Management of levodopa-induced dyskinesias in Parkinson's disease

Journal of Neurology - Long-term administration of levodopa in Parkinson's disease (PD) can cause motor complications such as dyskinesias and motor response fluctuations. An increased risk is...     

Serotonergic involvement in levodopa-induced dyskinesias in Parkinson's disease

Levodopa-induced dyskinesias (LID) represent a substantial barrier to effective symptomatic management of Parkinson's disease, but current treatment options for this debilitating side effect are limited, despite an increasing understanding of their pathophysiology from animal models. Increasing evidence suggests that serotonin neurons have a pivotal role in the induction and maintenance of dyskinesias, and provide a promising target for anti-dyskinetic therapies. Here, we review the evidence for serotonergic involvement in dyskinesias from animal and human data, and highlight some of the translational gaps which may explain why the success of serotonin autoreceptor agonists as anti-dyskinetic agents in experimental models has failed to be replicated in clinical trials.     

Accelerometric assessment of levodopa-induced dyskinesias in Parkinson's disease.

Our objective was to develop parameters for objective ambulatory measurements of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). Twenty-three PD patients with mild to severe LID were submitted to a standardized protocol of 1-minute recordings during rest, talking, stress, and four activities of daily life (ADL). Patients were simultaneously monitored with portable multi-channel accelerometry (four pairs of bi-axial sensors mounted onto the most affected arm, leg, and at the trunk) and recorded by video. LID severity was assessed with a modified Abnormal Involuntary Movement Scale (m-AIMS). The signals were analyzed, and every 1/8-second interval the amplitude was obtained of the dominant frequency within 1-4 Hz and 4-8 Hz frequency bands (Amp1-4 and Amp4-8). For both measures, convergent validity, reproducibility, and responsiveness were determined. In absence of voluntary movements, a significant relation was found between Amp1-4 and Amp4-8 and m-AIMS. Repeated measurements during rest showed a high reproducibility (intraclass correlation coefficient = 0.90 [Amp1-4] and 0.86 [Amp4-8]). The extent to which LID increased with talking and stress correlated significantly (p = 0.02) between the objective and clinical measures (intraclass correlation for differences = 0.67). During ADL, LID occurred in a similar frequency band as voluntary movements and only Amp1-4 and Amp4-8 of the trunk and leg sensor remained highly correlated with m-AIMS. Although objective measures of LID are reliable and responsive, they fail to distinguish LID from voluntary movements. These measures are of value only when obtained during rest (all sensor sites) or during ADL when derived from those body segments that are normally not involved in these ADL tasks (trunk and leg).     

Bradykinesia in patients with Parkinson's disease having levodopa-induced dyskinesias

We investigated the likelihood that bradykinesia coexisted with levodopa-induced dyskinesias (LID) in 10 dyskinetic Parkinson's disease patients (DPD). Their motor performance was compared to that of 10 age/gender-matched non-dyskinetic patients (NDPD) and 10 healthy controls. Whole-body movement (WBM) and rapid alternating movements (RAM) at the wrist were recorded simultaneously using 6-degree of freedom magnetic motion tracker and forearm rotational sensors, respectively. WBM was recorded prior to, and while subjects performed pronation-supination movements of their dominant hand with maximal rotational excursion, and as fast as possible for 10s. RANGE, VELOCITY and IRREGULARITY of pronation-supination cycles were quantified to assess motor performance. Results show that DPD patients had greater WBM than NDPD and controls during rest and RAM performance, as expected. There were no differences in motor performance between DPD and NDPD groups for RANGE and VELOCITY, despite significantly longer disease duration for the DPD group (15.5+/-6.2 years versus 6.6+/-2.6 years). However, both the NDPD and DPD groups showed significantly lower RANGE and reduced VELOCITY compared to controls, suggesting the presence of bradykinesia. For IRREGULARITY, DPD patients showed increased fluctuations in pronation-supination cycle amplitude compared to NDPD and controls. However, the lack of correlation between WBM magnitude and IRREGULARITY within the DPD group (Spearman's rank order, rho = 0.31, p > 0.05), suggests that LID were not the primary cause of increased IRREGULARITY. In conclusion, our results demonstrated that bradykinesia can coexist with dyskinesias, suggestive of distinct neural circuits. Our results also demonstrated that the occurrence of LID is not inevitably accompanied with worsening of motor performance.     

Metoclopramide and pimozide in Parkinson's disease and levodopa-induced dyskinesias.

Metoclopramide is an antiemetic drug which occasionally produced acute dystonic reactions. Although known to interfere with central dopamine mechanisms, it is frequently used in Parkinson's disease to prevent levodopa-induced nausea and vomiting. In this study metoclopramide did not increase Parkinsonism or reduce levodopa-induced involuntary movements in patients with Parkinson's disease. Pimozide, by contrast, increased Parkinsonism and reduced involuntary movements. The capacity of metoclopramide to produce acute dyskinesias while being apparently free of Parkinsonism effects is pharmacologically unique and differentiates this drug from the phenothiazines and butyrophenones.     

Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias

Levodopa-induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa-induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [¹¹C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [¹¹C]diprenorphine to assess changes in cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.     

Effects of etybenzatropine and diazepam on levodopa-induced diphasic dyskinesias in Parkinson's disease

Levodopa-induced onset and end-of-dose dyskinesia are rare but disabling disorders. Although they can be attenuated by increasing and dividing the daily dose of levodopa, this does not constitute a therapeutic approach. In this pilot study, etybenzatropine, an anticholinergic drug, and diazepam, a selective benzodiazepine, were administered in addition to a single dose of levodopa in nine patients with Parkinson's disease. Both drugs tended to decrease the severity and the duration of onset and end-of-dose dyskinesia and to increase the duration of action of levodopa on parkinsonian symptoms.     

Poor self-awareness of levodopa-induced dyskinesias in Parkinson's disease: Clinical features and mechanisms

ObjectivesTo study the factors and possible mechanisms associated with decreased self-awareness of levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD).MethodsWe enrolled 30 PD patients with LIDs. Patients were video-recorded in an “on” phase while experiencing LIDs. LIDs were objectively rated by means of the Unified Dyskinesias Rating Scale (UDyRS) by two movement disorders specialists while examining the patients. Patients were asked to rate the body site and the severity of their LIDs according to the 5-point UDyRS. Patients then rated their own LIDs while watching the video recording of themselves. Lastly, the patients rated the LIDs of other reference PD patients on a video recording. The same reference video recordings were shown to 15 healthy individuals matched for age, gender and education.ResultsSeven of the 30 PD patients investigated were subjectively unaware of the presence of their LIDs. The majority of patients, however, recognized their LIDs when watching video recording of themselves. Patients displayed a specific poor self-awareness of trunk LIDs, in both the subjective evaluation and in the video recording-based subjective evaluation. By contrast PD patients correctly recognized LIDs in video recordings of reference PD patients. Poor self-awareness correlated with predominance of motor symptoms on the left body side.ConclusionsPoor self-awareness of LIDs is present in a proportion of PD patients as a form of anosognosia. The poor self-awareness of LIDs in the trunk is likely to be due to a complex interplay involving both anosognosic mechanisms and deficits in proprioceptive axial kinesthesia.     

Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease.

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P=0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P=0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.     

The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study

We performed a double-blind, placebo-controlled, crossover study to assess the effect of amantadine versus placebo on levodopa-induced dyskinesias in Parkinson's disease. We found a 24% reduction in the total dyskinesia score after amantadine administration (p = 0.004). This improvement was achieved without any influence on the severity of "on" period parkinsonism. The results confirm that amantadine reduces levodopa dyskinesias and support the hypothesis that dyskinesias can be reduced by blockade of excitatory pathways in the basal ganglia.     

Gender effect on time to levodopa-induced dyskinesias

Levodopa-induced dyskinesias (LID) are commonly observed during long-term treatment of patients with Parkinson’s disease (PD). The impact of non-pharmacological factors on the latency to LID appearance is not known. The aim of the paper was to identify factors associated with time to appearance of LID. Consecutive PD patients treated with levodopa (n = 155) were included in this historical prospective analysis and LID and non-LID groups were compared. The relationship between possible risk factors and the time of LID onset was explored using the Kaplan–Meier method and the Cox multivariate regression model, controlling for the confounding effects of gender, age of disease onset, time to initiation of levodopa treatment, and history of smoking. Patients with LID (57.4%) were significantly younger at disease onset and had a slightly longer latency from diagnosis to levodopa treatment than those without; disease duration and age had no effect on LID appearance. Female gender was associated with a shorter time to LID and the median time to LID was 6 years for males and 4 years for females (p = 0.004). In the multivariate survival analysis a younger age of onset of PD and a longer time from diagnosis to levodopa treatment initiation were also associated with a shorter time to LID appearance (p = 0.030 and 0.036, respectively). Female gender is associated with a significantly shorter latency to LID appearance. Younger age at PD diagnosis and a longer time until starting levodopa are associated with both higher likelihood to develop LID, and a shorter latency until LID were observed.     

Pathogenesis of dyskinesias in Parkinson's disease

Abnormal involuntary movements complicate the management of a majority of patients with advanced Parkinson's disease. The ability of levodopa to induce dyskinesias and alleviate parkinsonism has generally been considered a continuous dose-dependent pharmacological spectrum. In this study, the acute dose-response profile of intravenously administered levodopa for both inducing dyskinesia and alleviating parkinsonism, and its duration of action on these motor manifestations were evaluated in 52 parkinsonian patients. The minimum dose of levodopa required to produce mild dyskinetic movements was significantly lower in patients with fluctuations in motor response compared with those who had a stable response to standard oral therapy; the minimum dose for antiparkinsonian benefit, however, failed to show significant differences. The rate of disappearance of dyskinetic movements was faster than the rate of reappearance of parkinsonian signs following withdrawal of a steady-state infusion of levodopa. The dissociation of the pharmacodynamic profile of the two major motor effects of levodopa suggests their mediation through two different central pharmacological mechanisms, perhaps involving the two classes of dopamine receptors or other transmitter systems, and could have important implications for the design of future antiparkinsonian agents.     

Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease.

We evaluated the tolerability and preliminary efficacy of levetiracetam (LEV; Keppra) in reducing levodopa-induced dyskinesias in Parkinson's disease (PD) in an open-label pilot study. Nine PD patients who were experiencing peak-dose dyskinesias for at least 25% of the awake day and were at least moderately disabling were treated with LEV in doses up to 3,000 mg for up to 60 days. The primary outcome measure was the percent of the awake day that patients spent on without dyskinesia or with nontroublesome dyskinesia (good on time). The mean dose of LEV at endpoint was 625+/-277 mg/day. LEV significantly improved percent of the awake day on without dyskinesia or with nontroublesome dyskinesia at endpoint compared to baseline (43% +/- 12% vs. 61% +/- 17%; P=0.02). Percent on time with troublesome dyskinesia decreased from 23% +/- 10% at baseline to 11% +/- 6% at endpoint, although not significantly. There was no significant increase in off time from baseline to endpoint. There was a 56% dropout rate, mostly due to somnolence. In PD patients who experienced peak-dose dyskinesia for at least 25% of the awake day, LEV significantly improved on time without dyskinesia or with nontroublesome dyskinesia.     

Levodopa-induced ocular dyskinesias in Parkinson's disease.

Levodopa-induced ocular dyskinesias are very uncommon. Usually they occur simultaneously with limb peak-dose choreatic dyskinesias. We report on a patient with leftward and upward deviations of gaze during the peak effect of levodopa, and hypothesize that a severe dopaminergic denervation in the caudate nucleus is needed for the appearance of these levodopa-induce ocular dyskinesias.