Jean-Louis Montastruc

Early Treatment of Parkinson’s Disease with Cabergoline Delays the Onset of Motor Complications

SummaryThis multicentre randomised double-blind 3- to 5-year trial was designed to assess whether initial therapy with cabergoline alone or in combination with levodopa prevents or delays the occurrence of long term motor complications in patients with early Parkinson’s disease.Patients eligible for study inclusion (n = 412) had early idiopathic Parkinson’s disease (Hoehn and Yahr stages 1 to 3) and had received no previous treatment with levodopa, selegiline or dopamine agonists. Patients were randomised to receive either cabergoline (0.25 to 4mg once daily) or levodopa (100 to 600 mg/day) titrated over a maximum period of 24 weeks. Once the optimum or maximum tolerated dose was achieved, it was maintained up to the end-point (development of motor complications confirmed at 2 consecutive 3-month visits) or up to a minimum of 3 years’ treatment. Open labelled levodopa was added in both treatment arms when the improvement in motor disability [Unified Parkinson’s Disease Rating Scale (UPDRS) factor III] decreased below 30% vs baseline. Both treatments improved motor disability, decreasing UPDRS factor III scores and factor II scores for activities of daily living.The development of motor complications (end-point) was significantly less frequent in patients treated with cabergoline than in levodopa recipients (22% vs 34%; p < 0.02). The relative risk of developing motor complications during treatment with cabergoline was more than 50% lower than with levodopa.Serious adverse events, either drug related or not, were slightly more frequent in cabergoline-treated patients (31%) than in those treated with levodopa (25%). The withdrawal rate in the cabergoline vs levodopa group was 16 vs 13%.In conclusion, the study shows that, in patients with early Parkinson’s disease, cabergoline is effective either as monotherapy or combined with levodopa. Moreover, starting treatment with cabergoline significantly delays the development of motor complications.

Prevalence of orthostatic hypotension in Parkinson’s disease

OBJECTIVES To investigate the prevalence of orthostatic hypotension and the nature of the postural events related to a fall in blood pressure in patients with Parkinson’s disease. METHODS Blood pressure was measured first in a supine position after a rest of at least 15 minutes and every minute during 10 minutes of an active standing up procedure. Orthostatic hypotension was considered as present when a fall of at least 20 mm Hg of systolic blood pressure was recorded. Postural events which occurred during the standing test were identified from a questionnaire and self reporting. Statistical analysis was performed to determine the relation between orthostatic hypotension and disease characteristics (duration, severity) and the use of antiparkinsonian drugs. Ninety one consecutive patients with Parkinson’s disease (48 women, 43 men, mean age 66 (SD 9) years) participated to the study. RESULTS A fall of at least 20 mm Hg of systolic blood pressure was found in 58.2% of the patients. Orthostatic hypotension was asymptomatic in 38.5% and associated with postural events in 19.8% of the patients. Symptomatic (but not asymptomatic) orthostatic hypotension was related to duration and severity of the disease and with the use of higher daily levodopa and bromocriptine doses. The analysis of the relation between the postural symptoms (and the need for standing test abortion) with the fall in systolic blood pressure allowed the identification of six clinical criteria specific of orthostatic hypotension. A direct relation between the postural changes in systolic blood pressure and the number of clinical events in this clinical scale was found. CONCLUSION The frequency of orthostatic hypotension in Parkinson’s disease is high and it is possible to establish a clinical rating scale which could be used to assess the effects of drugs employed in the management of orthostatic hypotension.

A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: a five year follow up.

This pilot study was performed to compare the occurrence of long term motor complications in Parkinsons disease when the introduction of levodopa was delayed by an initial treatment with high doses of bromocriptine alone. The trial was a prospective randomised controlled study comparing 31 previously untreated patients with Parkinsons disease initially given bromocriptine alone to which levodopa was later added (group B/D) and 29 other previously untreated patients with Parkinsons disease immediately given levodopa alone (group D). The end point was the occurrence of the first motor complications (wearing off or dyskinesia). Group B/D patients received bromocriptine (52 (SEM 5) mg/day) for 2.7 years, to which levodopa was later added (471 (SEM 46) mg/day). Group D patients received a comparable dose of levodopa alone (569 (SEM 47) mg/day). Both had similar disability scores at the end of the study. Motor complications were fewer and appeared later in group B/D than in group D (56% after 4.9 (SEM 0.5) years of treatment v 90% after 2.7 (SEM 0.5) years, p < 0.01). Wearing off appeared later (p < 0.01) in group B/D (4.5 (SEM 0.6) years) than in group D (2.9 (SEM 0.6) years). Peak dose dyskinesia occurred less often in group B/D patients (three v 14 cases, p < 0.01). This study showed that a three year initial monotherapy with high doses of bromocriptine followed by addition of levodopa delayed the occurrence of long term motor complications usually found in patients with Parkinsons disease treated with levodopa alone from the beginning.

Sleep attacks and Parkinson's disease treatment

Three patients with Parkinsons disease had so-called sleep attacks at the wheel while taking bromocryptine, lisuride pergolide, or piribedil. We believe that all dopamine agonists can induce sleep attacks.

Limitations of current Parkinson's disease therapy.

Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinsons disease in the early stages of the disease. However, once the “honeymoon” period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from “dopa‐resistant” motor symptoms (speech impairment, abnormal posture, gait and balance problems), “dopa‐resistant” nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug‐related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety. Ann Neurol 2003;53 (suppl 3):S3–S15

Prescription of drugs during pregnancy in France

A survey of the records of the French Health Insurance Service of drug prescriptions during pregnancy in 1000 women living in Haute-Garonne, southwest France, showed that 99% of the women received a prescription for at least one drug during pregnancy with a mean of 13.6 medications per woman. 1.6% of women received one or more prescriptions of drugs from the US Food and Drug Administration X category (fetal risk outweighs benefits). 59% of women had a prescription of drugs from the D category (fetal risk but benefits may be acceptable) and 79% of women were exposed to drugs for which information about safety in pregnancy was not available from animal or human studies.

Normal activation of the supplementary motor area in patients with Parkinson's disease undergoing long-term treatment with levodopa.

Regional cerebral blood flow (rCBF) changes in cortical motor areas were measured during a movement of the dominant right hand in 15 patients with Parkinsons disease deprived of their usual levodopa treatment, in 11 patients with Parkinsons disease undergoing long-term treatment with levodopa, and in 15 normal volunteers. The supplementary motor areas were significantly activated in the normal subjects and in the patients receiving levodopa but not in the patients deprived of levodopa. The contralateral primary sensory motor area was significantly activated in all three groups. The ipsilateral primary sensory motor cortex was not activated in the normal subjects and the non-treated patients but was in the patients treated with levodopa. It is concluded that the supplementary motor area hypoactivation which is observed in akinetic non-treated patients with Parkinsons disease is not present in patients undergoing long-term treatment with levodopa. This result suggests that (a) levodopa improves the functional activity of supplementary motor areas in Parkinsons disease and (b) there is no pharmacological tolerance to this effect. The ipsilateral primary motor cortex activation observed in the patients treated with levodopa could be related to levodopa-induced abnormal involuntary movements.

Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease

Dyskinesia is a frequent and disabling side effect in patients with Parkinsons disease treated with chronic dopatherapy. Preclinical data in the 1‐methyl‐4‐phenyl‐1,2,3,6,‐tetrahydropyridine (MPTP) monkey suggest that alpha‐2 antagonists may reduce dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia. We assessed, in a pilot randomised placebo‐controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha‐2 antagonist, on motor parkinsonian disability and L‐DOPA‐induced dyskinesia following an acute oral challenge of L‐DOPA in 18 patients with Parkinsons disease. The severity of L‐DOPA‐induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L‐DOPA. These results suggest that blocking alpha‐2 receptors in patients with Parkinsons disease might improve L‐DOPA‐induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long‐term management of dyskinetic patients with Parkinsons disease.

Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy

We studied mitochondrial respiratory chain function in skeletal muscle taken from 27 patients with idiopathic Parkinsons disease (PD; 21 Dopa-treated PD patients and 6 de novo patients), 5 patients with multiple system atrophy (MSA) and from 43 age-matched controls in order to determine the occurrence of mitochondrial respiratory chain abnormalities in parkinsonian syndromes. In our control subjects, we found a significant age-related decrease in the activity of respiratory chain complex I. As compared to carefully age-matched control subjects, activity of complex (NADH:ubiquinone reductase) was significantly lower in muscle mitochondria from patients with PD and MSA and a mean remaining activity < 30% of controls was observed. Mean activities of complexes III (ubiquinol:cytochrome c reductase) and IV (cytochrome c oxidase) were also lower in PD patients than controls, but a low activity (remaining activity < 30% of controls) was observed in only 5 PD patients for complex I and III or I and IV. No deficit in complex II activity (succinate:ubiquinone reductase) was observed. Our results support the hypothesis of a wide-spread mitochondrial complex I deficiency in PD and MSA as compared to age-matched controls, who showed age-related deficiency. This deficit can be found in de novo PD patients as well as in treated patients. The observed respiratory enzyme chain deficiency could not be explained by the dose and duration of L-Dopa or dopaminergic agonist treatment, the severity of the disease, anxiety or depression since no significant correlation was found between these parameters and enzyme complexes activities.

The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study.

AbstractObjectives: Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson’s disease. Study design and methods: This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson’s disease. A total of 419 levodopa-, DA-and selegiline-naive patients with newly diagnosed Parkinson’s disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1–5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8–2.9mg, with added levodopa at mean daily doses ranging from 322mg at year 1 to 431mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784mg. Thus, patients in the cabergoline group received >50% levodopa than patients in the levodopa group. Results: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001).Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients).Consistent improvements relative to baseline in average Unified Parkinson’s Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician-and patient-rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively.While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. Conclusion: This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson’s disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.