Restless legs syndrome (RLS) is a sensory-motor disorder characterized by abnormal circadian rhythm with an increase in the severity of sensory and motor symptoms at night. Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, to date, cognitive functions especially cognitive control in RLS has been poorly understood. Given that cognitive control is a key to leading a self-serving and successful life, including many aspects of employment, social life, and attaining long-term goals, this thesis aimed to examine cognitive control and the underlying mechanisms in RLS. Thalamic gamma aminobutyric acid (GABA), which has been linked to RLS sensory-motor symptoms, also plays an important role in cognitive control. Therefore, the potential relationship between thalamic GABA level and cognitive control in RLS was examined (Study I). RLS patients displayed reduced working memory-based control performances as compared to healthy controls. Elevated thalamic GABA was found to attenuate the observed control deficits in RLS, even though changes in thalamic GABA levels might not be the ultimate causes of these deficits. According to the modulatory effect of thalamic GABA on thalamic activity and thalamo-cortical connectivity, relatively higher GABA levels may have helped RLS patients compensate for their pathological changes such as thalamic hyperactivity and hypoconnectivity, which may underpin the observed control deficits. The critical feature of RLS, abnormal circadian rhythm is thought to be related to nocturnal striatal dopamine deficiency. Concerning the dopaminergic modulation of cognitive control, the circadian variation of cognitive control processes has been investigated (Study II & III). RLS patients displayed reduced attentional control (Study II) and automatic response activation (Study III) at night, which resulted from decreased activation within the extra-striate visual cortex, the superior parietal cortex, and the premotor cortex. As there were no activity changes within the prefrontal cortex, it is likely that cortico-basal ganglia cognitive loops were less prone to RLS. Instead, striatal dopamine deficiency at night may have influenced the cortico-cortical functional connectivity and cortico-basal ganglia motor loops in RLS. These findings not only shed light on the underlying mechanisms of cognitive control, but also advance early clinical treatment possibilities for cognitive changes in RLS patients. Furthermore, recent insights into daytime-related cognition may help patients develop a suitable daytime schedule to minimize the detrimental effects induced by cognitive deficits.

Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. / Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

Le syndrome des impatiences musculaires de l’éveil (SIME) est un trouble sensitivo-moteur causant des perturbations du sommeil. Il fut décrit que ce syndrome est plus fréquent chez les sujets vivant avec la sclérose en plaques (SEP) que dans la population générale. L’objectif principal de ce travail est de décrire l’impact du SIME sur le sommeil des sujets avec la sclérose en plaques, comparé au sommeil de sujets avec la SEP, mais sans SIME. Des questionnaires validés et des études de polysomnographie seront utilisés pour réaliser nos objectifs. Les études de PSG de nos 49 sujets révèlent qu’indépendamment de la présence ou de l’absence du SIME, le sommeil des sujets avec la SEP est grandement perturbé. De plus, même en l’absence du SIME, les sujets avec la SEP présentent des mouvements périodiques des jambes. Cette étude démontre que le SIME se manifeste différemment dans la SEP. De plus amples recherches sont nécessaires pour mieux caractériser le SIME en SEP. / The Restless legs syndrome is a sleep related movement disorder. It causes sleep disruptions, affecting sleep quality. It has been described as being more frequent in an MS population than in the general population. Our main objective was to evaluate its impact on MS subjects’ sleep in comparison to MS subjects without RLS Validated questionnaires and polysomnography was used to achieve our objective. PSG studies of our 49 subjects revealed that independently of RLS status, MS subjects experience bad sleep quality, based on various sleep quality markers. Moreover, MS subjects without RLS also have periodic leg movements. This study reveals that RLS in MS manifests itself differently. Further research is needed to characterise RLS in MS.

No description available.

Síndrome das pernas inquietas (SPI) é um distúrbio do sono com alta prevalência entre pacientes em hemodiálise, nos quais o mecanismo é pouco conhecido. Tem sido postulado que alterações do metabolismo mineral e ósseo relacionadasà doença renal crônica, especialmente o hiperparatireoidismo secundário, possam estar relacionadas à patogênese da SPI. Este trabalho teve como objetivo principal avaliar a SPI antes e após paratireoidectomia (PTX). Além disso, avaliamos dados objetivos do sono por meio de polissonografia, com ênfase em apneia do sono. Estudamos prospectivamente 19 pacientes (6 homens, idade 48 ± 11 anos) com hiperparatireoidismo grave pré e pós-PTX. O diagnóstico e o escore de gravidade da SPI foram avaliados de acordo com o Grupo de Estudo Internacional de SPI. Polissonografia pré e pós-PTX forneceu dados de arquitetura do sono, movimentos periódicos de pernas e apneia do sono, medida por meio do índice de apneia-hipopneia/hora de sono (IAH). SPI foi encontrada em 10 pacientes (53%) e se associou com maiores níveis de fosfato (p=0,005) e maior gravidade da dor (p=0,003). Após a PTX, houve redução dos níveis séricos de paratormônio, fosfato e aumento dos níveis de 25-hidroxivitamina D, calicreína-6 e fetuína-A. A PTX reduziu a SPI para 21% (p=0,044), acompanhada por redução nos escores de gravidade e alívio da dor e do prurido. A análise de regressão logística mostrou que o fosfato pré-PTX permaneceu independentemente associado com SPI (OR=7,28; p=0,035), em modelo ajustado para hemoglobina, idade e sexo. Apneia do sono (IAH > 5) foi encontrada em 11 pacientes pré e 14 pós-PTX (63% vs. 74%, p=0,698). Observamos uma correlação entre o IAH e a relação água corporal extracelular/massa magra (r=0,535, p=0,018), assim como correlação com a circunferência do pescoço pré-PTX (r=0,471, p=0,042). Entretanto, não observamos correlação do IAH com o deslocamento de fluidos da perna direita durante o sono (p=0,09), que aumentou significativamente após PTX (p=0,011). Concluímos que a PTX melhora a SPI, com cura completa ou melhora significativa. Se essa melhora está relacionada à diminuição do paratormônio ou do fósforo necessita de investigação adicional. Além disso, o presente estudo confirma a alta prevalência de apneia do sono entre pacientes em hemodiálise, o que não se modificou com a PTX / Restless legs syndrome (RLS) is a sleep disorder with high prevalence among patients on hemodialysis, which underlying mechanism is still unknown. It has been postulate that bone metabolism disorder, especially secondary hyperparathyroidism may be implicated in the pathogenesis. The present study aimed to evaluate RLS before and after parathyroidectomy (PTX). In addition, we evaluated objective data through polysomnography, focusing on sleep apnea. We prospectively evaluated 19 patients (6 men, aged 48 ± 11 years) with severe hyperparathyroidism pre and post-surgical treatment, parathyroidectomy (PTX). RLS diagnosis and rating scale were accessed based on the International RLS Study Group. Polysomnography pre and post PTX provided data on sleep architecture, periodic leg movements of sleep and apnea-hypopnea index (AHI). RLS was observed in 10 patients (53%), and was associated with higher levels of phosphate (p=0,005) and severe pain (p=0,003). After PTX, there was a reduction of serum parathyroid hormone, serum phosphate, and an increase of 25hydroxyvitamin D, kallicrein-6 and Fetuin-A. PTX improved RLS to 21% (p=0,04), accompanied by a decrease in rating scale, in association with alleviation of pain and pruritus. Logistic regression shows that serum phosphate pre PTX remained independently associated with RLS (HR=7,28; p=0,035), in a model adjusted for hemoglobin, age and gender. Sleep apnea (AHI > 5) was found in 11 patients pre and 14 patients post PTX (63% vs. 74%, p=0,698). There was a correlation between AHI and the relation extracellular water/ lean body mass (r=0,535; p=0,018) as well as a correlation between AHI and neck circumference (r=0,471; p=0,042). However, there was no correlation between AHI and spontaneous rostral fluid shift (p=0,09) that has increased after PTX (p=0,011). We concluded that PTX provided an opportunity to improve RLS. Whether RLS may be improved by reduction of serum phosphorus or parathyroid hormone, merits further investigation. In addition, PTX had no impact on the high prevalence of sleep apnea in this population

No description available.

Le syndrome des impatiences musculaires de l’éveil (SIME) est un trouble sensitivo-moteur causant des perturbations du sommeil. Il fut décrit que ce syndrome est plus fréquent chez les sujets vivant avec la sclérose en plaques (SEP) que dans la population générale. L’objectif principal de ce travail est de décrire l’impact du SIME sur le sommeil des sujets avec la sclérose en plaques, comparé au sommeil de sujets avec la SEP, mais sans SIME. Des questionnaires validés et des études de polysomnographie seront utilisés pour réaliser nos objectifs. Les études de PSG de nos 49 sujets révèlent qu’indépendamment de la présence ou de l’absence du SIME, le sommeil des sujets avec la SEP est grandement perturbé. De plus, même en l’absence du SIME, les sujets avec la SEP présentent des mouvements périodiques des jambes. Cette étude démontre que le SIME se manifeste différemment dans la SEP. De plus amples recherches sont nécessaires pour mieux caractériser le SIME en SEP. / The Restless legs syndrome is a sleep related movement disorder. It causes sleep disruptions, affecting sleep quality. It has been described as being more frequent in an MS population than in the general population. Our main objective was to evaluate its impact on MS subjects’ sleep in comparison to MS subjects without RLS Validated questionnaires and polysomnography was used to achieve our objective. PSG studies of our 49 subjects revealed that independently of RLS status, MS subjects experience bad sleep quality, based on various sleep quality markers. Moreover, MS subjects without RLS also have periodic leg movements. This study reveals that RLS in MS manifests itself differently. Further research is needed to characterise RLS in MS.

Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. / Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.

La sécrétion de mélatonine chez des patients atteints du syndrome d’impatience musculaire de l’éveil (SIME) débute approximativement 2 heures avant l’aggravation des symptômes en soirée (Michaud et al., 2004). Le but de ce projet était de préciser le rôle de la mélatonine dans l’augmentation de la sévérité des symptômes en soirée. Huit sujets atteints de SIME primaire ont été étudiés dans trois conditions : contrôle, avec administration de mélatonine, avec exposition à la lumière vive. La sévérité des symptômes a été évaluée par l’administration de tests d’immobilisation suggérée (TIS). Les résultats ont démontré une augmentation significative des mouvements périodiques des jambes durant l’éveil (MPJE) lorsque de la mélatonine avait été administrée comparativement à la condition contrôle et celle où les sujets étaient exposés à la lumière vive. La lumière vive n’a pas eu d’effet significatif sur les symptômes moteurs comparativement à la condition contrôle mais elle a amélioré significativement les symptômes sensoriels comparativement à la condition contrôle. Ainsi, bien que la mélatonine exogène ait un effet aggravant sur les symptômes moteurs du SIME, l’augmentation de la sécrétion endogène au cours de la soirée ne saurait expliquer à elle seule les variations de la sévérité des symptômes du SIME. / A close temporal relationship was shown between the onset of melatonin secretion at night and the worsening of restless legs syndrome (RLS) symptoms, suggesting that melatonin may play a role in the genesis of this phenomenon. Thus, we studied the effects of the administration of exogenous melatonin and the suppression of endogenous melatonin secretion by bright light exposure on the severity of RLS symptoms. Eight RLS subjects were studied in three conditions: at baseline, after administration of melatonin and during bright light exposure. The severity of RLS symptoms was assessed by the Suggested Immobilization Test (SIT), which allows quantification of both sensory and motor manifestations (SIT-PLM – periodic leg movements) of RLS. Analyses showed a significant increase of SIT-PLM index when subjects received exogenous melatonin compared to both baseline and bright light conditions, but bright light exposure had no effect on leg movements compared to the baseline condition. Analyses also revealed a small but significant decrease in sensory symptoms with bright light exposure compared to baseline. Although that exogenous melatonin may have a detrimental effect on motor symptoms, the augmentation of endogenous secretion during the evening is insufficient to explain the variations of the severity of the RLS symptoms.

Síndrome das pernas inquietas (SPI) é um distúrbio do sono com alta prevalência entre pacientes em hemodiálise, nos quais o mecanismo é pouco conhecido. Tem sido postulado que alterações do metabolismo mineral e ósseo relacionadasà doença renal crônica, especialmente o hiperparatireoidismo secundário, possam estar relacionadas à patogênese da SPI. Este trabalho teve como objetivo principal avaliar a SPI antes e após paratireoidectomia (PTX). Além disso, avaliamos dados objetivos do sono por meio de polissonografia, com ênfase em apneia do sono. Estudamos prospectivamente 19 pacientes (6 homens, idade 48 ± 11 anos) com hiperparatireoidismo grave pré e pós-PTX. O diagnóstico e o escore de gravidade da SPI foram avaliados de acordo com o Grupo de Estudo Internacional de SPI. Polissonografia pré e pós-PTX forneceu dados de arquitetura do sono, movimentos periódicos de pernas e apneia do sono, medida por meio do índice de apneia-hipopneia/hora de sono (IAH). SPI foi encontrada em 10 pacientes (53%) e se associou com maiores níveis de fosfato (p=0,005) e maior gravidade da dor (p=0,003). Após a PTX, houve redução dos níveis séricos de paratormônio, fosfato e aumento dos níveis de 25-hidroxivitamina D, calicreína-6 e fetuína-A. A PTX reduziu a SPI para 21% (p=0,044), acompanhada por redução nos escores de gravidade e alívio da dor e do prurido. A análise de regressão logística mostrou que o fosfato pré-PTX permaneceu independentemente associado com SPI (OR=7,28; p=0,035), em modelo ajustado para hemoglobina, idade e sexo. Apneia do sono (IAH > 5) foi encontrada em 11 pacientes pré e 14 pós-PTX (63% vs. 74%, p=0,698). Observamos uma correlação entre o IAH e a relação água corporal extracelular/massa magra (r=0,535, p=0,018), assim como correlação com a circunferência do pescoço pré-PTX (r=0,471, p=0,042). Entretanto, não observamos correlação do IAH com o deslocamento de fluidos da perna direita durante o sono (p=0,09), que aumentou significativamente após PTX (p=0,011). Concluímos que a PTX melhora a SPI, com cura completa ou melhora significativa. Se essa melhora está relacionada à diminuição do paratormônio ou do fósforo necessita de investigação adicional. Além disso, o presente estudo confirma a alta prevalência de apneia do sono entre pacientes em hemodiálise, o que não se modificou com a PTX / Restless legs syndrome (RLS) is a sleep disorder with high prevalence among patients on hemodialysis, which underlying mechanism is still unknown. It has been postulate that bone metabolism disorder, especially secondary hyperparathyroidism may be implicated in the pathogenesis. The present study aimed to evaluate RLS before and after parathyroidectomy (PTX). In addition, we evaluated objective data through polysomnography, focusing on sleep apnea. We prospectively evaluated 19 patients (6 men, aged 48 ± 11 years) with severe hyperparathyroidism pre and post-surgical treatment, parathyroidectomy (PTX). RLS diagnosis and rating scale were accessed based on the International RLS Study Group. Polysomnography pre and post PTX provided data on sleep architecture, periodic leg movements of sleep and apnea-hypopnea index (AHI). RLS was observed in 10 patients (53%), and was associated with higher levels of phosphate (p=0,005) and severe pain (p=0,003). After PTX, there was a reduction of serum parathyroid hormone, serum phosphate, and an increase of 25hydroxyvitamin D, kallicrein-6 and Fetuin-A. PTX improved RLS to 21% (p=0,04), accompanied by a decrease in rating scale, in association with alleviation of pain and pruritus. Logistic regression shows that serum phosphate pre PTX remained independently associated with RLS (HR=7,28; p=0,035), in a model adjusted for hemoglobin, age and gender. Sleep apnea (AHI > 5) was found in 11 patients pre and 14 patients post PTX (63% vs. 74%, p=0,698). There was a correlation between AHI and the relation extracellular water/ lean body mass (r=0,535; p=0,018) as well as a correlation between AHI and neck circumference (r=0,471; p=0,042). However, there was no correlation between AHI and spontaneous rostral fluid shift (p=0,09) that has increased after PTX (p=0,011). We concluded that PTX provided an opportunity to improve RLS. Whether RLS may be improved by reduction of serum phosphorus or parathyroid hormone, merits further investigation. In addition, PTX had no impact on the high prevalence of sleep apnea in this population