The use of pergolide, a potent dopamine agonist, in Parkinson's disease.

Pergolide, a semisynthetic ergoline and a potent long-acting adenylcyclase-linked dopamine agonist, was given to 40 patients with advanced Parkinson's disease whose response to levodopa had diminished considerably. The group included 31 patients with marked diurnal oscillations in performance ("wearing off" and/or "on-off" phenomena). Pergolide alone (7 patients) or combined with levodopa (33 patients), resulted in a reduction in disability (P less than or equal to 0.01) as assessed in both the patients' "on" and "off" periods. Pergolide also resulted in an increase (P less than or equal to 0.001) in the number of hours in which patients were on from 3.8 (+/-0.4) to 11.9 (+/-0.9). The mean daily dose of pergolide was 2.4 mg (range 0.1 to 10.0). The mean duration of the study was 12 mo (range 1 to 24). Pergolide is effective in Parkinson's disease and will change the management of patients whose response to levodopa has diminished.

Neuropathy with susceptibility to compression aggravated by herniated disk. Early pathological and electrodiagnostic studies.

We describe a patient with a foot drop attributable to both herniated disk and peripheral neuropathy susceptible to external compression. Early electrodiagnostic studies and sural nerve biopsy indicated a role for myelin dysfunction in this disorder.

Bromocriptine in Parkinson disease: further studies.

Bromocriptine was administered to 66 patients with advanced Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Forty-five patients tolerated at least 25 mg per day of bromocriptine (the "adequately treated" group) in addition to Sinemet and had significantly decreased rigidity, tremor, bradykinesia, gait disturbance, and total score, but increased involuntary movements. Twenty-five of these 45 patients improved by at least one stage. Among the 45 patients, 27 had "on-off" effects, and in 19 the "on-off" effects decreased on bromocriptine. The mean dose of bromocriptine in adequately treated patients las 47 mg, permitting a 10 percent reduction in the dose of levodopa. Twelve adequately treated patients received bromocriptine for at least 1 year, and 8 continued for longer than this. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). All adverse effects were reversible. Despite adverse effects, expense, and scarcity, bromocriptine, when added to levodopa, is useful in patients with advanced disease who no longer respond satisfactorily to levodopa, and for whom no other treatment is available.

Lergotrile in Parkinson disease: further studies.

Lergotrile was administered to 53 patients with advanced Parkinson disease (PD), who had increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Thirty-nine patients who could tolerate at least 20 mg per day lergotrile (thus considered "adequately treated") had significant descreases in rigidity, tremor, bradykinesia, gait disturbance, and total score without increased involuntary movements. Twenty-one of these 39 patients improved by at least one stage. Among the 39 patients, 23 had "on-off" effects, and in 13 of these the "on-off" effects decreased on lergotrile. The mean daily dose of lergotrile in adequately treated patients was 49 mg, permitting a 10 percent reduction in the dose of levodopa. Lergotrile was discontinued in 33 of the 53 patients because of adverse effects, including hepatotoxicity (11 patients), mental changes (12 patients) and orthostatic hypotension (8 patients). Although lergotrile, when added to levodopa, has a definite antiparkinsonian effect, the incidence of adverse effects, particularly hepatotoxicity, makes it unlikely that this ergot alkaloid will become widely available for the treatment of PD. Analogues of lergotrile have been synthesized, and it is hoped that they will duplicate the antiparkinsonian effect of this drug without its toxicity.

Lisuride combined with levodopa in advanced Parkinson disease.

Lisuride, a semisynthetic ergoline and potent central dopamine and serotonin agonist, was combined with levodopa in 20 patients with advanced Parkinson disease who were no longer responding satisfactorily to levodopa, including 14 patients with "on-off' phenomena. Every patient who completed the 8-week trial improved significantly (p greater than or equal to 0.01), with a decrease in all symptoms. The mean dose of lisuride was 2.4 mg per day. The dose of levodopa (mg of levodopa in Sinemet) was reduced from 1030 to 920 mg. Among the patients with "on-off' phenomena, there was a significant increase in the time in which they were 'on' (mobile) from 4.6 to 9.6 hours. In 5 of 10 patients who have been on lisuride for at least 1 year, there has been no decline in efficacy.

Combined use of benserazide and carbidopa in Parkinson's disease.

The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa. Peak dopa levels are higher, occur sooner, but decline more rapidly with benserazide. Although many patients respond better to one drug than the other, we sought to exploit the differences in pharmacokinetics by giving both drugs to the same patient. Benserazide was combined with carbidopa in 38 patients who were experiencing a diminished response to carbidopa, including 22 patients with diurnal oscillations in performance, "wearing off" or on-off phenomena. Previous attempts to change the dose, sequence, or ratio of levodopa to carbidopa in these patients had been unrewarding. Ten of the patients improved on the combination of benserazide and carbidopa, with a 30% decline in disability. The mean dose of levodopa:carbidopa before benserazide was 910:100 (9 to 1 ratio); the mean dose of levodopa:benserazide was 355:90 (4 to 1 ratio). The mean dose of levodopa:carbidopa + benserazide was 925:155 (6 to 1 ratio). The combination of carbidopa with benserazide is useful in some parkinsonian patients.

Further studies with pergolide in Parkinson disease.

Pergolide was administered to 56 patients with advanced Parkinson disease who were no longer satisfactorily responding to levodopa. The group included 45 patients with on-off phenomena. Pergolide, when combined with levodopa, resulted in a 44% decrease in disability as assessed in the on period, a 15% decrease in disability as assessed in the off period, and a 148% increase in the number of hours in which patients were on (from 4.6 +/- 0.3 hours to 11.4 +/- 0.6 hours). All these changes were significant at 1%. Forty-one of the 56 patients (59%) improved when pergolide was added to levodopa. Mean dose of pergolide was 2.5 mg (range, 0.2 to 10.0 mg). Mean duration of the study was 13 months (range, 1 day to 34 months). Maximum improvement occurred within 2 months and began to decline, usually after 6 months. The major adverse effects necessitating discontinuing pergolide were the occurrence of an organic confusional syndrome (six patients), increased dyskinesias (four patients), and cardiovascular abnormalities (three patients). Nine patients discontinued pergolide because of a lack of effect or declining effect.

Long-term treatment with pergolide: decreased efficacy with time.

We studied the effect of pergolide (combined with levodopa) in 17 patients with Parkinson's disease, including 15 with "wearing off" or on-off phenomena, who had been taking pergolide for at least 2 years. Mean duration of the study was 27.8 months. All 17 patients improved initially, but the improvement later faded. Mean disability score, which decreased initially by 60% (significant), was decreased only by 20% after 2 years (not significant). Wearing off and on-off phenomena, which improved initially, became prominent again. Four patients lost all the improvement, nine patients lost much of the improvement, and four maintained much of the improvement. Mean dose of pergolide was 2.2 mg (range, 0.8 to 5.0 mg).

Temporal dissociation of the prehension pattern in Parkinson's disease.

This study assesses the reach to grasp movement of eight Parkinson and eight control subjects. The reach was of either 15, 27.5 or 40 cm. The grasp was either of a small (0.7 cm) or a large diameter (8 cm) dowel. When comparing Parkinson to control subjects, no differences were found in the regulation of movement parameters according to changes in object distance or size. However, for Parkinson's disease patients the onset of the manipulation component was delayed with respect to the onset of the transport component. It is proposed that this reflects a deficit in the simultaneous or sequential implementation of different segments of a complex movement.

Acute clonidine withdrawal syndrome following open-heart operation.

A patient who underwent cardiopulmonary bypass developed a syndrome of malignant hypertension with agitated delirium, unresponsive to antihypertensive agents, following abrupt withdrawal of clonidine. The literature on this syndrome is reviewed with emphasis placed on prompt recognition. The syndrome can be reversed by resumption of clonidine administration and can be prevented by maintenance of clonidine levels through the perioperative period.

Transient resolution of bilateral tremor after unilateral thalamotomy, associated with focal injury of the corpus callosum: case report.

We present a patient with Parkinson's disease whose bilateral tremor transiently resolved after a unilateral left ventrolateral thalamotomy. The transient resolution of the bilateral tremor was associated with a focal thalamic lesion and a second lesion in the corpus callosum. The mechanism of this phenomenon may be related to temporary disruption of descending bilateral corticostriate projections by the callosal lesion.

Long term survival among patients with malignant brain tumors.

Eight of 57 patients (14%) with malignant astrocytomas lived at least 2 years. The mean survival time was 143 weeks (range, 104 to 250 weeks). All of the patients were treated with operation, radiation, and chemotherapy. Four of the 8 patients died because of tumor recurrence, 1 died from a second primary tumor, 2 died of cases unrelated to the tumor, and 1 is still alive. Diffuse cortical dysfunction associated with cortical atrophy that could not be related to tumor regrowth and was not explained by focal deficits, psychotic of depressive thought disorders, metabolic or endocrine abnormalities, or hydrocephalus developed in the 3 longest-surviving patients. The diffuse dysfunction was initially apparent only through psychometric testing, but eventually became so disabling as to result in 2 of the 3 patients retiring from work. Although small, but gratifying, gains have been made in the treatment of patients with malignant brain tumors, accompanying these gains have been problems of a magnitude that is only now beginning to be appreciated.

Management of levodopa failures: the use of dopamine agonists.

In the past decade, dopamine agonists have emerged as important treatment options for patients with Parkinson's disease. Originally, dopamine agonists were used only in patients with advanced disease in whom the response to levodopa had decreased (levodopa failures). The decreased response to levodopa, usually associated with diurnal oscillations in performance and the 'wearing-off' and 'on-off' phenomena, is secondary to disease progression with continued degeneration of the nigrostriatal neurons. In addition, chronic levodopa treatment itself may contribute to the decreased drug response and the diurnal oscillations in performance. Dopamine receptor agonists bypass the degenerating nigrostriatal neurons and directly stimulate the striatal dopamine receptors. Dopamine receptor agonists also permit a reduction in the dose of levodopa. Five ergoline dopamine agonists--bromocriptine, lergotrile, pergolide, lisuride, mesulergine, and the nonergoline agonist, ciladopa--have undergone clinical trials in Parkinson's disease. In 10 years, we treated a total of 278 patients with advanced Parkinson's disease, a declining response to levodopa, and diurnal oscillations in performance with five ergoline dopamine agonists (in addition to levodopa). The mean duration of treatment was one year (with a range of 1-60 months). Improvement was noted in 140 (50%) of our patients. Adverse effects necessitating discontinuation of the agonist occurred in 131 patients (46%). We compared our results with those of others who, unlike us, began treatment with a dopamine agonist earlier, using the agonist alone or adding it to levodopa before the response to levodopa had decreased. Many of the patients so treated had mild or moderate Parkinson's disease. A total of 1,599 patients were treated with ergoline dopamine agonists. Of these patients, 976 (61%) improved, while 407 (25%) experienced adverse effects. We believe that a greater number of these patients improved and fewer experienced adverse effects, in comparison to our patients, because the patients had less advanced disease.

Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease.

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the "tyramine effect," may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the "on" state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p less than 0.01 for each parameter). No significant improvement occurred in the objective quality of the "on" state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.

The effects of pergolide on the cardiovascular system of 40 patients with Parkinson's disease.

The effect of pergolide, a semisynthetic ergot alkaloid, on the cardiovascular system of 40 patients with Parkinson's disease (PD) was evaluated. The mean daily dose of pergolide was 2.4 mg (range, 0.1 to 10 mg). The mean duration of follow-up was 6 months (range, 2 weeks to 20 months). The 40 patients were selected only on the basis of severe PD. All 13 patients in the first part of the study underwent 1 to 5 days of Holter monitoring before starting pergolide. Monitoring was then carried out for an additional period of between 2 and 10 weeks while the patients were on pergolide. Seven of the 13 patients manifested repetitive ventricular rhythms. These were isolated and unassociated with increases in premature ventricular contractions. The dose at which the RVRs occurred was a function of the presence or absence of heart disease. The changes occurred below 3 mg/day in patients with heart disease and above 3 mg/day in patients without heart disease. Pergolide was discontinued in three of the patients with heart disease. It was concluded that pergolide may, in the diseased heart, predispose to RVRs. In the second part of the study, Holter monitoring was carried out only at the discretion of the cardiologist, and five patients were so monitored. None of these patients was rejected from the study. Only one patient (with heart disease) of the 27 patients in the second part of the study experienced an arrhythmia. This consisted of an increase in PVCs on 4 mg/day of pergolide. Pergolide was discontinued. Eight of the 40 patients in these early dose-ranging studies experienced orthostasis, two with syncope, immediately on addition of pergolide (0.1 to 0.4 mg) to levodopa. The orthostasis could be eliminated in all but two patients by reducing or discontinuing levodopa.

Pergolide and lisuride in advanced Parkinson's disease.

In a retrospective study, treatment with lisuride was compared to pergolide in 25 patients with advanced PD in whom the response to levodopa had diminished. Sixteen patients had wearing off and/or ON-OFF phenomena. Lisuride or pergolide, when added to levodopa, resulted in comparable and significant decreases in disability in both ON and OFF periods; pergolide resulted in a greater increase in the number of hours in which patients were ON. Adverse reactions were comparable on both drugs. However, patients who developed an adverse reaction on one drug did not necessarily develop the same reaction on the other drug. Both lisuride and pergolide are effective anti-Parkinson drugs.

Comparative efficacy of pergolide and bromocriptine in patients with advanced Parkinson's disease.

Treatment with pergolide was compared with bromocriptine in 25 patients, all of whom were also receiving levodopa and in all of whom the response to levodopa had diminished. All 25 patients had "on-off" phenomena. At the time bromocriptine was added to levodopa, the mean age of the patients was 61.8 years, mean duration of disease was 9.0 years, and mean duration of levodopa treatment was 6.1 years. For the group as a whole, disability as determined in the "on" period decreased by 36%, from 28.7 to 18.5; and 11 patients improved at least one stage. Disability as determined in the "off" period decreased by 25%, from 59.5 to 44.4. The number of hours in which patients were "on" increased by 62%, from 7.1 to 11.5. All of these changes were significant (p less than or equal to 0.05). Bromocriptine had to be discontinued in nine patients (eight because of mental changes). In the remaining 16 patients, bromocriptine was eventually discontinued because of diminishing efficacy. Mean dose of bromocriptine was 50 mg (range, 10-100 mg), and mean duration of treatment was 23 months (range, 2-65 months). At the time of their treatment with pergolide, the patients were older, 65.5 years, had the disease longer, 12.7 years, and were more disabled. Nonetheless, for the group as a whole, disability score as determined in the "on" period decreased significantly by 40%, from 43.5 to 26.3, and 14 patients improved at least one stage. Disability as determined in the "off" period decreased significantly by 21%, from 69.0 to 54.8. The number of hours in which patients were "on" increased significantly by 224%, from 3.4 to 11.0 hr. The mean dose of pergolide was 2.1 mg (range, 0.1-10.0 mg), and the mean duration of treatment was 6.2 months (range, 0.5-20 months). Pergolide was discontinued in eight patients: three because of asymptomatic tachyarrhythmias of unknown clinical significance (detected only by Holter monitoring); two because of orthostatic hypotension; and two because of mental changes. Although pergolide appears to be more potent than bromocriptine because of its greater effect in a larger number of patients at a more advanced stage of their disease, both drugs are useful, and both enhance our ability to manage patients with PD.

Point of view: Dementia in Parkinson's disease.

The prevalence of dementia in Parkinson's disease (PD) was analyzed in eight reports from peer-reviewed journals. Each report examined at least 100 patients, the period covered being 1966 to 1996. Among 1907 patients, 513,27%, were demented. The prevalence of dementia was similar in prospective and retrospective reports, and in clinic- and community-based reports. Demented patients were older than non-demented patients: 70.3 yr versus 64.3 yr. Disease duration was similar in demented and non-demented patients: 7.7 yr versus 7.9 yr. The incidence of dementia in PD was calculated from two prospective community-based reports and one retrospective clinic-based report. For the age range 55 to 64 yr, the incidence is 2.7 patients per 100 patients per year (2.7% per year). For the age range 70 to 79 yr, the incidence increased to 13.7%. For the age range 80 + yr, the incidence is 9.3%. The pathology of PD dementia was analyzed in 15 reports, each report examined at least 10 patients. Among 412 demented patients, 28%, had a pathology characterized primarily by Lewy bodies (Lbs) and 40% of the patients with Lbs (10% of all demented PD patients), had subcortical changes, only 60% of the patients with Lbs (17% of all demented PD patients), had subcortical and cortical Lbs. Among the 412 demented patients, 72%, the pathology consisted of subcortical Lbs and cortical AD changes: plaques and neurofibrillary tangles (nfts). Some of these patients also had cortical Lbs. It is postulated there are two types of PD dementia, and by inference two types of PD. One type, which may include familial PD, is characterized by cortical Lbs. The second, related to AD, or frontotemporal dementia (FTD), is characterized by cortical senile plaques and nfts. As 90% of demented PD patients have cortical changes, it is argued that PD dementia should be referred to as a cortical not a subcortical dementia.

Prevalence of tremor and Parkinson's disease.

To determine the prevalence of essential tremor (ET) and Parkinson's disease (PD) in a retirement community, all residents of Carefree, Arizona, aged over 65 years were contacted. All participants completed validated questionnaires for PD and ET, and were examined using the Unified Parkinson's Disease Rating Scale. Of 356 individuals evaluated, 155 (43.5%) had tremor; 73 (20.5%) had ET; 26 (7.3%) had PD; and 56 (15.7%) had postural tremor (PT). Thus, a large percentage of individuals were found to have tremor, in the plurality of whom it could be classified as ET. The number of individuals with Parkinson's disease exceeded our expectations.