Publications by authors named "Michel Panisset"

59 Publications

Combined 5-HT and mGlu modulation for the treatment of dyskinesia and psychosis in Parkinson's disease.

Neuropharmacology 2021 03 22;186:108465. Epub 2021 Jan 22.

Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Movement Disorder Clinic, Division of Neurology, Department of Neuroscience, McGill University Health Centre, Montreal, QC, Canada. Electronic address:

Antagonising the serotonin 2A (5-HT) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu) receptors, in which 5-HT blockade and mGlu activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (l-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT antagonism and mGlu activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu positive allosteric modulator LY-487,379 and the 5-HT antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l-DOPA. In the last series of experiments, we investigated whether mGlu blockade would diminish the effects of antagonising 5-HT receptors. To this end, the mGlu orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l-DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of l-DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108465DOI Listing
March 2021

Detecting the Cognitive Prodrome of Dementia in Parkinson's Disease.

J Parkinsons Dis 2020 ;10(3):1033-1046

Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, CIUSSS du Nord-de-l'Île-de-Montréal, Montreal, QC, Canada.

Background: More than 75% of Parkinson's disease (PD) patients will develop dementia. Previous studies on the cognitive predictors of dementia in PD had some methodological limitations and the cognitive tests identified as good predictors vary greatly.

Objective: This prospective cohort study aims to identify the optimal cognitive predictors of dementia in PD using complementary statistical methods.

Methods: Eighty PD patients without dementia underwent polysomnographic recording, a neurological examination, and a complete neuropsychological assessment at baseline. They were then followed for a mean of 4.3 years. Baseline group comparisons and survival analyses were used to identify optimal cognitive predictors. Moreover, patients who developed dementia were pair-matched at baseline according to age, sex, and education to healthy controls (2 : 1), and receiver operating characteristic curves were calculated for cognitive tests.

Results: At follow-up, 23 patients (29%) developed dementia. PD patients who developed dementia had poorer baseline performance and a higher proportion of clinically impaired performance on several cognitive tests. Impaired baseline performance on the Block Design subtest was the best independent predictor of dementia (HR = 8). Moreover, the Trail Making Test part B (time) and Verbal Fluency (semantic) had the best psychometric properties (area under the curve >0.90) for identifying PD patients at risk of dementia.

Conclusion: The present study identified three cognitive tests as the most accurate to detect individuals with PD at high risk of developing dementia.
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http://dx.doi.org/10.3233/JPD-191857DOI Listing
January 2020

Effect of Antidepressants on Psychotic Symptoms in Parkinson Disease: A Review of Case Reports and Case Series.

Clin Neuropharmacol 2020 May/Jun;43(3):61-65

Département de Pharmacologie et Physiologie, Université de Montréal.

Objectives: The treatment of Parkinson disease (PD) psychosis remains a challenge. Only a few treatments eliciting significant relief of psychotic symptoms have passed the test of randomized controlled trials.

Methods: Here, we conducted a review of the literature on the effect of antidepressants on PD psychosis. Because there is no randomized controlled trial that assessed the antipsychotic effects of antidepressants in PD, only case reports, case series, and open-label trials were available to review. Because of the scarce literature, statistical analysis could not be performed.

Results: The following antidepressants alleviated hallucinations in PD: amoxapine, citalopram, clomipramine, escitalopram, mianserin, mirtazapine, and venlafaxine. The antidepressants were generally well tolerated, with the exception of amoxapine, which exacerbated parkinsonism.

Conclusions: Whereas the conclusions that can be drawn on the efficacy of antidepressants at reducing PD psychosis are limited because of the poor quality of the reported studies, it is encouraging to notice that there are positive anecdotal reports. Further studies are needed to confirm the potential of these drugs and also to determine if a subtype of patients or of psychotic features may be more likely to be improved by antidepressants.
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http://dx.doi.org/10.1097/WNF.0000000000000384DOI Listing
April 2021

Selective metabotropic glutamate receptor 2 positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.

Eur J Pharmacol 2020 Apr 28;873:172957. Epub 2020 Jan 28.

Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada; Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada. Electronic address:

Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD.
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http://dx.doi.org/10.1016/j.ejphar.2020.172957DOI Listing
April 2020

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.

J Parkinsons Dis 2020 ;10(1):301-313

Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.

Background: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository.

Objective: To present the QPN and to perform preliminary analysis of the QPN data.

Methods: A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups.

Results: QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN.

Conclusions: The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.
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http://dx.doi.org/10.3233/JPD-191775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029361PMC
April 2021

Brain atrophy in Parkinson's disease with polysomnography-confirmed REM sleep behavior disorder.

Sleep 2019 06;42(6)

Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada.

We aimed to investigate cortical and subcortical brain alterations in people with Parkinson's disease with polysomnography-confirmed rapid eye movement (REM) sleep behavior disorder (RBD). Thirty people with Parkinson's disease, including 15 people with RBD, were recruited and compared with 41 healthy controls. Surface-based cortical and subcortical analyses were performed on T1-weighted images to investigate thickness and shape abnormalities between groups, and voxel-based and deformation-based morphometry were performed to investigate local volume. Correlations were performed in patients to investigate the structural correlates of motor activity during REM sleep. People with RBD showed cortical thinning in the right perisylvian and inferior temporal cortices and shape contraction in the putamen compared with people without RBD. Compared with controls, people with RBD had extensive cortical thinning and volume loss, brainstem volume was reduced, and shape contraction was found in the basal ganglia and hippocampus. In comparison to controls, people without RBD showed more restricted thinning in the sensorimotor, parietal, and occipital cortices, reduced volume in the brainstem, temporal and more posterior areas, and shape contraction in the pallidum and hippocampus. In Parkinson's disease, higher tonic and phasic REM sleep motor activity was associated with contraction of the thalamic surface, extensive cortical thinning, and subtle volume reduction in the middle temporal gyrus. In Parkinson's disease, the presence of RBD is associated with extensive cortical and subcortical abnormalities, suggesting more severe neurodegeneration in people with RBD. This provides potential neuroanatomical correlates for the more severe clinical phenotype reported in people with Parkinson's disease with RBD.
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http://dx.doi.org/10.1093/sleep/zsz062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559168PMC
June 2019

Portrait of blood-derived extracellular vesicles in patients with Parkinson's disease.

Neurobiol Dis 2019 04 5;124:163-175. Epub 2018 Nov 5.

Centre de recherche du CHU de Québec, Québec, QC, Canada; Département de psychiatrie & neurosciences, Université Laval, Québec, QC, Canada. Electronic address:

The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) - for comparative purposes in individuals with another chronic neurodegenerative condition - and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD.
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http://dx.doi.org/10.1016/j.nbd.2018.11.002DOI Listing
April 2019

Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases.

Mol Neurobiol 2019 Jun 12;56(6):4317-4321. Epub 2018 Oct 12.

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Essential Tremor is a prevalent neurological disorder of unknown etiology. Studies suggest that genetic factors contribute to this pathology. To date, no causative mutations in a gene have been reproducibly reported. All three structures of the olivocerebellar motor circuitry have been linked to Essential Tremor. We postulated that genes enriched for their expression in the olivocerebellar circuitry would be more susceptible to harbor mutations in Essential Tremor patients. A list of 11 candidate genes, enriched for their expression in the olivocerebellar circuitry, was assessed for their variation spectrum and frequency in a cohort of Canadian Essential Tremor cases. Our results from this list of 11 candidate genes do not support an association for Essential Tremor in our cohort of Canadian cases. The heterogenic nature of ET and modest size of the cohort used in this study are two confounding factors that could explain these results.
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http://dx.doi.org/10.1007/s12035-018-1369-1DOI Listing
June 2019

No rare deleterious variants from , , and are associated with essential tremor.

Neurol Genet 2017 Oct 19;3(5):e195. Epub 2017 Oct 19.

Montreal Neurological Institute and Hospital (G.H., A.A., J.-F.S., C.S.L., D.S., S.B.L., C.V.B., P.A.D., G.A.R.), Quebec, Canada; Department of Human Genetics (G.H., A.A., C.S.L., P.A.D., G.A.R.) and Department of Neurology and Neurosurgery (J.-F.S., P.A.D., G.A.R.), McGill University, Montreal, Quebec, Canada; Xenon Pharmaceuticals Inc (C.G.), Burnaby, British Columbia, Canada; André Barbeau Movement Disorders Unit (M.P., S.C.), Centre Hospitalier Universitaire de Montréal (CHUM)-Notre-Dame, Quebec, Canada; Department of Medicine (N.D.), Faculty of Medicine, Laval University, Quebec, Canada; Département des Sciences Neurologiques (N.D.), CHU de Québec (Enfant-Jésus), Quebec, Canada; Department of Medical Genetics (C.V.-G.), University of British Columbia, Vancouver, British Columbia, Canada; Division of Neurology (A.R.), Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region, Saskatoon, Canada; and Département des Sciences Fondamentales (S.L.G.), Université du Québec à Chicoutimi, Saguenay, Canada.

Objective: To assess the contribution of variants in , , and as essential tremor (ET) predisposing factors following their association in a 2-stage genome-wide association study (GWAS).

Methods: The coding regions of these genes was examined for the presence of rare variants using two approaches: (1) Looking at whole-exome and whole-genome sequencing data of 14 autosomal dominant multiplex ET families. (2) Conducting a targeted massive parallel sequencing to examine the three genes in cohorts of 269 ET cases and 287 control individuals. The cumulative impact of rare variants was assessed using SKAT-O analyses using (1) all variants, (2) only rare variants, and (3) only the rare variants altering the mRNA.

Results: Thirty-four variants were identified. No difference emerged regarding the distributions of individual variants (or gene) between cases and controls.

Conclusion: No rare exonic variants further validated one of these genes as a risk factor for ET. The recent GWAS offers promising avenues, but the genetic heterogeneity of ET is nonetheless challenging for the validation of risk factors, and ultimately larger cohorts of cases should help to overcome this task.
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http://dx.doi.org/10.1212/NXG.0000000000000195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281551PMC
October 2017

Prevalence of Convergence Insufficiency-Type Symptomatology in Parkinson's Disease.

Can J Neurol Sci 2017 Sep;44(5):562-566

1École d'Optométrie,Université de Montréal,Montréal,Québec,Canada.

Background: Individuals with Parkinson's disease (PD) often present with visual symptoms (e.g., difficulty in reading, double vision) that can also be found in convergence insufficiency (CI). Our objective was to estimate the prevalence of CI-type visual symptomatology in individuals with PD, in comparison with controls.

Methods: Participants ≥50 years with (n=300) and without (n=300) PD were recruited. They were administered the Convergence Insufficiency Symptom Survey (CISS-15) over the phone. A score of ≥21 on the CISS-15, considered positive for CI-type symptomatology, served as the cutoff. Data from individuals (n=87 with, n=94 without PD) who were approached but who reported having a known oculovisual condition were analysed separately. Student's t test and chi-square at the 0.05 level were employed for statistical significance.

Results: A total of 29.3% of participants with versus 7.3% without PD presented with a score of ≥21 on the CISS-15 (p=0.001). Of the participants having a known oculovisual condition, 39.1% with versus 19.1% without PD presented with a score of ≥21 on the CISS-15 (p=0.01).

Conclusions: The prevalence of CI-type visual symptoms is higher in individuals with versus without PD whether or not they have a coexisting oculovisual condition. These results suggest that PD per se places individuals with the disease at greater risk of visual symptomatology. These results further underline the importance of providing regular eye exams for individuals with PD.
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http://dx.doi.org/10.1017/cjn.2017.39DOI Listing
September 2017

REM Sleep Behavior Disorder and Cognitive Impairment in Parkinson's Disease.

Sleep 2017 08;40(8)

Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada.

Study Objectives: REM sleep behavior disorder (RBD) is a parasomnia affecting 33% to 46% of patients with Parkinson's disease (PD). The existence of a unique and specific impaired cognitive profile in PD patients with RBD is still controversial. We extensively assessed cognitive functions to identify whether RBD is associated with more severe cognitive deficits in nondemented patients with PD.

Methods: One hundred sixty-two participants, including 53 PD patients with RBD, 40 PD patients without RBD, and 69 healthy subjects, underwent polysomnography, a neurological assessment and an extensive neuropsychological exam to assess attention, executive functions, episodic learning and memory, visuospatial abilities, and language.

Results: PD patients with RBD had poorer and clinically impaired performance in several cognitive tests compared to PD patients without RBD and healthy subjects. These two latter groups were similar on all cognitive measures. Mild cognitive impairment (MCI) diagnosis frequency was almost threefold higher in PD patients with RBD compared to PD patients without RBD (66% vs. 23%, p < .001). Moreover, subjective cognitive decline was reported in 89% of PD patients with RBD compared to 58% of PD patients without RBD (p = .024).

Conclusions: RBD in PD is associated with a more impaired cognitive profile and higher MCI diagnosis frequency, suggesting more severe and widespread neurodegeneration. This patient subgroup and their caregivers should receive targeted medical attention to better detect and monitor impairment and to enable the development of management interventions for cognitive decline and its consequences.
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http://dx.doi.org/10.1093/sleep/zsx101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806543PMC
August 2017

Orthoptic Treatment of Convergence Insufficiency in Parkinson's Disease: A Case Series.

Gerontol Geriatr Med 2017 Jan-Dec;3:2333721417703735. Epub 2017 Apr 11.

School of Optometry and Vision Science, University of Waterloo.

This study reports a case series of orthoptic treatment (OT) for convergence insufficiency (CI) in individuals with Parkinson's disease (PD). We are reporting two cases of individuals with PD who completed OT for CI. Both had a confirmed diagnosis of CI, accompanied by CI-type symptomatology. They each underwent an OT program consisting of three office-based visits and 8 weeks of home-based exercises. Treatment outcome was based on the changes measured pre- versus post-OT on the near point of convergence, positive fusional vergences, and symptomatology score. The two participants successfully completed therapy, gained ability to converge, had fewer symptoms, and were satisfied with the OT-induced changes they felt in their day-to-day lives. This case series show that OT for CI in PD is possible. Further research is required as these results demonstrate that OT has the potential to improve symptomatic CI in these patients. In the meantime, the positive results obtained in these two cases should encourage clinicians to consider OT (a therapy with no/minimal risk) for CI in patients with PD whose quality of life is affected by this binocular dysfunction.
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http://dx.doi.org/10.1177/2333721417703735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406117PMC
April 2017

Enteral Feeding Using Levodopa-Carbidopa Intestinal Gel Percutaneous Endoscopic Gastrostomy Tube.

Mov Disord Clin Pract 2017 Sep-Oct;4(5):787-788. Epub 2017 May 5.

Service de Neurologie du Département de Médecine Unité des Troubles du Mouvement André-Barbeau Centre Hospitalier de l'Université de Montréal Montréal Canada.

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http://dx.doi.org/10.1002/mdc3.12490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353387PMC
May 2017

Teneurin transmembrane protein 4 is not a cause for essential tremor in a Canadian population.

Mov Disord 2017 02 3;32(2):292-295. Epub 2017 Feb 3.

Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.

Introduction: Mutations in teneurin transmembrane protein 4 were reported to be a risk factor for essential tremor, but the relevance of this across different population remains to be examined. The aim of this study was to determine the frequency and spectrum of variations in teneurin transmembrane protein 4 in a cohort of Canadian essential tremor cases.

Methods: The coding portion of teneurin transmembrane protein 4 was sequenced in 269 unrelated essential tremor cases and 288 matched control individuals using a targeted and high-throughput sequencing approach.

Results: A total of 157 single nucleotide variations were identified, and from these 99 were a missense or nonsense mutation. A total of 68 cases were carriers of ≥1 rare missense or nonsense mutations, and 39 control individuals were carriers of the same types of variations. Gene-based association tests were used to jointly analyze the single nucleotide variations.

Conclusions: Our results do not support a positive association between teneurin transmembrane protein 4 and the Canadian population. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26753DOI Listing
February 2017

Establishing a Standard of Care for Deep Brain Stimulation Centers in Canada.

Can J Neurol Sci 2017 Mar 22;44(2):132-138. Epub 2016 Nov 22.

4Division of Neurosurgery,University of British Columbia,Vancouver,British Columbia,Canada.

During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to share their knowledge regarding deep brain stimulation (DBS) management of movement disorders in three domains: (1) the programming algorithms, (2) the necessary team to run a neurosurgery program, and (3) the appropriate scales to better define in a more comprehensive fashion the effect of the brain surgery. Each presentation was followed by an open discussion, and this article reports on the conclusions of this meeting on these three questions. Concerning programming, the role of the pulse width and the switching off of the stimulation at night for thalamic stimulation for the control of tremor have been discussed. The algorithms proposed in the literature for programming in Parkinson's disease (PD) need validation. In dystonia, the use of monopolar vs bipolar parameters, the use of low vs high frequencies and the use of smaller versus larger pulse widths all need to be examined properly. Concerning the necessary team to run a neurosurgical program, recommendations will follow the suggestions for standardized outcome measures. Regarding the outcome measures for DBS in PD, investigations need to focus on the non-motor aspects of PD. Identifying which nonmotor symptoms respond to DBS would allow a better screening before and satisfaction postoperatively. There is an important need for more data to determine the optimal programming protocol and the standard measures that should be performed routinely by all centers.
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http://dx.doi.org/10.1017/cjn.2016.409DOI Listing
March 2017

Prevalence of Convergence Insufficiency in Parkinson's Disease.

Mov Disord Clin Pract 2017 May-Jun;4(3):424-429. Epub 2016 Nov 20.

School of Optometry University of Montréal Montréal QC Canada.

Background: We recently reported that convergence insufficiency (CI)-type visual symptomatology was more prevalent in participants with Parkinson's disease (PD), compared to controls. The objective of this work was to determine the prevalence of a confirmed clinical diagnosis of CI in PD, compared to controls.

Methods: Participants with (n = 80) and without (n = 80) PD were recruited and received an eye exam. Published criteria were used to arrive at a clinical diagnosis of CI. The Convergence Insufficiency Symptom Survey (CISS-15) questionnaire was administered to each participant, with a score of ≥21 being considered positive for CI symptomatology. Student test, chi-square, or nonparametric tests at the 0.05 level were used for statistical significance.

Results: A total of 43.8% of participants with versus 16.3% without PD had a clinical diagnosis of CI ( 0.001). A total of 53.8% of participants with versus 18.8% without PD had scores on the CISS-15 of ≥21 ( 0.001).

Conclusions: These results indicate that individuals with PD have a higher prevalence of CI and CI symptomatology than controls. These data provide evidence supporting the notion that treatment for symptomatic CI should be investigated in individuals with PD.
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http://dx.doi.org/10.1002/mdc3.12453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174402PMC
November 2016

Open-Label Study of Sleep Disturbances in Patients with Parkinson's Disease Treated with Rasagiline.

Can J Neurol Sci 2016 Nov;43(6):809-814

1Centre Hospitalier de l'Université de Montréal (University of Montreal Hospital Center) and Centre de recherche du Centre Hospitalier de l'Université de Montréal (University of Montreal Hospital Center Research Center) Hôpital Notre-Dame,Département de médecine (Neurologie) Université de Montréal,Montréal,Québec.

Background: The prevalence of sleep disturbances among patients with Parkinson's disease (PD) is estimated to occur in 37% to 98% of patients. Sleep disturbances have been associated with a reduced quality of life for patients with PD. The objective of this study was to assess the impact of rasagiline treatment on the severity of sleep disturbances among patients with idiopathic PD.

Methods: In this open-label, multicentre study, 110 adult patients with idiopathic PD were treated with rasagiline either as monotherapy or as adjunct therapy. The primary endpoint was the change in severity of sleep disturbances, assessed with the PD Sleep Scale from baseline to month 2. Exploratory endpoints included change in daytime sleepiness, assessed with the Epworth Sleep Scale, treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication, patient's overall improvement or deterioration over time measured with the Clinical Global Impression of Improvement, tolerability, and safety.

Findings: Patients treated with rasagiline as mono- or adjunct therapy showed a statistically significant improvement in sleep quality after 2 months. There was no change in daytime sleepiness. Overall, patients were satisfied with rasagiline treatment with a mean Treatment Satisfaction Questionnaire for Medication [standard deviation] total score at month 2 of 68% [16.1]. At the end of study, 64 patients (65.9%) were judged, by the investigator, as being at least minimally improved from baseline on the Clinical Global Impression of Improvement. Rasagiline was safe and well-tolerated.

Interpretation: Rasagiline as mono- or adjunct-therapy may improve sleep experience in patients with PD in the short term.
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http://dx.doi.org/10.1017/cjn.2016.289DOI Listing
November 2016

Genome-wide association study in essential tremor identifies three new loci.

Brain 2016 12 20;139(Pt 12):3163-3169. Epub 2016 Oct 20.

15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
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http://dx.doi.org/10.1093/brain/aww242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382938PMC
December 2016

Medical Management of Parkinson's Disease after Initiation of Deep Brain Stimulation.

Can J Neurol Sci 2016 Sep;43(5):626-34

1Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease,Toronto Western Hospital,and Division of Neurology,University Health Network,University of Toronto,Toronto,Ontario,Canada.

In this review, we have gathered all the available evidence to guide medication management after deep brain stimulation (DBS) in Parkinson's disease (PD). Surprisingly, we found that almost no study addressed drug-based management in the postoperative period. Dopaminergic medications are usually reduced, but whether the levodopa or dopamine agonist is to be reduced is left to the personal preference of the treating physician. We have summarized the pros and cons of both approaches. No study on the management of cognitive problems after DBS has been done, and only a few studies have explored the pharmacological management of such DBS-resistant symptoms as voice (amantadine), balance (donepezil) or gait disorders (amantadine, methylphenidate). As for the psychiatric problems so frequently reported in PD patients, researchers have directed their attention to the complex interplay between stimulation and reduction of dopaminergic drugs only recently. In conclusion, studies addressing medical management following DBS are still needed and will certainly contribute to the ultimate success of DBS procedures.
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http://dx.doi.org/10.1017/cjn.2016.274DOI Listing
September 2016

Eligibility Criteria for Deep Brain Stimulation in Parkinson's Disease, Tremor, and Dystonia.

Can J Neurol Sci 2016 Jul 3;43(4):462-71. Epub 2016 May 3.

1Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease,Toronto Western Hospital,University Health Network,Toronto,Ontario,Canada.

In this review, the available evidence to guide clinicians regarding eligibility for deep brain stimulation (DBS) in the main conditions in which these forms of therapy are generally indicated-Parkinson's disease (PD), tremor, and dystonia-is presented. In general, the literature shows that DBS is effective for PD, essential tremor, and idiopathic dystonia. In these cases, key points in patient selection must include the level of disability and inability to manage symptoms using the best available medical therapy. Results are, however, still not optimal when dealing with other aetiologies, such as secondary tremors and symptomatic dystonia. Also, in PD, issues such as age and neuropsychiatric profile are still debatable parameters. Overall, currently available literature is able to guide physicians on basic aspects of patient selection and indications for DBS; however, a few points are still debatable and controversial. These issues should be refined and clarified in future studies.
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http://dx.doi.org/10.1017/cjn.2016.35DOI Listing
July 2016

Deep Brain Stimulation Target Selection for Parkinson's Disease.

Can J Neurol Sci 2017 Jan 15;44(1):3-8. Epub 2016 Mar 15.

6Division of Neurology,Department of Medicine,Hôpital Notre-Dame,University of Montreal Health Centre,Montréal,Québec,Canada.

During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.
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http://dx.doi.org/10.1017/cjn.2016.22DOI Listing
January 2017

Electroencephalographic prodromal markers of dementia across conscious states in Parkinson's disease.

Brain 2016 Apr 16;139(Pt 4):1189-99. Epub 2016 Feb 16.

Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada Department of Psychology, Université du Québec à Montréal, Montreal, Quebec, Canada

In Parkinson's disease, electroencephalographic abnormalities during wakefulness and non-rapid eye movement sleep (spindles) were found to be predictive biomarkers of dementia. Because rapid eye movement sleep is regulated by the cholinergic system, which shows early degeneration in Parkinson's disease with cognitive impairment, anomalies during this sleep stage might mirror dementia development. In this prospective study, we examined baseline electroencephalographic absolute spectral power across three states of consciousness (non-rapid eye movement sleep, rapid eye movement sleep, and wakefulness) in 68 non-demented patients with Parkinson's disease and 44 healthy controls. All participants underwent baseline polysomnographic recordings and a comprehensive neuropsychological assessment. Power spectral analyses were performed on standard frequency bands. Dominant occipital frequency during wakefulness and ratios of slow-to-fast frequencies during rapid eye movement sleep and wakefulness were also computed. At follow-up (an average 4.5 years after baseline), 18 patients with Parkinson's disease had developed dementia and 50 patients remained dementia-free. In rapid eye movement sleep, patients with Parkinson's disease who later developed dementia showed, at baseline, higher absolute power in delta and theta bands and a higher slowing ratio, especially in temporal, parietal, and occipital regions, compared to patients who remained dementia-free and controls. In non-rapid eye movement sleep, lower baseline sigma power in parietal cortical regions also predicted development of dementia. During wakefulness, patients with Parkinson's disease who later developed dementia showed lower dominant occipital frequency as well as higher delta and slowing ratio compared to patients who remained dementia-free and controls. At baseline, higher slowing ratios in temporo-occipital regions during rapid eye movement sleep were associated with poor performance on visuospatial tests in patients with Parkinson's disease. Using receiver operating characteristic curves, we found that best predictors of dementia in Parkinson's disease were rapid eye movement sleep slowing ratios in posterior regions, wakefulness slowing ratios in temporal areas, and lower dominant occipital frequency. These results suggest that electroencephalographic slowing during sleep is a new promising predictive biomarker for Parkinson's disease dementia, perhaps as a marker of cholinergic denervation.
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http://dx.doi.org/10.1093/brain/aww018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841211PMC
April 2016

A Man With Persistent Dopamine Agonist Withdrawal Syndrome After 7 Years Being Off Dopamine Agonists.

Can J Neurol Sci 2016 Nov 4;43(6):859-860. Epub 2016 Feb 4.

1Espera Neuroscience Inc,Montreal, QC,Canada.

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http://dx.doi.org/10.1017/cjn.2015.389DOI Listing
November 2016

Brain Connectivity Alterations Are Associated with the Development of Dementia in Parkinson's Disease.

Brain Connect 2016 Apr;6(3):216-24

2 Centre for Advanced Research in Sleep Medicine , Hôpital du Sacré-Cœur de Montréal, Montreal, Canada .

Dementia affects a high proportion of Parkinson's disease (PD) patients and poses a burden on caregivers and healthcare services. Electroencephalography (EEG) is a common nonevasive and nonexpensive technique that can easily be used in clinical settings to identify brain functional abnormalities. Only few studies had identified EEG abnormalities that can predict PD patients at higher risk for dementia. Brain connectivity EEG measures, such as multiscale entropy (MSE) and phase-locking value (PLV) analyses, may be more informative and sensitive to brain alterations leading to dementia than previously used methods. This study followed 62 dementia-free PD patients for a mean of 3.4 years to identify cerebral alterations that are associated with dementia. Baseline resting state EEG of patients who developed dementia (N = 18) was compared to those of patients who remained dementia-free (N = 44) and of 37 healthy subjects. MSE and PLV analyses were performed. Partial least squares statistical analysis revealed group differences associated with the development of dementia. Patients who developed dementia showed higher signal complexity and lower PLVs in low frequencies (mainly in delta frequency) than patients who remained dementia-free and controls. Conversely, both patient groups showed lower signal variability and higher PLVs in high frequencies (mainly in gamma frequency) compared to controls, with the strongest effect in patients who developed dementia. These findings suggest that specific disruptions of brain communication can be measured before PD patients develop dementia, providing a new potential marker to identify patients at highest risk of developing dementia and who are the best candidates for neuroprotective trials.
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http://dx.doi.org/10.1089/brain.2015.0390DOI Listing
April 2016

Observational Study of the Relation between Parkinson's Disease and Sleep Apnea.

J Parkinsons Dis 2015 ;5(4):805-11

Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada.

Background: Parkinson's disease is characterized by numerous non-motor symptoms, including sleep disorders. Sleep apnea has been reported in a substantial proportion of patients with Parkinson's disease, but it is unclear whether it has significant consequences for the quality of life of those affected or whether it is associated with other manifestations of the disease.

Objective: To verify whether sleep apnea is associated with more severe motor and non-motor clinical features in Parkinson's disease.

Methods: Parkinson's disease patients underwent polysomnography to diagnose the presence of sleep apnea (apnea-hypopnoea index >10). Participants also underwent an extensive assessment, blinded to sleep apnea status, to determine disease severity, quantitative motor indices, motor subtypes, treatment complications, and sleep, autonomic, psychiatric, and sensory dysfunctions. Cognitive status was also determined with a complete neuropsychological assessment. Results were assessed using regression analysis adjusted for age, sex, and disease duration.

Results: Of 92 patients examined, 19 had sleep apnea (21%) and 73 did not. We found no significant differences in motor and non-motor symptoms or signs between apneic and non-apneic Parkinson's disease patients. The use of different apnea-hypopnoea index cut-offs (>5 and >15) produced similar results.

Conclusions: Our results show that sleep apnea is not associated with more severe motor or non-motor manifestations in Parkinson's disease. More studies including control groups are needed to confirm the implications of those results.
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http://dx.doi.org/10.3233/JPD-150602DOI Listing
September 2016

Development and evaluation of a dyadic intervention for elderly couples living with moderate-stage Parkinson disease.

Appl Nurs Res 2015 Nov 26;28(4):e21-7. Epub 2015 Feb 26.

Faculty of Nursing, Université de Montréal, H3C 3J7 Montréal, Canada; Faculty of Medicine, Université de Montréal, H3C 3J7 Montréal, Canada.

Purpose: The purpose of this qualitative study was to develop, test and evaluate a dyadic intervention for elderly couples living with moderate-stage Parkinson disease.

Methods: Based on Meleis's theory of transitions and following systemic and participatory approaches, the study comprised four steps informed by the intervention mapping process: 1) assessing couples' intervention needs, preferences and objectives; 2) developing and validating a dyadic intervention proposal; 3) formalizing the dyadic intervention; and 4) testing and evaluating the dyadic intervention.

Results: The dyadic intervention consisted of seven 90-minutes sessions held every other week. Intervention content and strategies used were based on couples' needs, preferences and objectives, as well as specific theories, models and empirical findings.

Conclusion: This study can assist nurses involved in different domains of practice and interested in developing and evaluating theoretically based dyadic interventions.
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http://dx.doi.org/10.1016/j.apnr.2015.02.004DOI Listing
November 2015

Sleep spindles in Parkinson's disease may predict the development of dementia.

Neurobiol Aging 2015 Feb 18;36(2):1083-90. Epub 2014 Sep 18.

Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Quebec, Canada; Department of Psychology, Université du Québec à Montréal, Montreal, Quebec, Canada. Electronic address:

Sleep disturbances and cognitive impairment are common non-motor manifestations of Parkinson's disease (PD). Recent studies suggest that sleep spindles and slow waves play a role in brain plasticity mechanisms and are associated with cognitive performance. However, it remains unknown whether these sleep parameters could serve as markers of cognitive decline in PD. Therefore, we examined whether alterations in sleep spindles and slow waves at baseline visit were associated with increased likelihood of developing dementia at follow-up in PD. Sixty-eight nondemented PD patients (64.9 ± 8.8 years old; 46 men) participated in the study, along with 47 healthy individuals (65.0 ± 10.6 years old; 30 men). All participants underwent baseline polysomnographic recording and a comprehensive neuropsychological assessment. Sleep spindles (12-15 Hz) and slow waves (>75 μV and <4 Hz) were automatically detected on all-night non-rapid eye movement sleep electroencephalography. At follow-up (mean: 4.5 years later), 18 PD patients developed dementia (70.2 ± 7.6 years old; 13 men) and 50 remained dementia-free (63.0 ± 8.5 years old; 33 men). Sleep spindle density and amplitude were lower in PD patients who converted to dementia compared with both patients who remained dementia-free and controls, mostly in posterior cortical regions (p < 0.05). Dementia-free PD patients were intermediate between dementia patients and controls, with lower baseline sleep spindle density in all cortical areas compared with controls (p < 0.01). In demented PD patients, lower sleep spindle amplitude in parietal and occipital areas was associated with poorer visuospatial abilities. Although slow wave amplitude was lower in PD patients compared with controls (p < 0.0001), no difference was observed between those who developed or did not develop dementia. Results demonstrate non-rapid eye movement sleep electroencephalographic abnormalities in PD patients. Sleep spindle activity was particularly impaired in PD patients who developed dementia, with a more posterior topographic pattern. Sleep spindle alterations are associated with later development of dementia in PD, and thus may serve as an additional marker of cognitive decline in these patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.009DOI Listing
February 2015

Physical activity in advanced Parkinson's disease: impact of subthalamic deep brain stimulation.

J Parkinsons Dis 2015 ;5(1):85-93

Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal, Montréal, Québec, Canada Département de Kinanthropologie, Université du Québec à Montréal, Montréal, Québec, Canada.

Background: Maintaining a physically active lifestyle promotes general health. Recent studies have demonstrated that patients with Parkinson's disease (PD) fail to meet the suggested levels of physical activity and that targeted interventions do not always improve this behavior. One validated treatment for motor symptoms in PD is subthalamic stimulation (STN DBS).

Objective: Assess whether motor symptom improvement following STN DBS translated into increased physical activity behavior.

Methods: Twenty patients with PD scheduled for bilateral STN DBS filled-out the Phone-FITT physical activity questionnaire and the SF-36 quality of life questionnaire prior to surgery and 6 to 9 months postoperatively. Data were compared to age- and gender-matched healthy controls.

Results: Our results demonstrate that PD patients' quality of life is significantly lower than healthy controls. While STN DBS improves motor symptoms in the intermediate term, it only improves some aspects of quality of life related to physical function. Furthermore, STN DBS does not modify physical activity behavior measured by the Phone-FITT, whether for household or recreational activities.

Conclusion: The current study demonstrates that the motor improvements observed after STN DBS do not lead to systematic improvements in all aspects of quality of life or increased levels of physical activity. This highlights the need to develop and implement intervention strategies to promote an active lifestyle in this population, even if clinical improvement is evident following surgery.
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http://dx.doi.org/10.3233/JPD-140426DOI Listing
November 2015

Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO).

Pharmacotherapy 2014 Dec 14;34(12):1250-8. Epub 2014 Oct 14.

Hôpital Notre-Dame du CHUM, Montréal, Québec, Canada.

Background: The serotonin toxicity syndrome (STS) is a potential risk with concurrent use of the monoamine oxidase type-B inhibitor rasagiline and antidepressants.

Objective: To assess systematically the occurrence of STS in patients with Parkinson disease (PD) treated with rasagiline plus antidepressants (R+ATD), rasagiline without antidepressants (R), or antidepressants plus anti-PD dopaminergic medications (ATD) other than either rasagiline or selegiline.

Methods: A phase IV multicenter retrospective cohort study was conducted of patients with PD who began receiving R+ATD, R, or ATD between September 1, 2006, and December 31, 2008. Medical records were reviewed for patient demographics, treatment details, and hospitalizations/emergency department (ED) visits. An adjudication committee independently reviewed records to verify case ascertainment and used the Hunter Serotonin Toxicity Criteria for case definition. Outcome variables were analyzed by descriptive statistics.

Results: A total of 1504 patients with PD (471 with R+ATD; 511 with R; and 525 with ATD) were enrolled from 37 sites. In the R+ATD and ATD groups, selective serotonin reuptake inhibitors (SSRIs) were most frequently used (74.5% and 77%, respectively). In the R+ATD and ATD groups, mean duration of antidepressant use (tricyclic, SSRI, and other) were 50.5-53.5 weeks and 51.7-80.9 weeks, respectively. Overall, 195 patients (13%) from all three groups had one or more hospitalization/ED visits. No cases of STS were identified in any group.

Conclusions: In this large multicenter retrospective cohort study, concurrent administration of R+ATD was not associated with STS. The findings of this phase IV study expand the drug interaction and pharmacovigilance safety awareness for the use of antidepressants in patients with PD.
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http://dx.doi.org/10.1002/phar.1500DOI Listing
December 2014

Increased Prevalence of Non-motor Symptoms in Essential Tremor.

Tremor Other Hyperkinet Mov (N Y) 2014 2;4:162. Epub 2014 Sep 2.

André-Barbeau Movement Disorders Unit Service of Neurology, Centre Hospitalier de l'Université de Montréal and Department of Medicine, Université de Montréal, Montréal, Québec, Canada.

Background: Cases with essential tremor (ET) have been described with Lewy body inclusions, the hallmark of Parkinson disease (PD). Patients with PD may suffer from anosmia, depression, constipation, and rapid eye movement sleep behavior disorder (RBD), sometimes years before the appearance of their motor syndrome. The objective of this study was to evaluate the prevalence of these non-motor Parkinson's associated symptoms in patients with ET.

Methods: Fifty ET subjects were contacted by phone and given questionnaires evaluating the presence or absence of anosmia, depression, constipation, and RBD. Frequencies of these symptoms were compared with their published prevalence in the general population.

Results: Of the patients with ET, 4.5% reported having anosmia or hyposmia and 21.7% reported being constipated, similar to what is observed in the general population. Using a screening questionnaire for RBD, 43.5% of ET patients are possibly suffering from RBD, whereas in the general population prevalence is estimated to be 0.5%. Finally, depression was detected in 21.7% of ET patients; in the general population, prevalence is 5%.

Discussion: Patients with ET seem to have more RBD and more depression than found in the general population. Prospective studies with normal control groups are needed to confirm these findings.
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http://dx.doi.org/10.7916/D82V2D91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159683PMC
September 2014