Clinical aspects and pathogenesis of the "on-off" phenomenon in Parkinson syndrome

It was the aim of our study based on a group of 460 patients suffering from Parkinson's disease to find out possible pathogenetic linkups for the so-called "on-off" phenomenon. The method was based on two questionnaires of different structure, and in 90 cases we also called personally on the patient in his home. The patients were either known from neurological treatment they received at the Department of Neurology of the University of Essen, or were approached on-target via their membership in the German Parkinson Association. After evaluation, 43 patients with an on-off phenomenon and 81 with end-of-dose akinesia, as well as 336 patients without fluctuations of motility, could be classified and evaluated further. All patients with an on-off phenomenon or end-of-dose akinesia had received L-dopa treatment for several years; the average treatment period was 8.4 years in a patient with on-off phenomenon and 7.3 years in case of end-of-dose akinesia. Compared therewith, patients without fluctuations had only an average L-Dopa intake period of 5 years. It is a striking fact that in the patient group without fluctuations (n = 336) 51 patients (15.7%) had never taken an L-dopa preparation. 72.1% of the on-off group suffered from hyperkinesia before abrupt onset of the phase, while at the same time a recession of L-dopa efficacy was seen after several years of treatment. In about 40% of the questioned on-off patients we found that end-of-dose akinesia had preceded the on-off condition, and that the time correlation of the akinesia with the intake of the preparation was gradually abandoned. The age of the patients with on-off or end-of-dose patterns was, at the time of diagnosis, 55.6 or 54.2 years respectively. These patients were therefore much younger on the average than those of the comparative group without any disturbance of motility (60.1 years). On-off patients suffered comparatively more often from concomitant cardiovascular disease and their more active smoking habits were very noticeable. Taking the pathological specialities into consideration, it is recommended to critically reconsider the early use of L-dopa in relatively young patients with concomitant cardiovascular diseases, and to give preference in case of an indication for L-dopa to a combination treatment especially with MAO-B inhibitors and dopamin antagnonists in order to keep the daily L-dopa dose low. Arguments against L-dopa to be taken three times daily are discussed, as are the pros and cons of concomitant therapy.     

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study

Summary Long-term levodopa treatment in Parkinson's disease is typically associated with motor side effects consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit.Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p=0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p=0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with >50% substitution by bromocriptine exhibited half the risk observed in those with <30% (p=0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p=0.046).In conclusion, partial substitution of levodopa by bromocriptine (>30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.Dedicated to Dr. H. Bühlmann on the occasion of his 80th birthday     

Treatment of the on-off syndrome in Parkinsonism with low dose bromocriptine in combination with levodopa.

The addition of bromocriptine, given in divided doses up to 30 mg per day, to conventional anti-Parkinsonism therapy has been studied in a double-blind placebo controlled clinical trial in 11 patients with Parkinsonism with the "on-off" syndrome. Four patients withdrew because of side effects. Of the seven remaining, three had clinical benefit from bromocriptine with reduction in severity and frequency of fluctuations. There was, however, no statistically significant benefit of bromocriptine when the group as a whole was assessed in terms of severity or frequency of fluctuations measured by three different methods. The mean frequency of major fluctuations on placebo was 2.9/day and on bromocriptine 1.8/day (P less than 0.1 greater than 0.05). There appears to be a limited role for bromocriptine as additional therapy in the management of some patients with the on-off syndrome.     

A double-blind, controlled study of high-dose L-deprenyl in the treatment of Parkinson's disease

The conventional dose of deprenyl used in Parkinson's disease is 10 mg/day, having been established by in vitro platelet studies and clinical evaluation. Twelve patients with Parkinson's disease on treatment with L-dopa who showed evidence of wearing-off effects or motor oscillation were studied in a double-blind, placebo-controlled, crossover trial to compare conventional doses of deprenyl with higher doses (up to 40 mg/day) and placebo. We did not find higher doses of deprenyl to be superior to conventional doses and in 17% of cases treatment had to be withdrawn because of side effects.     

Sexuelle Delinquenz und Morbus Parkinson

The risk of aberrant sexual behaviour such as hypersexuality, exhibitionism, or pederasty may be underestimated in Parkinson's disease and its therapy with high-dosage L-dopa or dopamine agonists. We describe two legal cases which are representative of the forensic assessment of these side effects. The first case brought to court was a 45-year-old man suffering for 20 years from Parkinson's disease who developed hypersexuality and exhibitionism under high-dose therapy with ropinirol. The second patient, a 57-year-old man with an 11-year history of Parkinson's disease, developed increased libido and pederasty under therapy with L-dopa and bromocriptine. We discuss the present literature concerning hypersexuality and sexually deviant behaviour in Parkinson's disease and dopaminergic therapy in the German legal context. Doctors treating Parkinson patients should be aware of increased sexual impulses or reduced behavioural control and ask specifically about them during anamnesis, and counteractive therapeutic strategies should be considered to prevent the occurrence of illegal sexually aberrant behavioural disorders.     

Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications?

Levodopa-carbidopa (LD) in low dosages adequately controls symptoms in most patients with Parkinson's disease and delays the appearance of fluctuations and dyskinesias. It has been suggested that early combination therapy with bromocriptine and levodopa delays or prevents the onset of late treatment complication associated with LD monotherapy in Parkinson's disease. We have conducted this study to assess the possible benefit of combined therapy compared with levodopa monotherapy. Seventy-eight previously untreated patients with Parkinson's disease were recruited over a period of 54 months and randomly allocated to either a levodopa-carbidopa (LD) Group or a levodopa-carbidopa in combination with low-dose bromocriptine (LD-Br) Group. The appearance of motor complications determined the end point of the study. We gradually increased the doses of bromocriptine (2.5–15 mg/d) or levodopa (125–500 mg/d) until the maximum "on" time was reached. In six patients, the doses of levodopa had to be increased up to the optimal dose (625–1000 mg/day). In the last evaluation the on-time and parkinsonian disability were similar in both treatment groups. We did not find statistically significant differences in the frequency of motor complications when comparing the two groups of treatment. Our study suggests that early combination of levodopa and bromocriptine does not confer any clinical benefit over levodopa alone in treating early Parkinson's disease, nor will it influence the evolution of the disease.     

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.     

Comparison of bromocriptine and levodopa as first line treatment of Parkinson's disease: results of a 3-year prospective randomized study

The long term effects of a first line treatment with levodopa or bromocriptine were compared in 36 previously untreated patients with Parkinson's disease in a prospective randomized trial: 18 patients were treated with levodopa alone (mean dose: 485 +/- 71 mg daily) whereas 18 others received bromocriptine alone (mean dose: 55 +/- 6 mg daily) during 36 +/- 3 and 31 +/- 3 months respectively. We observed a similar decrease in the Columbia rating scale but the nature of long term side effects was different in the two groups: patients on levodopa developed peak-dose dyskinesias (5 cases), wearing off akinesia (1 case) and on-off effects (1 case). Under bromocriptine treatment, 2 patients developed severe psychosis whereas one suffered from primary lack of drug effectiveness and 5 others from late decrease of drug effectiveness. These results suggest the potential value of relatively high doses of D2 dopamine agonists (such as bromocriptine) in the first line treatment of Parkinson's disease: however, their use can be limited by their decrease of effectiveness after several years and/or the occurrence of severe neuropsychiatric side-effects.     

Influence of dietary protein on motor fluctuations in Parkinson's disease

On a nearly zero protein diet, 11 patients with Parkinson's disease with the "on-off" effect demonstrated great sensitivity to levodopa (L-dopa)-carbidopa and reduced fluctuations. Eight patients required a 41% reduction in total L-dopa dosage and discontinuation of all adjuvant therapy to reduce the preponderance of chorea. On a high-protein diet, all patients were immobilized by bradykinesia for most of the day. A low-protein dietary regimen during the daytime offers an important technique for the control of fluctuations in patients with Parkinson's disease who are receiving L-dopa-carbidopa.     

Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years.

One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinson's disease have survived. The original study compared low-dose levodopa with low-dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L-dopa-induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long-term problems of Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's disease should be judged by their ability to improve non-L-dopa-responsive aspects of the disease, rather than just by their capacity to delay the introduction of L-dopa or reduce its associated side effects.     

CSF studies on the relationship between dopamine and 5-hydroxytryptamine in Parkinsonism and other movement disorders.

In Parkinson's disease, the concentration of homovanillic acid (HVA) was reduced in lumbar CSF from patients with idiopathic Parkinsonism (n = 54, P less than 0.05) and post-encephalitic Parkinsonism (n = 19, P less than 0.01). The reduction in the concentrations of 5-hydroxyindolylacetic acid (5-HIAA) was not significant, and there was no alteration in the levels of 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). Treatment with L-dopa increased the concentration of HVA in the CSF (P less than 0.05) but had no effect on the levels of 5-HIAA and MHPG. Carbidopa given in combinations with L-dopa produced similar CSF concentrations of dopa as did L-dopa alone but caused less than half the rise in HVA. Fourteen patients who became functionally independent on treatment with L-dopa had higher 5-HIAA levels than 23 patients who showed no such improvement (P less than 0.001), suggesting that intact 5-hydroxyltryptamine neurones may be important in the therapeutic response to L-dopa. In a variety of movement disorders, the levels of HVA, 5-HIAA, and MHPG were not significantly different from age-matched controls. Treatment with tetrabenazine did not significantly alter the metabolite levels in patients in whom it produced either improvement, or side effects.     

Treatment of Parkinson's disease: Problems with a progressing disease

Summary Long-term follow-up of parkinsonian patients has shown that although levodopa treatment significantly improves the parkinsonian symptoms and the quality of life of parkinsonian patients for several years, various distressing difficulties arise during chronic levodopa treatment, such as the loss of benefit, dyskinesias, on-off phenomena, postural instability and dementia. Clinical, neuropsychological, mortality and post-mortem brain studies indicate that levodopa as a replacement therapy does not modify the progression of the underlying pathology and the natural course of the disease. It seems that levodopa has only a limited period of optimal usefulness in the treatment of Parkinson's disease. However, at present there is no better or more potent therapeutic agent available than levodopa and it is still the primary treatment of Parkinson's disease. It would be reasonable not to begin levodopa treatment in patients with mild symptoms but to withold levodopa until the severity of symptoms really makes its use necessary. Thus it is possible to get the maximal long functional benefit.Post-mortem brain studies have shown that in Parkinson's disease there is not only a progressive loss of dopaminergic substantia nigra neurons but there are also significant changes in the striatal dopamine receptors. In some patients a denervation supersensitivity seems to develop and in some others a loss of dopamine receptors in the striatum. However, in advanced parkinsonian patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors directly to improve the parkinsonian disability. Indeed, recent evidence indicates that dopaminergic agonists, such as bromocriptine, seem to be a significant and valuable adjuvant therapy to levodopa in parkinsonian patients with a deteriorating response and/or the on-off phenomena. Although bromocriptine is not completely satisfactory, it is a significant opening to a new mode of treatment. In the future it will be very important to develop more potent and selective dopaminergic agonists affecting only those striatal receptors which are mainly responsible for the parkinsonian symptoms. Then a better therapeutic response is likely to occur and many central side effects can be avoided.Current difficulties in the management of Parkinson's disease greatly depend on the fact that we are dealing with a symptomatic therapy. It is hoped that future research will soon lead to a discovery of the primary cause and consequently to a causal therapy of Parkinson's disease.     

Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases

Seven patients developed chronic and severe parkinsonism after repeatedly injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously. Levodopa and bromocriptine controlled the symptoms; however, within months, five of the seven patients experienced dyskinesias or on-off fluctuations. Therefore, neither prolonged levodopa treatment nor progressive disease was necessary for on-off phenomena. Because the neurotoxic effects of MPTP seem limited to the substantia nigra, damage to this system alone may produce all the motor features of Parkinson's disease. MPTP differs from other neurotoxins in that it consistently produces a pure parkinsonian state.     

Long-term bromocriptine treatment of de novo patients with Parkinson''s disease. A seven-year follow-up

Thirty-nine de novo patients with Parkinson's disease were treated with bromocriptine alone and followed on average for 5.9 years. Fifteen of the 39 patients did not complete the first year of observation, 12 of them because of drug intolerance. The symptomatology was tolerated well by other 24 for the first 2 years treatment. During the third year of follow-up levodopa treatment had to be instituted because of loss of response to bromocriptine. The number of fluctuations in disability was smaller in the patients whose symptomatology was controlled by bromocriptine monotherapy than in those requiring levodopa, either alone or combined with bromocriptine.     

Smooth pursuit during dose-related on-off fluctuations in Parkinson's disease

Smooth pursuit was studied during predictable L-dopa dose-related "off" periods of morning akinesia and wearing off and during "on" periods in eight patients with idiopathic Parkinson's disease. Smooth pursuit gain was significantly reduced in patients during both on and off phases. Despite marked fluctuations between parkinsonism and periods of near normal skeletal motion, there were no changes in smooth pursuit gain. We conclude that unvarying paresis of smooth pursuit in Parkinson's disease signifies involvement of neural circuits that are distinct from the dopaminergic mechanisms that mediate the on-off phenomenon of somatic motor control.     

Treatment of Parkinson's disease with sodium valproate: clinical, pharmacological, and biochemical observations.

Because there is biochemical evidence of decreased GABAergic function in Parkinson's disease, sodium valproate, an inhibitor of GABA catabolism, was administered to eight Parkinsonian patients. Valproate treatment did not significantly alter any Parkinsonian feature, but tended to increase the dyskinesia in the "on-off" patients. The increased dyskinesias were not a result of altered peripheral metabolism of L-dopa. Despite obtaining high plasma levels of valproate, no consistent alteration of CSF GABA levels could be demonstrated. Thus, in these patients, an effect of valproate on GABA metabolism is unproven, and in turn, the role of GABA in Parkinsonism and dyskinesia uncertain.     

A six-month multicentre, double-blind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by L-dopa

OBJECTIVES: To compare the safety and efficacy of ropinirole and bromocriptine as adjunct therapy in patients with Parkinson's disease (PD) not optimally controlled by L-dopa. METHODS: A randomised, double-blind trial in which 555 patients were assigned to three treatment groups according to the level of daily dosage of L-dopa, presence of motor fluctuations, and use of dopamine agonist before study entry. Patient response was defined as at least a 20% reduction in daily L-dopa dose plus: for patients with no prior treatment and no motor fluctuations, a 20% reduction in UPDRS motor score; for patients with motor fluctuations, a 20% reduction in time spent "off"; and for patients already taking an agonist, an improvement on the CGI scale. RESULTS: Safety assessments showed no significant differences in the two treatment groups for patients without prior dopamine-agonist therapy. In the group of patients with prior dopamine-agonist therapy, more patients reported adverse events in the ropinirole group (90% versus 79%, p < 0.001). The proportions of responders tended to be higher in ropinirole groups compared with bromocriptine groups and, in the subgroup with motor fluctuations, this difference was statistically significant (9.1% versus 0.0%, respectively; p < 0.05). CONCLUSIONS: Both drugs were well tolerated. In patients receiving a relatively high dose of L-dopa and requiring the addition of a dopamine agonist to control motor fluctuations or dyskinesias, ropinirole was significantly more effective than bromocriptine.     

Bromocriptine: long-term low-dose therapy in Parkinson's disease

Low-dose bromocriptine therapy (average dose 14.5 mg/day at 2 years) produced significant improvement in 25 of 39 parkinsonian patients. Bradykinesia was less in de novo subjects; tremor and rigidity improved most in the levodopa subjects. Five of six patients improved after a low-dose bromocriptine drug "holiday." After the addition of bromocriptine any reductions in levodopa dosage were small, with repeated cuts made gradually over months preventing the deterioration commonly seen with larger sudden reductions in levodopa dosage. Five patients withdrew because of intolerable adverse effects, two because of worsening response. Adverse effects were mild and generally dose dependent, and in some patients they disappeared without reduction in continuing bromocriptine therapy. Eighty percent of those who tolerated bromocriptine maintained response over 2 years. Bromocriptine did not induce dyskinesia, the wearing-off response, or the on-off phenomenon in de novo subjects and was used as a first choice drug in these parkinsonian patients. Best results were obtained from a combination of bromocriptine and levodopa.     

Impaired cardiovascular autonomic control in newly and long-term-treated patients with Parkinson's disease: involvement of L-dopa therapy

In idiopathic Parkinson's disease (PD), autonomic dysfunction is frequent, causing orthostatic hypotension. The respective roles of disease progression and dopaminergic treatment remain unclear. In this study, we investigated the autonomic control of cardiovascular functions and its relation to L-dopa therapy in both newly diagnosed (ND) and long-term-treated (LT) patients. Study subjects were: (1) nine ND patients never having undergone treatment with L-dopa; (2) 18 LT patients who had been receiving L-dopa treatment for a long period. ND patients were investigated before L-dopa treatment and after stabilization of their L-dopa dosage. LT patients were investigated once with their regular treatment and once after a 12-h interruption of L-dopa treatment; (3) nine healthy subjects served as controls. At each test session, blood pressure (BP), heart rate (HR), plasma catecholamines, heart rate variability (HRV), and spontaneous baroreflex sensitivity were assessed in the supine and upright positions. Before receiving L-dopa medication, ND patients had reduced E/I ratios (HR response/deep breathing) and lowered HRV when compared to controls; this was evidence of early effects of the disease on autonomic HR control. Introduction of L-dopa treatment reduced BP, HR, and plasma levels of adrenaline and noradrenaline. Similar changes were found in LT patients when contrasting the short-term treatment interruption and the usual L-dopa dosage. The treatment-linked increase in plasma dopamine also correlated with the decrease in noradrenaline. These results showed that mild impairment of autonomic cardiovascular control occurred early in the course of PD. They also provided evidence that the side effects of L-dopa aggravated the impairment of the autonomic control of BP and HR.     

A six-month multicentre,double-blind,bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by <Emphasis Type="SmallCaps">l</Emphasis>-dopa

Summary. Objectives: To compare the safety and efficacy of ropinirole and bromocriptine as adjunct therapy in patients with Parkinson's disease (PD) not optimally controlled by L-dopa. Methods: A randomised, double-blind trial in which 555 patients were assigned to three treatment groups according to the level of daily dosage of L-dopa, presence of motor fluctuations, and use of dopamine agonist before study entry. Patient response was defined as at least a 20% reduction in daily L-dopa dose plus: for patients with no prior treatment and no motor fluctuations, a 20% reduction in UPDRS motor score; for patients with motor fluctuations, a 20% reduction in time spent "off"; and for patients already taking an agonist, an improvement on the CGI scale. Results: Safety assessments showed no significant differences in the two treatment groups for patients without prior dopamine-agonist therapy. In the group of patients with prior dopamine-agonist therapy, more patients reported adverse events in the ropinirole group (90% versus 79%, p < 0.001). The proportions of responders tended to be higher in ropinirole groups compared with bromocriptine groups and, in the subgroup with motor fluc-tuations, this difference was statistically significant (9.1% versus 0.0%, respectively; p < 0.05). Conclusions: Both drugs were well tolerated. In patients receiving a relatively high dose of L-dopa and requiring the addition of a dopamine agonist to control motor fluctuations or dyskinesias, ropinirole was significantly more effective than bromocriptine. Received January 31, 2001; accepted October 23, 2001