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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
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dose of L-dopa and utilize more frequent doses during the 24-h day; combining it with a dopamine agonist or a long-acting preparation may be helpful Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications may reduce the on-off phenomenon Based on the notion that alimentary-derived amino acids antagonize the clinical effects of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor uctuations described above (Pincus and Barry) Symptoms can sometimes be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch Moreover, this dietary regimen may permit the patient to reduce slightly the total daily dose of L-dopa Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients with advance disease who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa Surgical Measures Until recently, success with L-dopa had practically replaced the use of the ablative surgical therapy pioneered by Cooper This involved the stereotactic placement of lesions in either the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chie y affected The best results were obtained in relatively young patients, in whom unilateral tremor or rigidity rather than akinesia were predominant The symptoms that responded least well to operation (and indeed to treatment with L-dopa) in Cooper s patients were postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia, and speech dif culties In the last two decades, through the work of Laitinen and others, this mode of therapy has been revived and advanced by the newer technique of implanted electrical stimulators Both the ablative approach and the implantation of electrodes involve the placement, under precise stereotactic control, of a lesion or a wire in the posterior and ventral (medial) part of the subthalamic nucleus or the globus pallidus Improvement of parkinsonian symptoms is reliably effected, particularly on the side opposite the procedure Also, there is in most patients an enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias In patients who have been studied for more than a few years after the unilateral ablative procedure, the bene cial effects on dyskinesias contralateral to the operation are sustained to some extent, but not in the ipsilateral limbs The improvement in off-state bradykinesia is lost after 2 or so years and any betterment in axial rigidity and imbalance abates in many patients within a year of operation, as reported by Gregory and by Lang et al In a randomized trial comparing pallidotomy to continued medical treatment of patients with dyskinesias, bradykinesia, or severe uctuations in response to L-dopa, de Bie and colleagues demonstrated a clear improvement in motor function after surgery, while the group treated with medication continued to worsen These improvements are in part due to the ability to reduce the dose of L-dopa Most groups have abandoned the pallidum as a surgical target in favor of the subthalamic nucleus The technique of high-frequency electrical stimulation has given probably better results than surgical ablation It is now used almost exclusively In particular, stimulation of the subthalamic nucleus has produced improvement in all features of the disease but least of all in gait and balance (Limousin et al) A study by The Deep-Brain Stimulation for Parkinson s Disease Group has demonstrated at least short-term bene t in motor uctuations after the bilateral implantation of stimulating electrodes in both subthalamic nuclei, but the durability of this effect is not known The patients
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