Peak-dose Dyskinesia Research Articles

Levodopa-Entacapone-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson's Disease: A Single Center Real-World Experience.

Levodopa-entacapone-carbidopa intestinal gel infusion is a relatively new treatment option for advanced Parkinson's disease. We aimed to describe and analyze the characteristics of de novo levodopa-entacapone-carbidopa intestinal gel therapy in 20 consecutive patients with advanced Parkinson's disease. We assessed the profile of motor complications by evaluating the following: motor fluctuations, dyskinesias, and the freezing phenomenon at baseline (before the testing period) and before discharge. The treatment significantly reduced the duration of daily hours spent in off time compared with baseline pre-treatment values from a mean of 4.8 ± 0.9 h/day to a mean of 1.4 ± 0.5 h per day (p < 0.001). The duration and severity of peak-dose dyskinesia were also significantly reduced compared with baseline values. Out of the 10 patients who reported freezing, 8 did not present this complication at the pre-discharge assessment. Significant improvements were observed in Hoehn and Yahr scale scores in both the on and off states. The levodopa-entacapone-carbidopa intestinal gel therapy was well tolerated during the follow-up period immediately after initiation. Despite a relatively severe stage of the disease, all patients experienced a significant improvement in motor fluctuations, dyskinesias, and the freezing phenomenon.

A video-atlas of levodopa-induced dyskinesia in Parkinson's disease: terminology matters.

Dyskinesia is a common complication of long-term levodopa therapy in patients with Parkinson's disease (PD), which often worsens the quality of life. It is usually dose-dependent and emerges possibly due to pulsatile stimulation of dopamine receptors. Delineating the pattern of dyskinesia is crucial for determining the most effective therapeutic approach, a task that often presents challenges for numerous neurologists. This article comprehensively describes various patterns of dyskinesia in PD patients and features video demonstration of some of the common forms of dyskinesia. We have used a real case scenario as an example to lead the discussion on the phenomenology, distinguishing features, and management of various types of dyskinesia. A comprehensive literature search was conducted in PubMed using "dyskinesia" as a keyword. The prototype case with videos highlights the differentiating features of dyskinesia along with the treatment strategies. A wide range of descriptive rubrics have been used for certain dyskinesia which are described in detail in this article. The newer types of dyskinesia associated with continuous dopaminergic stimulation in patients with advanced PD and their implications have been described. As there are distinct ways of managing various types of dyskinesia, understanding the phenomenology and chronology of dyskinesia is vital for the optimal management of dyskinetic PD patients. We suggest that dyskinesia should be classified broadly into peak-dose dyskinesia (PDD), biphasic dyskinesia (BD), and OFF-period dystonia. The occurrence of low-dose dyskinesia and complex dyskinesia of continuous dopaminergic treatments should be known to specialists and will require additional studies.

Effect of the mGlu4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.

Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. ADX-88178 mildly worsened global PLBs at the dose of 1mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158min of on-time, while the duration of on-time was 212min (34% increase, P = 0.011), after adding ADX-88178 1mg/kg to L-DOPA. Accordingly, ADX-88178 1mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis.

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

Nelotanserin is a serotonin 2A and 2C (5-HT2A/2C) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD.

Teaching Video Neuro Images : The underrecognized diphasic dyskinesia of Parkinson disease

Dyskinesia is a common motor complication in levodopa-treated Parkinson disease (PD), associated with higher doses, greater disease severity, and longer disease duration.1 Often assumed to be a peak-dose phenomenon, the diphasic (beginning-of-dose or end-of-dose) variant may be ignored, as exemplified by a patient with PD whose dyskinesia was initially interpreted as peak-dose (video at [Neurology.org][1]). Rapid improvement with apomorphine, a short-acting levodopa-equipotent dopamine agonist, confirmed its diphasic nature.2 Recognition of dyskinesia subtype based on the relationship with levodopa dose cycles (figure) facilitates their differing management in PD: while dopaminergic stimulation needs reduction in peak-dose dyskinesia, it should be increased in diphasic. [1]: http://neurology.org/lookup/doi/10.1212/WNL.0000000000004238

The use of the drug L-Carnitine Rompharm in patients with Parkinson's disease in the context of rational pharmacotherapy

The basic drug therapy for Parkinson's disease (PD) includes levodopa, dopamine receptor agonists (ADRs), type B monoamine oxidase enzyme inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. In recent years, the efficacy of L-carnitine in neurodegenerative diseases and depression, which is often associated with PD, has been reported.&#x0D; Aim. To study the efficacy and safety of levocarnitine (L-Carnitine Rompharm) in PD patients of different ages and disease histories combined with ADR and levodopa.&#x0D; Materials and methods. A total of 142 patients with PD (aged 43 to 82 years) were followed-up from February 2020 to July 2022. All of these patients underwent clinical-neurological and neuropsychological examinations. In all patients, L-Carnitine Rompharm was used in the complex therapy of PD in combination with ADR and levodopa. Therapy efficacy was assessed using the International Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS).&#x0D; Results. After the course of therapy, significant (p0.05) improvements in non-motor manifestations of PD (MDS UPDRS scale I), motor manifestations of PD (MDS UPDRS scale II), and motor function indices (MDS UPDRS scale III) were observed in all age groups. Improvements in hypokinesia, rigidity, motor fluctuations (depletion of levodopa effect), peak dose dyskinesia, and postural instability were observed; thought processes, behavior, mood, and daily life activity were also improved. L-carnitine showed good tolerability and absence of side effects.&#x0D; Conclusion. The efficacy and safety of L-Carnitine Rompharm in PD patients of different ages have been demonstrated.

Successful Treatment of Biphasic and Peak-dose Dyskinesia With Combined Unilateral Subthalamic Nucleus and Contralateral Globus Pallidus Interna Deep Brain Stimulation.

Successful Treatment of Biphasic and Peak-dose Dyskinesia With Combined Unilateral Subthalamic Nucleus and Contralateral Globus Pallidus Interna Deep Brain Stimulation.

Altered functional connectivity of cerebellar dentate nucleus in peak-dose dyskinesia in Parkinson's disease.

The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the z-FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the z-FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.

Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia.

The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.

Ten-year trends of the characteristics in patients with advanced Parkinson's disease at the time of intestinal gel therapy introduction

Introduction: Parkinson's disease is a neurodegenerative disease, the symptoms of which can be treated reasonably well; however, therapeutic recommendations need to be refined based on the observations from everyday practice. Objective: We aimed to analyze the extent by which published expert recommendations were reflected in the manage-ment of patients with advanced Parkinson's disease, prior to the introduction of the intestinal gel. Method: Data from patients treated with levodopa-carbidopa intestinal gel were retrospectively examined. The period from 2011 to 2021 was divided into two five-year periods, prior and after the usage of the 5-2-1 rule in clinical decision-making. Results: Levodopa-carbidopa intestinal gel treatment was initiated in 150 patients during the study period. In the second five-year period, the mean age of the patients was lower and the time from diagnosis was shorter. Also, there were significantly fewer patients with peak-dose dyskinesias (p = 0.02), biphasic dyskinesias (p<0.001), and early morning akinesias (p = 0.02). Furthermore, in the last five years of the study, fewer patients were affected by delayed on (p = 0.03), no on (p = 0.02), and freezing (p = 0.01). The mean score measured on the Hoehn-Yahr scale was also lower in the second period, while the mean MMSE score was higher (p<0.001). Daily doses of levodopa were higher (p<0.01) in the second period, but with similar dosing frequency. Conclusion: Our retrospective analysis of trends during a ten-year period revealed that, in the second five-year period, levodopa-carbidopa intestinal gel was started in advanced Parkinson's disease patients with a significantly better physical and cognitive state. Compared to expert recommendations, our patients still had a more severe clinical pic -ture at the start of device-aided therapy, but acceptance of this invasive method has improved both for patients and for general practitioners and neurologists.

How I treat Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative condition. Treatment strategies through all stages of disease progression could affect quality of life and influence the development of future complications, making it crucial for the clinician to be on top of the literature. This paper reviews the current treatment of PD, from early to advanced stages. A literature review was conducted focusing on the treatment of PD, in the different stages of progression. Every individual with a new diagnosis of PD should be encouraged to start exercising regularly. In the early stage, treatment should focus on using the lowest dose of levodopa or combination therapy that provides maximum functional capacity, and does not increase the risk of complications, such as peak dose dyskinesias and impulse control disorders. At the moderate and advanced stages, motor fluctuations and complications of treatment dominate the picture, making quality of life one important issue. Rehabilitation programs can improve motor symptoms and should be offered to all patients at any stage of disease progression. Many factors need to be considered when deciding on the best treatment strategy for PD, such as disease progression, presence of risk factors for motor and behavioral complications, potential side effects from dopaminergic therapy and phenotypical variabilities. Treatment should focus on functional capacity and quality of life throughout the whole disease course.

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.

Czy preparaty lewodopy z karbidopą oraz lewodopy z benserazydem są klinicznie równoważne?

Parkinson’s disease is the only neurodegenerative disease that can be effectively treated symptomatically. Treatment of motor symptoms is based primarily on the use of drugs that increase the activity of the nigrostriatal dopaminergic system and compensate for dopamine deficiency. Levodopa remains the gold standard of dopaminergic therapy. It is the most effective and best tolerated anti-parkinsonian drug, it causes the fewest side effects, also in the elderly patients. Oral preparations of levodopa additionally contain one of the aromatic L-amino acid decarboxylase inhibitors: benserazide or carbidopa. Inhibitors have a beneficial effect on the bioavailability of levodopa in the central nervous system, its clinical efficacy and tolerability. In practice, according to common opinion, the preparations of levodopa with carbidopa and levodopa with benserazide are clinically equivalent and can be used interchangeably. The case of a 69-year-old patient treated for 6 years for Parkinson’s disease is presented. The patient presented motor symptoms of advanced Parkinson’s disease: wearing-off motor fluctuations and peak dose dyskinesia. The was treated with levodopa in a dose of 5 × 200 mg (preparation of levodopa with benserazide) as a monotherapy. Due to the worsening availability of the drug used so far in pharmacies, it was changed to a preparation containing levodopa and carbidopa, while maintaining the same dose of levodopa. During the next visit, the patient reported that the change of the formulation had a beneficial effect in the form of a slight but significant reduction in the incidence and severity of peak dose dyskinesia. Pharmacokinetic studies showed that the mean maximum concentration of levodopa after administration of levodopa + benserazide was significantly higher than after administration of levodopa + carbidopa. The preparation containing benserazide caused a rapid increase and then a rapid decrease of the lewodopa plasma concentration. When levodopa was combined with carbidopa, the concentration of levodopa increased and decreased slowly. The results of these pharmacokinetic studies may explain the patient’s observation of the amelioration of peak dose dyskinesia after switching from a levodopa + benserazide formulation to a levodopa + carbidopa combination.

P-MD004. Peak dose ballistic movements towards the implantable pulse generator life end in deep brain stimulation

Introduction . The objective of this case report is to highlight the unusual presentation of peak dose ballistic movements towards the end of the implantable pulse generator (IPG) life span in a patient with bilateral sub-thalamic nucleus (STN) deep brain stimulation (DBS). Results . We report a case of sudden severe peak dose ballistic movements and increased “off” periods in a PD patient with bilateral STN DBS towards the end life of the IPG despite a normal battery range according to the Medtronic Battery Status Indicator. The Unified Parkinson Disease Rating Scale III (UPDRS III) escalated by 12 points (from 63 to 75 points) with severe uncontrollable peak dose dyskinesia despite no medication adjustment. Stimulation settings were cut down to as low as 1.0 V on the left STN, and 1.5 V on the right STN at a frequency of 130 Hz and pulse width of 60 μs, yet the ballistic movements were still noticeable. The patient remained in “on” period with no dyskinesia throughout the day after replacement of the IPG with similar stimulation settings prior to the replacement of the IPG, with 2.1 V on the left STN, and 1.6 V on the right STN at a frequency of 130 Hz and pulse width of 60 μs. The patient’s UPDRS-III score was at 62 points after the replacement of IPG. Conclusion . We observed that the battery status indicator did not accurately predict the battery life of the IPG. Peak dose ballistic movements towards the end life of the IPG is an unusual presentation and could be an indicator of end life of the IPG in DBS.

Practical aspects of prescribing antiparkinsonian drugs. The place of amantadines in the management of Parkinson’s disease

Treatment of Parkinson’s disease (PD) includes the administration of dopaminergic and occasionally non-dopaminergic drugs, in mono- or in combination therapy. One of the key drug used to treat Parkinson’s disease is levodopa considered a gold standard. In addition levodopa can also be used as a challenge test to confirm the accuracy of diagnosis of PD known as the “Levodopa challenge test”. However many non levodopa class of drugs are also used and consist of dopamine agonists (ADRs), MAO-B and COMT inhibitors, as well as drugs working on glutamate such as a group of drug with NMDA receptor inhibitor activity (amantadines). The successful treatment of PD therefore depends on the correct choice of drugs to initiate treatment and sustainance of such therapy. The main parameters for personolised treatment include the patient’s age, severity and pattern of motor deficit, the state of cognitive function and lifestyle. Levodopa, although the most effective, is almost invariably associated with motor fluctuations and dyskinesias. Before prescribing levodopa, in addition to MAO-B inhibitors and ADRs, amantadines can be used as a monotherapy. Once replacement of therapy is required, then it is necessary to use a coefficient to calculate an equivalent dose of levodopa known as the levodopa equivalent dose. Progression of PD is inevitable inspite of adequate symptomatic therapy and at the advanced stage of PD approaches for the management of motor complications of levodopa need to be considered. For motor fluctuations these strategies require a change in the dosage regimen of levodopa (daily dose and frequency of intake), as well as the addition of an adjunct drug – ADRs, MAO-B inhibitor or COMT inhibitor. When dyskinesias arise, the management depends on correct identification of the type of dyskiensias. The commonest type of dyskinesia is peak dose dyskinesias related to peak plasma levodopa levels after intake. Amantadine provides a quick and long-lasting antidyskinetic effect which has been confirmed in open label as well as double-blind placebo-controlled studies. Compared to аmantadine chloride, amantadine sulfate has more stable pharmacokinetic parameters and a better safety profile. In addition, parenteral administration of amantadine sulfate can be utilized for severely ill patients with akinetic crisis in PD. Amantadine also has a broad spectrum effect and these may include improvement of fatigue and apathy. Some data also suggest that the use of amantadine in patients may increase life expectancy, improve survival and reduce the risk of dementia.

Bilateral subthalamic nucleus deep brain stimulation is an effective treatment for diphasic dyskinesia.

The purpose was to assess the effect of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on diphasic dyskinesia in patients with Parkinson disease (PD) and to assess the factors associated with the remission of diphasic dyskinesia. Medical records for PD patients who underwent bilateral STN DBS at the Movement Disorder Center of Seoul National University Hospital from March 2005 to November 2016 were reviewed. Patients were evaluated preoperatively and at 3, 6 and 12months after surgery, and annually thereafter. The presence of peak-dose dyskinesia and diphasic dyskinesia is based on the interview and examination of patients at baseline and at each follow-up. Amongst 202 patients who underwent STN DBS, 66 patients who had diphasic dyskinesia preoperatively were included in the analysis. Diphasic dyskinesia disappeared in 49 (74%) after surgery. In 27 (55.1%) patients whose diphasic dyskinesia disappeared after DBS, peak-dose and diphasic dyskinesia disappeared persistently from as early as 3months postoperatively. Age at onset was younger and disease duration at surgery was longer in patients whose diphasic dyskinesia persisted compared with patients whose diphasic dyskinesia disappeared. Multivariate Cox regression analysis demonstrated that patients with greater postoperative decrease of dopaminergic medications were more likely to have remission of diphasic dyskinesia. This study showed that bilateral STN DBS is effective in controlling diphasic dyskinesia and should be considered in PD patients with diphasic dyskinesia.

Effect of the mGlu2 positive allosteric modulator CBiPES on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu2) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10mg/kg), after which their behaviour was rated. CBiPES 10mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu2 positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.

The MPTP-lesioned marmoset model of Parkinson's disease: proposed efficacy thresholds that may potentially predict successful clinical trial results.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset has been used extensively to model Parkinson's disease, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and, more recently, dopaminergic psychosis. Whereas several experimental drugs have been tested in this primate, many of which subsequently underwent clinical trials, efficacy thresholds in the marmoset that would predict efficacy in the clinic are lacking. Here, we aimed to determine such efficacy end points that would be indicative of likely efficacy in clinical studies. To do so, we used the evidence-based medicine reviews published by the International Parkinson and Movement Disorder Society (IPMDS) to select drugs that were rated as clinically efficacious, likely efficacious or not efficacious for the treatment of parkinsonism, dyskinesia and psychosis. We then reviewed the literature in the MPTP-lesioned marmoset and identified articles reporting the effects of drugs that were included in the IPMDS recommendations, following which we estimated efficacy thresholds in the marmoset that would predict efficacy at the clinical level. We propose that, when drugs are administered as monotherapy, ≥ 50% reduction of global parkinsonism may be necessary to predict the possibility of clinical efficacy. As adjunct to a low dose of L-DOPA, we propose that an additional reduction of global parkinsonism ≥ 25% might predict clinical efficacy. As adjunct to an optimal dose of L-DOPA, we propose that additional anti-parkinsonian benefit ≥ 20%, with global parkinsonism as the end point, might predict clinical efficacy. For the treatment of dyskinesia, we suggest that the predictability threshold be set at ≥ 25% reduction of peak dose dyskinesia, while we believe that this threshold should be > 50% reduction of peak dose psychosis-like behaviours for psychosis-related end points. This article represents the first step in determining what efficacy might be necessary to achieve in pre-clinical studies in the MPTP-lesioned marmoset prior to confidently advancing drugs to clinical trials. We hope that it will help in the drug discovery and development process, notably by avoiding exposing patients to drugs that have little probability of clinical efficacy based upon pre-clinical experiments.

Complex dyskinesias in Parkinson patients on levodopa/carbidopa intestinal gel

BackgroundLevodopa-carbidopa intestinal infusion is an effective treatment for motor fluctuations in Parkinson's disease. However, it has been recently associated with emergent complex/atypical dyskinesias. We sought to characterize patients who developed these dyskinesias after levodopa infusion initiation, and to compare these patients to a control population with conventional motor fluctuations. Methods208 Parkinson's disease patients, treated with levodopa intestinal infusion due to motor fluctuations, were screened for onset and/or worsening of dyskinesias after initiation of levodopa infusion, resistant to the routine titration, and presenting with atypical or unexpected patterns. Patients with extensive follow-up data were enrolled for a longitudinal analysis. Cases were compared to a control sample with conventional motor fluctuations in order to investigate predisposing factors, difference in dyskinesia phenotype, management strategies and dropouts. ResultsThirty patients out of 208 (14.4%) reported atypical (i.e. long-lasting) biphasic, biphasic-like (i.e. continuous) or mixed (peak-dose and continuous biphasic) dyskinesias after levodopa infusion. They were compared at baseline and follow-up to a sample of 49 patients with conventional motor fluctuations on levodopa infusion. Both groups had similar demographic and clinical features, except the former having higher prevalence of biphasic dyskinesias while on oral therapy. Biphasic-like dyskinesias in nearly half the number of cases improved with increasing the dopaminergic load, while mixed dyskinesias had the worst outcome and highest dropout rate (58%). ConclusionsAtypical biphasic, biphasic-like and complex dyskinesias could hinder the course of patients treated with levodopa infusion. This study further informs the selection process of advanced therapies, particularly in dyskinetic patients.