the striatum, which is comprised of the putamen and the caudate nucleus. All of these structures are part of the basal ganglia, which in turn is part of the extrapyramidal system that mediates the fine tuning and coordination of voluntary motor actions. Many nerve cells within the substantia nigra transmit dopamine, and within the basal ganglia is located eighty percent of all the dopamine in the brain (Kandel, 654). From this amount, eighty percent of the dopamine must be lost from the substantia nigra, and thus the striatum, before Parkinsonian symptoms appear (Walton, 323). Dopamine can have both an inhibitory and excitatory effect on the striatum. It is postulated that the inhibitory effect of dopamine counterbalance the excitatory effects of other neurotransmitters in the striatum such as acetylcholine, which is found in normal concentration in Parkinson patients (Rowland, 527). The result of this imbalance is an overactive striatum, causing the resting tremor so often experienced by these individuals (Fitzgerald, 130).

Aside from projections to the striatum, there are also dopaminergic projections to the limbic system and the frontal lobe of the cortex. Depletion of dopamine in these systems are postulated to play a role in akinesia and certain cognitive problems respectively (Kandel, 655).

The brains of Parkinson patients also show degeneration of cells in the locus coeruleus of the midbrain, containing the transmitter norepinephrine. It is unclear exactly what contributions this loss plays in the symptomology of Parkinson disease, but it has been observed that patients with Parkinsonism who also suffer from severe depression and especially dementia, have more extensive death in the locus coeruleus (Chan-Palay, 1991).

There exists many circumstances which can induce the depletion or blockage of dopamine in the brain, such as encephalitis and certain drugs. However, the great majority of Parkinson disease cases are idiopathic. Investigators have attempted, but been unsuccessful at linking the disease to disorders of fat storage, protein synthesis and genetics (Walton ,326). There has been found to be a natural degeneration of neurons in the nigrostriatum with age, but certainly not all elderly patients present with Parkinsonism. The best hypotheses at present, is a vague one implicating some environmental insult which would enhance the degeneration of dopaminergic neurons to the eighty percent mark where Parkinson symptoms appear (Langston, 1989). There Is much work to be done in this area, if disease progression is ever to be stopped or reversed, a cause must be implicated.

Because no etiology to Parkinson disease has yet been pinpointed, and there has been found no way to reverse the degeneration of the substantia nigra, treatment of Parkinsonism has focused exclusively on relieving symptoms and keeping the patient as active and comfortable as possible, for as long as possible. Currently, the most common treatment is levodopa, alone or in combination with other drugs found to relieve symptoms by other mechanisms, or control the side effects of levodopa.

Levodopa, or L-dopa, is the immediate precursor for the dopamine which is missing in the nigrostriatum. Dopamine itself cannot be directly administered because it is unable to cross the blood-brain barrier. Levodopa is taken up by the brain, engulfed by cell processes in the striatum whose cell bodies lie in the substantia nigra, converted to dopamine, and released as the neurotransmitter. It is thought that levodopa is effective, even though it must undergo the last step in synthesis, because it allows the cell to skip the rate limiting step in dopamine synthesis catalyzed by tyrosine hydroxylase (Kandel, 655). This allows the remaining cells in the substantia nigra to work more efficiently in compensation for the huge cell death there.

Levodopa has been found to be quite effective in reducing the signs and symptoms of Parkinsonism, especially Brady- and akinesia. About two-thirds of Parkinson patients respond well initially to the drug. The remaining third may suffer nausea, depression, and/or hypotensive episodes. The nausea usually goes away with time when the drug is administered with meals and is often helped along with an anti-emetic (Adams, 941). Depression is often treated with cyclic antidepressants. There is recent information indicating that Parkinsonian depression may be related to the depletion of norepinephrine in the locus coeruleus, and that monoamine oxidase A (MAO-A) inhibitors may be of use in controlling the degradation of norepinephrine and thus control depression (Chan-Palay, 1991).

Unfortunately, there are more serious drawbacks to levodopa therapy: the on-off phenomenon and dyskinesia. These side effects are dosage dependent and time dependent. The longer patients are on levodopa therapy, the greater chance they have of experiencing these debilitating side effects.

L-dopa is usually administered orally three or four times day. Its effect on the motor system is "all or nothing". If dosage is high enough to be effective, the patient is said to be is an "on" period. The patient is mobile and usually feeling well at this point. However, it often occurs that before the next dose is administered, patients experience an "off" period, during which the patients status may actually be worse than when they wake up in the morning after having no L-dopa therapy all night. It is postulated that the amount of L-dopa remaining from first dose falls below a certain threshold level and can actually have an inhibitory affect upon the voluntary motor system. This "on-off" phenomenon can be psychologically distressing to the individual with Parkinson disease, because they cannot easily predict when this will occur and fear of it often forces these people to remain at home, even when they are capable of being very active. It has been found that if the dose is kept constant, either intravenously or through duodenal infusions, the on-off effects are kept to a minimum. Unfortunately, these procedures require the patient to be in a health care setting and have their own drawbacks. It has also been noted, that if higher doses of L-dopa are administered, although there are no benefits as to increased motor capabilities, its beneficial effects last longer and delay the onset of off periods (Lees 1989).

However, high doses of L-dopa also carry increased risks, especially of dyskinesia. Nearly all patients being treated with L-dopa for any period of time will experience dyskinesia. It is usually evidenced by uncontrollable choreiform movements, most notably of the face and feet. The dyskinesia-can be terribly unbecoming and unpleasant to the patient, and can only be controlled by lowering dosage of L-dopa or stopping treatment altogether for a while.

There has been some concern about the origin of the on-off phenomenon and dyskinesia.

"While these effects are viewed mainly as complications of levodopa, they have also been viewed as markers of the degenerating nigrostriatal neurons. Indeed, it has been postulated that the metabolism of levodopa generates free radicals, which damage the nigrostriatal neurons" (Lieberman 1992).

Although there is no direct evidence so far to determine if levodopa actually contributes to disease progression, there has been much research done in the past twenty years to find an adequate substitute for or adjunct to levodopa, allowing patients to have less levodopa administered. One of the more recent and successful agents is selegiline, an inhibitor of monoamine oxidase B (MAO-B). MAO-B is the enzyme which breaks down dopamine to generate free radicals which are potentially harmful to other neurons. The theory behind selegiline is that if MAO-B is inhibited then a) there will be fewer free radicals to damage remaining neurons and b) there will be more dopamine spared, and levodopa will not need to be given in such large concentrations. It has been found that when Parkinson patients are started immediately on selegiline, the time passing before the patients must begin levodopa therapy is extended by 50%. However, it is unclear if selegiline is actually delaying progression of the disease, or if selegiline also has a symptomatic effect, which postpones the need for levodopa treatment (Liebermann, 1992).

Because Parkinson’s disease is such a common neurological disorder among elderly patients, it is worthy of greater attention that it has been given in the past years. In the next few years it will be important for more investigation to be initiated into the etiology and treatment of the disease, because the older population of this country deserves to be to independent as long as possible and to remain a contributing part of society.

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Kandel, E. R., J. H. Schwarz, and T. M. Jessel. Principles of Neural Science. 3rd ed. Elsevier. New York: 1991.

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