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fully corroborated Technical problems in interpreting these results are discussed at length in the reviews by Wooten and by Clarke and Guttman The uncertainties here have to do with clinical grading systems, functional imaging techniques, and points of comparison to treatment with L-dopa Nevertheless, in the last few years these observations have led to the promotion of dopamine agonists as the initial therapy The notion that the administration of L-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some neurologists continue to adhere to it Cedarbaum et al, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of L-dopa treatment predisposed to the development of uctuations in motor response or to dyskinesia and dementia In discussing this with patients, we point out the ndings of the Elldopa trial by the Parkinson Study Group; in 361 individuals with Parkinson disease of less than 2 years duration who were treated with L-dopa for 40 weeks and then had the medication withdrawn, functional and other measures were better than in those who received no medication That is, L-dopa may have itself been neuroprotective Also, the large multicenter study reported by Diamond et al indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who began the medication late in the course These results emphasize the dif culty of assessing the protective effect of various drugs Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with mixed but generally negative results A possible exception has been the trial of coenzyme Q10 by Shults and colleagues Massive doses of this agent, 1200 mg per day, were found to offer some marginal advantages on the progression over 6 to 18 months as measured by certain standard scores of overall daily function but not on most neurologic scales Further study of this approach is advised For the moment, unless it presents a nancial burden, the use of this agent seems reasonable but not obligatory Side Effects of L-Dopa Treatment As already mentioned, the side effects of L-dopa are at times signi cant to the degree that its continuation cannot be tolerated Some patients are at rst troubled by nausea, although this can be mitigated by taking the medication with meals A few have mild orthostatic hypotensive episodes Nausea usually disappears after several weeks of continued use or can be allayed by the speci c dopaminergic chemoreceptor antagonist domperidone However, the most troublesome effects of L-dopa as the disease advances, usually after several years of treatment, are an endof-dose reduction in ef cacy (and the more precipitous on-off phenomenon) and the induction of involuntary dyskinetic movements restlessness, head wagging, grimacing, lingual-labial dyskinesia, and especially choreoathetosis and dystonia of the limbs, neck, and trunk A decline in ef cacy after the usual 2 to 4 h may be treated by more frequent dosing or the addition of a COMT inhibitor The on-off phenomenon is a rapid and sometimes unpredictable change in the patient, in a matter of minutes or from one hour to the next, from a state of relative freedom from symptoms to one of complete or nearly complete immobility Both dyskinesias and severe off periods eventually appear in about 75 percent of patients within 5 years Above a certain daily dose level of L-dopa, which varies from patient to patient, very few patients escape these effects, forcing an increased frequency of administration and usually a reduction in dosage.

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If involuntary movements are induced by relatively small doses of L-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminergic agents or by the concurrent administration of amantadine The use of lower doses of long-acting preparations of L-dopa may also be helpful in reducing dyskinesias, and the atypical antipsychotic medications have been said to be useful The onset of psychiatric symptoms coincident with the use of L-dopa may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly Depression, although frequent, is only occasionally a serious problem, even to the point of suicide Delusional thinking may also occur in these circumstances This combination of movement and psychiatric disorders is dif cult to treat, and one is faced with instituting an antidepressant regimen or perhaps using one of the newer class of antipsychotic medications that have the least extrapyramidal side effects (see below and Chap 50) While the selective serotonin reuptake inhibitors have been useful in cases of apathetic depression, they may cause slight worsening of parkinsonian symptoms In our hands, trazodone has been most helpful in treating depression and insomnia, the latter also being a major problem in some patients Excitement and aggressiveness appear in a few A return of libido may lead to sexual assertiveness Confusion and outright psychosis (hallucinations and delusions) are seen in advanced cases of Parkinson disease when high doses of L-dopa are required and the disease has been present for many years This may rst be treated by attempting to reduce the dose of the drug If this is not tolerated, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine in low doses are recommended by Friedman and Lannon The side effects of these drugs include sleepiness, orthostatic hypotension, and sialorrhea As noted above, clozapine has been said to provide an additional bene t of suppressing dyskinesias in advanced Parkinson disease (Bennett et al), but it requires surveillance of the white blood cell count because of the idiosyncratic occurrence of agranulocytosis in up to 2 percent of patients Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened The anticonvulsant valproate is also said to be useful in this circumstance, but in our hands it has not been as effective as clozapine and related drugs Despite their lesser tendency to produce rigidity, olanzapine and probably the other similar agents in high doses may slightly worsen motor disability An important note of warning: anticholinergic agents or Ldopa should not be discontinued abruptly in advanced Parkinson disease If this is done, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal Reducing the medication dose over a week or so is usually adequate With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter In some instances, the patient becomes so sensitive to L-dopa that as slight an excess as 50 to 100 mg will precipitate choreoathetosis; if the dose is lowered by the same amount, the patient may develop disabling rigidity With the end-of-dose loss of effectiveness and on-off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations Some patients function quite well in the morning and much less well in the afternoon, or vice versa In such cases, and for end-of-dose and on-off phenomena, one must titrate the.

FIGURE 11-13

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