Intestinal Levodopa/Carbidopa Infusion as a Therapeutic Option for Unresponsive Freezing of Gait after Deep Brain Stimulation in Parkinson's Disease

Background. Treatment of freezing of gait (FOG) is always challenging because of its unpredictable nature and multifactorial physiopathology. Intestinal levodopa infusion has been proposed in recent years as a valuable option for its improvement. FOG in Parkinson's disease (PD) can appear after deep brain stimulation in patients who never had gait symptoms. Objective. To study the effects of intestinal levodopa/carbidopa infusion in unresponsive-FOG that appears in PD patients treated with subthalamic nucleus deep brain stimulation. Methods. We retrospectively collected and analyzed demographic, clinical, and therapeutic data from five PD patients treated with subthalamic nucleus stimulation who developed unresponsive-FOG and received intestinal levodopa/carbidopa infusion as an alternative therapy. FOG was measured based on scores in item 14 of the Unified Parkinson's Disease Rating Scale before and after intestinal levodopa infusion. Results. Administration of intestinal levodopa caused improvement of FOG in the "ON" state in four patients (80%) by 2 or more points in item 14 of the Unified Parkinson's Disease Rating Scale. The improvement was maintained for at least 12 months. Conclusions. Intestinal levodopa infusion may be a valuable therapeutic option for unresponsive-FOG developed after subthalamic nucleus deep brain stimulation

Dopamine D2 receptor-mediated modulation of adenosine A2A receptor agonist binding within the A2AR/D2R oligomer framework

The molecular interaction between adenosine A(2A) and dopamine D-2 receptors (A(2A)Rs and D(2)Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A(2A)R challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D2R-mediated allosteric modulation of A(2A)R binding when an A(2A)R/D2R oligomer is established. Thus, we synthesized fluorescent A(2A)R agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A(2A)R binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A(2A)R agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A(2A)R agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D(2)Rs to modulate A(2A)R binding, thus serving to facilitate the preliminary selection of D2R-like candidate drugs in the management of Parkinson's disease. (c) 2013 Elsevier Ltd. All rights reserved

Opcions disponibles en la cirurgia de la malaltia de Parkinson i la tremolor essencial

Parkinson; Tremolor; CirurgiaParkinson; Temblor; CirugíaParkinson's; Shaking; SurgeryAquest document conté una revisió de revisions i d’informes de síntesi, en què s’han seleccionat els informes d’avaluació de tecnologies sanitàries i les guies de pràctica clínica, s’han descrit de forma narrativa els resultats i, mitjançant la tècnica qualitativa de grup nominal, s’ha elaborat una taula comparativa amb recomanacions sobre les indicacions per a cada tipus de tècnica quirúrgica.Este documento contiene una revisión de revisiones y de informes de síntesis, en que se han seleccionado los informes de evaluación de tecnologías sanitarias y las guías de práctica clínica. Se han descrito de forma narrativa los resultados y, mediante la técnica cualitativa de grupo nominal, se ha elaborado una mesa comparativa con recomendaciones sobre las indicaciones para cada tipo de técnica quirúrgica.This document contains review of reviews and synthesis reports has been prepared, in which health technology assessment reports and clinical practice guidelines were selected. The results have been described narratively, and, through a qualitative nominal group technique, a comparative table has been drawn up with recommendations on indications for each type surgical intervention

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation

Unusual Forehead Tremor in Four Patients with Essential Tremor

Forehead tremor has only been reported in two patients with essential tremor, one with rhythmic tremor and the other with dystonic tremor. We report 4 new patients with essential tremor who present a 4–6 Hz frontal tremor registered by electromyography and unusual features like frontal tremor preceding limb tremor or unilateral involvement. Frontal tremor is present in some patients with essential tremor, sometimes preceding limb tremor. Treatment with botulinum toxin may be useful

Sleep disorders in parkinsonian and nonparkinsonian LRRK2 mutation carriers

OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD./nRESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.This manuscript received support through the grant number 061130/31 from "La Fundació la Marató de TV3" to Eduard Tolosa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD