帕金森病患者运动障碍和症状波动的影响因素

目的 观察帕金森病患者运动障碍和症状波动发生情况，探讨两者发生的影响因素。方法 对确诊的帕金森病患者进行随访，记录患者详细资料并进行UPDRS、H-Y分级、Schwab和英格兰日常生活量表评分，观察有无运动障碍和症状波动发生。对所得资料进行统计分析。结果 63例帕金森病患者均接受左旋多巴治疗，观察发现11例(17．5%)出现运动障碍，其中10例表现为肌张力障碍；36例(57．1％)出现症状波动，其中28例表现为剂末现象。左旋多巴平均日剂量(r=9．768，P=0．001)、UPDRS—off评分(r=0．076，P=0．008)与运动障碍呈正相关，左旋多巴治疗时间与症状波动呈正相关(r=0．738，P=0．002)，控释剂的使用与其呈负相关(r=-3．378，P=0．015)。结论 本组患者运动障碍的发生率较低，而症状波动的发生率与国外报道相近，左旋多巴平均日剂量和病情严重程度是运动障碍的主要影响因素，其治疗时间是症状波动的影响因素。运动综合征主要表现为剂末现象和肌张力障碍。     

High-dose treatment with pergolide in Parkinson's disease patients with motor fluctuations and dyskinesias

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.     

rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease

The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.     

Amantadine infusion in treatment of motor fluctuations and dyskinesias in Parkinson's disease

Efficiency and safety of amantadine sulfate (AMS) infusions were investigated in late stage complications of Parkinson's disease (PD). In an open-label study, 21 PD patients suffering from motor fluctuations and/or dyskinesias were administered AMS infusions (PK-Merz, 400 mg per day) during seven days. Oral AMS treatment followed. Significant improvement of UPDRS motor scores was observed between day 0 and day 7, remaining improved until day 21. Based on patients' diary notes, both severity and occurrence of hypokinetic "off" state significantly decreased (from 6.6 to 3.1 hours, p < 0.001, average "off" time per day) as well as dopaminergic-induced dyskinesias (from 2.5 to 1.3 hours, p < 0.05, average duration of dyskinesias per day). AMS infusions followed by oral administration appeared as a safe method for improvement of both motor fluctuations and dyskinesias in advanced PD. In advantage to simple oral therapy, AMS infusions allowed fast introduction of a profound and durable treatment effect.     

Comparison of motor fluctuations and l-dopa-induced dyskinesias in patients with familial and sporadic Parkinson''s disease

The aim of the present work was to study the characteristics of motor complications in a group of familial Parkinson's disease (fPD) patients in comparison with matched sporadic PD (sPD) patients. Fifty-one fPD and 51 sPD patients matched for age and disease duration, used as controls, were included in the study. The Unified Parkinson's Disease Rating Scale was completed during clinical examination and all patients were questioned about the characteristics of motor complications. The mean time from start of L-dopa therapy to the onset of motor fluctuations (MF) and L-dopa-induced dyskinesias (LID) as well as the mean time from symptom onset to the development of MF and LID was significantly shorter in the fPD group of patients. An analysis revealed a higher occurrence of MF and LID in fPD patients in the group with disease duration of 5 years or less. FPD may be associated with a higher prevalence and earlier onset of motor complications during the initial stages of the disease. Genetic factors may contribute to the specific characteristics of motor complications in fPD.     

Inhibition of the COMPT with entacapone in the treatment of motor fluctuations in Parkinson disease

Motor fluctuations are a common problem in the long-term treatment of Parkinson's disease (PD). Entacapone (Comtan) is a potent, peripherally acting, reversible and selective inhibitor of catechol-O-methyltransferase (COMT). Used as an adjuvant to levodopa therapy, entacapone slows the elimination of levodopa by decreasing peripheral conversion to 3-O-methyldopa, increasing central extracellular levodopa and striatal dopamine concentrations. Coadministered with levodopa/carbidopa or levodopa/benserazide, at doses of 200 mg 2 to 10 times daily in patients with end-of-dose fluctuations, entacapone may increase the duration of clinical response, both after the first single dose and after repeated dosing. At this dosage, it has a time to peak plasma concentration of 1.2 h and an elimination half life of 3.4 h. In two multicentric, long-term (24 weeks), parallel, randomized and placebo-controlled studies, entacapone increased the duration of 'on' time (by approximately 1 hour daily) and decreased the duration of 'off' time with a concomitant reduction in the mean daily levodopa dose. In these and other phase III studies, entacapone was generally well tolerated, with most adverse effects being dyskinesias and gastrointestinal disorders. Increased dyskinesia were generally controlled by reducing levodopa doses. Entacapone appears to be a useful adjunct in extending the benefit of each levodopa dose in PD patients with end-of-dose fluctuations.     

Therapies for dopaminergic-induced dyskinesias in Parkinson disease

Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents.     

Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations.

The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients.     

Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease]

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.     

Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease

OBJECTIVE: To evaluate factors associated with pathological gambling (PG) in Parkinson disease (PD). DESIGN: Case-control study. SETTING: Outpatient tertiary clinic. Patients Twenty-one patients with idiopathic PD with PG after the patients began receiving medications compared with a consecutive sample of 42 patients with idiopathic PD without compulsive behaviors. MAIN OUTCOME MEASURES: Clinical features, comorbid psychiatric and substance use disorders, personality traits, and impulsivity scores. RESULTS: Patients with PG had a younger age at PD onset (P = .006), higher novelty seeking (P<.001), medication-induced hypomania or mania (P = .001), impaired planning (P = .002), or a personal or immediate family history of alcohol use disorders (P = .002). Novelty seeking, a personal or immediate family history of alcohol use disorders, and younger age at PD onset accurately predicted PG at 83.7% in a logistic regression model, with the model accounting for 62% of the variance. CONCLUSIONS: Patients with PD having a younger age at PD onset, higher novelty seeking traits, and a personal or family history of alcohol use disorders may have a greater risk for PG with dopamine agonists.     

A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations

BACKGROUND: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN: A double-blind, randomized, comparative clinical trial. SETTING: Forty-four sites in the United States and Canada. PATIENTS: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE: Change from baseline in total daily TTON as measured using home diaries. RESULTS: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.     

Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson's disease

Pharmacotherapy designed to alleviate the symptoms of Parkinson's disease is focused on the stimulation of striatal dopamine receptors. The ideal pharmacological treatment would involve continuous dopaminergic stimulation. Currently, the most effective pharmacotherapy available is levodopa delivered orally; however, its short plasma half-life in combination with erratic gastric emptying and intestinal absorption makes dopaminergic stimulation pulsatile. Motor fluctuations and dyskinesias develop with time as a consequence and can become disabling. A gel formulation of levodopa/carbidopa has been developed for enteral (duodenal or jejunal) infusion via a portable pump. The infusion provides smooth plasma levodopa levels, more continuous dopaminergic stimulation and effective treatment of motor complications.     

Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations.

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.     

Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease

Parkinson disease is one of the most common neurodegenerative diseases in the United States, and the number of late stage patients is rising. In advance-stage disease, fluctuations in motor function, variability in response to dopaminergic therapy, and dyskinesias related to increasing doses of dopamine agonists and levodopa, present a variety of challenges to a managing physician. Traditional methods of treatment have concentrated on therapies to anticipate or prevent states of poor motor function. With the approval of apomorphine as a rapid-acting, subcutaneous injectable anti-Parkinson disease therapy, these off periods may now be treated with apomorphine as a "rescue" medication when they occur. This article reviews the pharmacology of apomorphine, the clinical data that support its use and suggest dosing and methods for initiating therapy in this challenging population of patients with Parkinson disease.