Severe Dyskinesia Research Articles

Motor complications in an incident Parkinson's disease cohort.

Levodopa treatment in Parkinson's disease (PD) causes motor fluctuations and dyskinesias, but few data describe their development or severity in unselected incident cohorts. Demographic, clinical, treatment, smoking, caffeine and alcohol data from 183 people with PD were gathered from the Parkinsonism Incidence in Northeast Scotland (PINE) study, a community-based, incident cohort. With Kaplan-Meier survival analysis and Cox regression modelling the development, and severity, of dyskinesias and motor fluctuations and which factors independently influenced their onset were assessed. After a mean follow-up of 59months, 39 patients (21.3%) developed motor fluctuations and 52 (28.4%) developed dyskinesias. Kaplan-Meier estimates of the probability of motor fluctuations and dyskinesias after 5years of dopaminergic treatment were 29.2% [95% confidence interval (CI) 21.5%-38.8%] and 37.0% (95% CI 28.5%-47.1%) respectively. 19.8% developed motor fluctuations requiring treatment changes but only 4.0% (95% CI 1.5%-10.4%) developed dyskinesias requiring treatment changes by 5years. Cumulative levodopa dose [hazard ratio (HR) 1.38 (95% CI 1.19-1.60)], female sex [HR 2.41 (1.19-4.89)] and younger age at diagnosis [HR 1.08 (1.04-1.11)] were independently associated with development of motor fluctuations. Cumulative levodopa dose [HR 1.23 (1.08-1.40)] and female sex [HR 2.51 (1.40-4.51)] were independently associated with dyskinesias. In exploratory analyses, moderate caffeine exposure was associated with fewer motor fluctuations, longer symptom duration with more dyskinesias, and tremor at diagnosis with higher rates of both complications. In this community-based incident PD cohort, severe dyskinesias were rare. Cumulative levodopa dose was the strongest predictor of both dyskinesias and motor fluctuations.

The highly-selective 5-HT1A agonist F15599 reduces l-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque

l-3,4-dihydroxyphenylalanine (l-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of l-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising l-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of l-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with l-DOPA and its effect on dyskinesia and l-DOPA anti-parkinsonian was assessed. In combination with l-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to l-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to l-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on l-DOPA anti-parkinsonian action.

709. rAAV-Mediated Regulation of Striatal Nurr1 Expression Alters Development and Severity of Levodopa-Induced Dyskinesias in the 6-OHDA Rat Model of Parkinson's Disease

Primary motor symptoms in Parkinson's disease arise due to a loss of dopaminergic innervation in the striatum. Treatment with levodopa (L-DOPA) is the current gold standard treatment for the motor symptoms that arise in PD due to dopamine (DA) depletion. However, a large portion of patients receiving L-DOPA treatment develop a series of debilitating hyperkinetic and dystonic movements known as L-DOPA-induced dyskinesias (LIDs). The molecular mechanisms behind LID development are unclear, as well as why some patients are resistant to LIDs and never acquire these symptoms. In an attempt to identify transcriptional differences between LID responders and LID non-responders in the rat parkinsonian 6-hydroxydopamine (6-OHDA) model, we performed a full genome array to identify differential transcript expression between these two groups. The orphan nuclear receptor Nurr1 was one transcript that was expressed at significantly higher levels—greater than 30 fold—in LID+ animals when compared to LID- animals. In the current study we sought to determine whether Nurr1 expression both promotes, and is required for, LID formation. Adult male Sprague-Dawley rats were rendered parkinsonian using6-OHDA. Animals that did not show a difference in paw use compared to a pre-lesion state were removed from the study one month later. At this time, remaining animals received a striatal injection of recombinant adeno-associated virus (rAAV) type 2/5 overexpressing either: 1) Nurr1 (or GFP as a control)(5×1013 vector genomes (vg)/ml) in order to test whether Nurr1 overexpression causes LIDs or 2) A shRNA targeting Nurr1 (or a titer-matched scrambled shRNA control)(2×1013 vg/ml) in order to test whether Nurr1 is required for LIDs. Four weeks following the vector injection, animals received escalating doses (0mg/kg – 24mg.kg) of L-DOPA every other day (M-Fr), and were evaluated for LIDs at 25 min intervals for 2-4 hours using the abnormal involuntary movement (AIM) rating scale. At doses equal to or exceeding 12mg/kg, Nurr1 overexpressing animals exhibited both more severe and longer lasting LIDs than their rAAV-GFP control counterparts. Conversely, dyskinesias were attenuated in animals receiving Nurr1-shRNA up to 18mg/kg of L-DOPA. In addition, postmortem analysis of striatal tissue revealed that the overexpression of the Nurr1 shRNA effectively inhibited the induction of L-DOPA induced Nurr1. These results demonstrate that overexpression of Nurr1 in the DA-depleted striatum of parkinsonian rats has a causative role in the expression of LIDs. Further, our data show that Nurr1 silencing in the striatum effectively inhibits the LID development. These data suggest that the maladaptive upregulation of Nurr1 in striatal neurons is a core event in the formation of LIDs. Consequently, targeting striatal Nurr1 activity may represent a novel therapeutic modality in the treatment of LIDs.

Video-Documented Long-Term Follow-Up of a 10 Years' Old Girl with Severe Dyskinesia and Paroxysmal Choreoathetosis: A Variant Ataxia-Telangiectasia (A-T)

Case Study: We present a now 10-year-old girl with severe dyskinesia with paroxysmal choreoathetoid movements, which started at 24 months of age. Pregnancy and birth were uneventful. From the age of 3 months, a mild coordination disorder and muscular hypotonia were noted, the motor milestones were delayed (independent sitting with 12 months, independent walking with 2.5 years). Therapeutic trials with levodopa, carbamazepine, clonazepam, and carnitene did not significantly improve the dyskinesia nor the paroxysmal events. Cranial MRIs at the age of 12 months and 5 years were normal. Extensive metabolic investigations were normal. Alpha-Fetoprotein was normal. There are still no telangiectasias or ocular apraxia. The cognitive profile at the age of 9.5 years was within the lower range of normal limits. Genetic analysis revealed compound heterozygosity for the following two variants of ATM: c.1229T > C and p.V410 A (het.) which were described in a patient with ocular telangiectasia and c.5071A > C and p.S1691R (het.) which were detected in a British family with a history of A-T. Because of insufficient data, the pathogenicity of both variants remains unclear; however, the clinical presentation could argue for pathogenicity of the variants. Sequencing analysis of PRRT2 did not reveal any mutation. We present video sequences recorded over a period of 8 years of a now 10-year-old girl with a variant A-T with two missense mutations in the ATM gene. A variant A-T should be considered in a patient with dyskinesia and paroxysmal choreoathetosis, even with normal cranial imaging and normal AFP.

Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans.

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.

Pyridoxal 5 phosphate for neuroleptic-induced tardive dyskinesia.

Tardive dyskinesia is a chronic and disabling abnormal movement disorder affecting the muscles of the face, neck, tongue and the limbs. It is a common side effect of long-term antipsychotic medication use in individuals with schizophrenia and other related psychotic disorders. While there are no known effective treatments for tardive dyskinesia to date, some reports suggest that pyridoxal 5 phosphate may be effective in reducing the severity of tardive dyskinesia symptoms. To determine the effectiveness of pyridoxal 5 phosphate (vitamin B6 or Pyridoxine or Pyridoxal phosphate) in the treatment of neuroleptic-induced tardive dyskinesia among people with schizophrenia and other related psychotic disorders. The Cochrane schizophrenia group's register of clinical trials was searched (January 2013) using the phrase: [*Pyridoxal* OR *Pyridoxine* OR *P5P* OR *PLP* OR *tardoxal* OR *Vitamin B6* O *Vitamin B 6* R in title, abstract or index terms of REFERENCE, or interventions of STUDY. References of relevant identified studies were handsearched and where necessary, the first authors of relevant studies were contacted. Studies described as randomised controlled trials comparing the effectiveness pyridoxal 5 phosphate with placebo in the treatment of neuroleptic-induced tardive dyskinesia among patients with schizophrenia. The review authors independently extracted data from each selected study. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a fixed-effect model. For continuous data, we calculated mean differences (MD) with 95% CIs, again based on a fixed-effect model. We assessed risk of bias for each included study and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to rate quality of evidence. Of the 12 records retrieved by the search, three trials published in 2001, 2003 and 2007, involving 80 inpatients with schizophrenia, aged 18 to 71 years, admitted in a psychiatric facility and followed up for a period nine weeks to 26 weeks, were included. Overall, pyridoxal 5 phosphate produced a significant improvement in tardive dyskinesia symptoms when compared with placebo, assessed by a change in Extrapyramidal Symptoms Rating Scale (ESRS) scores from baseline to the end of the first phase of the included studies (2 RCTs n = 65, RR 19.97, CI 2.87 to 139.19, low quality evidence). The endpoint tardive dyskinesia score (a measure of its severity) assessed with the ESRS, was significantly lower among participants on pyridoxal 5 phosphate compared to those on placebo (2 RCTs n = 60, MD -4.07, CI -6.36 to -1.79, low quality evidence).It was unclear whether pyridoxal 5 phosphate led to more side effects (n = 65, 2 RCTs, RR 3.97, CI 0.20 to 78.59, low quality evidence) or caused deterioration in tardive dyskinesia symptoms when compared to placebo (n = 65, 2 RCTs, RR 0.16, CI 0.01 to 3.14, low quality evidence). Five participants taking pyridoxal 5 phosphate withdrew from the study because they were not willing to take more medications while none of the participants taking placebo discontinued their medications (n = 65, 2 RCTs, RR 8.72, CI 0.51 to 149.75, low quality evidence).There was no significant difference in the endpoint positive and negative psychiatric symptoms scores, measured using the Positive and Negative symptoms Scale (PANSS) between participants taking pyridoxal 5 phosphate and those taking placebo. For the positive symptoms: (n = 15, 1 RCT, MD -1.50, CI -4.80 to 1.80, low quality evidence). For negative the symptoms: (n = 15, 1 RCT, MD -1.10, CI -5.92 to 3.72, low quality evidence). Pyridoxal 5 phosphate may have some benefits in reducing the severity of tardive dyskinesia symptoms among individuals with schizophrenia. However, the quality of evidence supporting the effectiveness of pyridoxal 5 phosphate in treating tardive dyskinesia is low, based on few studies, short follow-up periods, small sample sizes and inadequate adherence to standardised reporting guidelines for randomised controlled trials among the included studies.

Long-term follow-up of bilateral subthalamic nucleus stimulation in Chinese Parkinson's disease patients

Background and purpose. The long-term benefits of deep bilateral brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with advanced Parkinson's disease (PD) are less well described, especially in Chinese cohorts. Here, we present a large group of Chinese PD patients treated with bilateral STN DBS. Methods. Between 2003 and 2010, 195 consecutive PD patients received implants at the Xuanwu Hospital affiliated to the Capital Medical University in Beijing (China) for bilateral STN DBS. The mean age at implantation was 58.2 ± 10.0 years, and they had a 5- to 15-year history of PD (mean: 6.8 years). Patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) at 1, 3, and 5 years, both on and off medication. Results. Except for speech, patients’ off-medication motor function scores at 5 years improved by 60.3% (P < 0.001) and those for activities of daily living improved by 54.2% (P < 0.001). With the exception of dyskinesia, on-medication motor function scores did not improve 1 year after surgery. On-medication akinesia, speech, postural stability, and freezing of gait worsened between years 1 and 5 (all P < 0.001). At 5 years, dopaminergic treatment dose and the duration and severity of levodopa-induced dyskinesia were reduced compared with baseline (all P < 0.001). There was one death associated with surgery to implant the STN DBS. Conclusions. PD patients who were treated with bilateral STN DBS exhibited marked motor function improvements over long-term follow-up while off medication and in dyskinesia while on medication.

Quantitative motor assessment of dyskinesias in Parkinson's disease.

Although Levodopa-induced dyskinesias (LID) are one of the most compromising complications of dopaminergic treatment in Parkinson's disease (PD), there is no widely accepted assessment tool available that evaluates LID quantitatively. This is of relevance as objective assessment may help to facilitate proof-of-concept studies with novel treatments and thus eventually contribute to better patient care. PD patients were asked to perform a grip-lift task as well as tapping tasks assessed with the "Q-Motor" system. PD patients were separated into three groups according to their modified abnormal involuntary movement scale (M-AIMS)-score: PD patients without dyskinesias (PD(LID-) n = 17), with slight dyskinesias (PD(LID+) n = 15) and with severe dyskinesias (PD(LID++) n = 15). An explorative analysis to identify measures detecting LID was performed with 5 PD(LID-) and 5 PD(LID++) patients; these measures were then used in the remaining patients to assess the accuracy of the system to differentiate LID. The measures "Orientation-Index" and "Position-Index" of the grip-lift task differed significantly between the explorative cohorts. Using these two parameters for the differentiation of the remaining cohorts, the area under the ROC curve (AUC) yielded 0.809 for the differentiation of PD(LID-) vs. PD(LID++), 0.852 for the differentiation of PD(LID-) vs. PD(LID+) patients, and 0.830 for the differentiation of PD(LID+) and PD(LID++). The "Orientation-Index" and "Position-Index" of the Q-Motor assessment are sensitive, easy to apply and non-invasive measures for the objective assessment of manifestation and severity of LID.

Abnormal movements in first-episode, nonaffective psychosis: Dyskinesias, stereotypies, and catatonic-like signs

Motor abnormalities represent a neurobehavioral domain of signs intrinsic to schizophrenia-spectrum disorders, though they are commonly attributed to medication side effects and remain understudied. Individuals with first-episode psychosis represent an ideal group to study innate movement disorders due to minimal prior antipsychotic exposure. We measured dyskinesias, stereotypies, and catatonic-like signs and examined their associations with: (1) age at onset of psychotic symptoms and duration of untreated psychosis; (2) positive, negative, and disorganized symptoms; (3) neurocognition; and (4) neurological soft signs. Among 47 predominantly African American first-episode psychosis patients in a public-sector hospital, the presence and severity of dyskinesias, stereotypies, and catatonic-like features were assessed using approximately 30-min video recordings. Movement abnormalities were rated utilizing three scales (Dyskinesia Identification System Condensed User Scale, Stereotypy Checklist, and Catatonia Rating Scale). Correlational analyses were conducted. Scores for each of three movement abnormality types were modestly inter-correlated (r=0.29–0.40). Stereotypy score was significantly associated with age at onset of psychotic symptoms (r=0.32) and positive symptom severity scores (r=0.29–0.41). There were no meaningful or consistent associations with negative symptom severity, neurocognition, or neurological soft signs. Abnormal movements appear to represent a relatively distinct phenotypic domain deserving of further research.

The role of pallidal serotonergic function in Parkinson's disease dyskinesias: a positron emission tomography study

We have investigated the role of globus pallidus (GP) serotonergic terminals in the development of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD). We studied 12 PD patients without LIDs, 12 PD patients with LIDs, and 12 healthy control subjects. We used 11C-DASB positron emission tomography (PET), a marker of serotonin transporter availability, and 11C-raclopride PET to measure changes in synaptic dopamine levels following levodopa administration. PD patients without LIDs showed a significant reduction of GP serotonin transporter binding compared with healthy controls although this was within the normal range in PD patients with LIDs. Levels of GP serotonin transporter binding correlated positively with severity of dyskinesias. 11C-raclopride PET detected a significant rise in GP synaptic dopamine levels of patients with LIDs after a levodopa challenge but not in patients with a stable response. Our findings indicate that LIDs in PD are associated with higher GP serotonergic function. This increased serotonin function may result in further dysregulation of thalamocortical signals and so promote the expression of dyskinesias.

Pharmacotherapy accompanied by deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease

To analyze pharmacotherapy accompanied by deep brain stimulation of the subthalamic nucleus. The study included 54 patients, who underwent bilateral STN DBS from 2003 to 2012. The severity of motor disturbances, activities of daily living and complications of dopaminergic therapy were estimated in accordance with II, III and IV parts of the Unified Parkinson's Disease Rating Scale (UPDRS) before operation and one, three and four years after it. L-dopa equivalent daily dose (LEDD) was assessed along with an analysis of the pharmacotherapy in whole. By the end of the 1st year, the severity of motor disturbances in OFF-period decreased by 52.3% and remained stable for 3 years (51.8%), a slight increase of severity of motor disturbances was observed later, however it didn't reach the pre-operative level. The severity of motor fluctuations and drug-induced dyskinesia fell by 64.9%, 70.7% and 42.7% by the end of the first, third and fourth year of observation. The maximal decrease in LEDD was reached by the end of the 1st year and accounted for 57.7%; by the end of the third and fourth years it was 52.4% and 38.2%, respectively. During the 1st year, 16.7% of patients didn't take levodopa. The dose of pure levodopa decreased by the end of the 1st year by 64.6%, and by 56.7% and 43.7% by the end of the 3rd and 4th years, respectively. Monotherapy by an agonist of dopamine receptors (ADR) was received by 12.9% of patients, thus the share of ADR as part of the combined therapy increased in the postoperative period from 24.1% to 35.2%.

Extrapyramidal symptoms and cognitive test performance in patients with schizophrenia

BackgroundMovement disorders are common in individuals with schizophrenia, even in those who are not exposed to antipsychotic medications. Extrapyramidal symptoms (EPS) are among the most common abnormal movements in schizophrenia, but their relationship with other features of the illness such as cognition is not well characterized. MethodsThree hundred and twenty-five individuals with schizophrenia who were not receiving any antipsychotic or anticholinergic medication and participated in the baseline visit of the Clinical Antipsychotic Treatment of Intervention Effectiveness study were included in the present study. EPSs were assessed using the Simpson-Angus Scale, while cognition was measured with a comprehensive neuropsychological test battery. The relationship between EPS and cognitive test performance was evaluated both dimensionally and categorically. ResultsGreater severity of EPS was significantly associated with worse cognitive test performance evaluated using a composite score. Eighty-six patients were identified as having parkinsonism and these patients performed worse on cognitive tests than non-parkinsonian patients. These findings remained significant even after accounting for other variables such as severity of psychopathology, sedation, akathisia and dyskinesia. ConclusionsThe present results demonstrate that severity of EPS is reliably linked with poorer scores on tests of cognition. While this may reflect a common pathophysiology underlying neuromotor and neurocognitive deficits, it may also be the case that parkinsonian symptoms such as rigidity and bradykinesia impede test taking ability. Regardless of mechanism, inferences regarding cognitive impairment should take into account the presence of EPS, as well as other variables that may mediate cognitive test findings.

Spontaneous locomotor activity and L-DOPA-induced dyskinesia are not linked in 6-OHDA parkinsonian rats.

Bradykinesia (slowness of movement) and other characteristic motor manifestations of Parkinson’s disease (PD) are alleviated by treatment with L-dihydroxyphenylalanine (L-DOPA). Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle), before treatment with L-DOPA, during L-DOPA treatment (the “ON” phase), and after the end of L-DOPA treatment (the “OFF” phase). We correlated the severity of dyskinesia (AIM scores) with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH) immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L-DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects.

Serotonergic antidepressant drugs and L-dopa-induced dyskinesias in Parkinson's disease.

Serotonergic system is believed to play a role in levodopa-induced-dyskinesias pathogenesis, and serotonin transporter has been evaluated as potential target. To retrospectively investigate the potential effect of selective serotonin reuptake inhibitors (SSRIs) during dopaminergic treatment, in the development of dyskinesias in patients with Parkinson's disease (PD). One hundred and thirty-five consecutive patients with PD, with 10-year follow-up since diagnosis. Age at PD onset, duration of levodopa treatment, maximum daily dose, and SSRIs exposure were collected. Risk, latency, and severity of dyskinesias were evaluated comparing patients with and without SSRIs exposure. Forty-nine patients received SSRIs for a variable period, 86 were never treated; no significant difference between the groups was observed (P=0.897) in the prevalence of dyskinesias. Considering latency between PD diagnosis and dyskinesias onset, patients exposed to SSRIs developed dyskinesias later (6.48±1.99 vs 5.70±1.89years, P=0.020). The median dyskinesia severity score was 0 in the exposed group vs 1 in non-exposed patients (P=0.025). Multivariate analysis demonstrated SSRIs exposure as the only independent predictor, protecting from severe dyskinesia. Use of SSRIs in patients with PD did not protect from dyskinesias; however, exposure may delay the onset and reduce the severity, confirming modulation of the serotonergic system as possible antidyskinetic strategy.

Effects of long-term treatment with rotigotine transdermal system on dyskinesia in patients with early-stage Parkinson's disease.

In two 6-month, double-blind, placebo-controlled studies, rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with rotigotine, with or without concomitant levodopa, for up to 6 years. Open-label rotigotine was titrated to optimal dose (≤16mg/24h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies. Of 596 participants who received open-label rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered 'not disabling' for all occurrences; the worst-case severity was 'mildly disabling' for 33/107 (31%), and 'moderately' or 'severely disabling' for 18/107 (17%; 3% of total participants). During treatment with rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally 'not disabling' or 'mildly disabling'.

Norepinephrine transporter inhibition with desipramine exacerbates L-DOPA-induced dyskinesia: role for synaptic dopamine regulation in denervated nigrostriatal terminals.

Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI + L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI + L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI + L-DOPA group compared with the L-DOPA- and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.

Severe familial paroxysmal exercise-induced dyskinesia.

Familial paroxysmal exercise-induced dyskinesia (PED) is a rare movement disorder that is mostly caused by mutations in the solute carrier family 2, member 1 (SLC2A1) gene and inherited in an autosomal dominant manner. Clinical, laboratory, and genetic studies were performed in three family members. The proband's symptoms were recorded in a private video. He was placed on clonazepam. The 42-year-old proband presented with a 34-year-history of "dancing fits" suggesting a psychogenic aetiology. They occurred spontaneously or were triggered by physical exercise with a frequency up to six episodes per month, duration up to 30 min and no impairment of consciousness. Cerebrospinal fluid-(CSF)-to-blood glucose ratio was slightly reduced (0.59) and electroencephalograms were unremarkable. His 63-year-old father had less severe symptoms with spontaneous recovery before age of 45. The proband and his 38-year-old only brother also reported daily absence episodes early in the morning with an onset at age three and spontaneous recovery before age 15. Genetic testing revealed a novel c.972G>A, p.S324S heterozygous variant in the SLC2A1 gene in three patients. No splicing defects at the RNA level could be demonstrated. Five milligrams per day of clonazepam allowed for excellent control of PED. PED may produce a broad range of bizarre movements mimicking psychogenic movement disorders. A positive family history suggests an organic aetiology. PED can effectively be treated with clonazepam. Clinical manifestations, autosomal dominant inheritance and CSF findings suggest a causative role of the SLC2A1 gene, although no splicing defect at the RNA level could be demonstrated for the novel variant. Additional studies such as exome sequencing are indicated.

Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA–Induced Dyskinesia

BackgroundΔFosB is a surrogate marker of L-DOPA–induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson’s disease L-DOPA long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown. MethodsWe used the Daun02 prodrug-inactivation method associated with lentiviral expression of β-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson’s disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability. ResultsWe first show that daunorubicin, the active product of Daun02 metabolism by β-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing β-galactosidase upon D1 dopamine receptor stimulation. We then demonstrate that the selective, and reversible, inhibition of FosB/ΔFosB-expressing striatal neurons with Daun02 decreases the severity of LID while improving the beneficial effect of L-DOPA. ConclusionsThese results establish that FosB/ΔFosB accumulation ultimately results in altered neuronal electrical properties sustaining maladaptive circuits leading not only to LID but also to a blunted response to L-DOPA. These findings further reveal that targeting dyskinesia can be achieved without reducing the antiparkinsonian properties of L-DOPA when specifically inhibiting FosB/ΔFosB-accumulating neurons.

Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation.

BackgroundThe aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the “brittle” phenomenon occurs in a relatively large DBS practice.MethodsAn Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis.ResultsThere were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an “off state,” or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS.DiscussionUnderstanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation.