Paul Lespérance

Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category

Thirty-four patients who presented with excessive daytime sleepiness (EDS) and who showed an elevated number of periodic leg movements during sleep (PLMS) were studied. None of these patients reported other symptoms or presented sleep laboratory manifestations of narcolepsy or of breathing disorders during sleep. A diagnosis of restless leg syndrome, head trauma or a past history of psychopathology or infectious diseases known to cause EDS were also ruled out. In addition, none of the patients reported a history of drug or alcohol abuse, chronic sleep deprivation or irregular sleep-wake schedule and none were taking medications known to influence sleep at the time of the study. Results of the present study showed no correlation between PLMS index and poor sleep efficiency or daytime sleepiness as measured by the multiple sleep latency test (MSLT). However, a significant negative correlation was found between sleep efficiency at night and the mean sleep latency on the MSLT. These results suggest not only that PLMS and nocturnal sleep disruption are not the primary cause of EDS, but that these sleepy patients have a high propensity to sleep both at night and during the daytime. Therefore, the presence of PLMS during nocturnal sleep recording should not preclude the diagnosis of idiopathic hypersomnia.

The efficacy of omega-3 supplementation for major depression: a randomized controlled trial.

OBJECTIVE To document the short-term efficacy of omega-3 supplementation in reducing depressive symptoms in patients experiencing a major depressive episode (MDE). METHOD Inclusive, double-blind, randomized, controlled, 8-week, parallel-group trial, conducted October 17, 2005 through January 30, 2009 in 8 Canadian academic and psychiatric clinics. Adult outpatients (N = 432) with MDE (Mini-International Neuropsychiatric Interview, version 5.0.0, criteria) lasting at least 4 weeks, including 40.3% taking antidepressants at baseline, were randomly assigned to 8 weeks of 1,050 mg/d of eicosapentaenoic acid (EPA) and 150 mg/d of docosahexaenoic acid (DHA) or matched sunflower oil placebo (2% fish oil). The primary outcome was the self-report Inventory of Depressive Symptomatology (IDS-SR(30)); the secondary outcome was the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS The adjusted mean difference between treatment and placebo was 1.32 points (95% CI, -0.20 to 2.84; P = .088) on the IDS-SR(30) and 0.97 points (95% CI, -0.012 to 1.95; P = .053) on the MADRS. Planned subgroup analyses revealed a significant interaction of comorbid anxiety disorders and study group (P = .035). For patients without comorbid anxiety disorders (n = 204), omega-3 supplementation was superior to placebo, with an adjusted mean difference of 3.17 points on the IDS-SR(30) (95% CI, 0.89 to 5.45; P = .007) and 1.93 points (95% CI, 0.50 to 3.36; P = .008) on the MADRS. CONCLUSIONS In this heterogeneous sample of patients with MDE, there was only a trend toward superiority of omega-3 supplementation over placebo in reducing depressive symptoms. However, there was a clear benefit of omega-3 supplementation among patients with MDE without comorbid anxiety disorders. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN47431149.

Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population.

Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (χ2 TDT =4.93, 1 df, P=0.026) and the putative ‘high-activity’ alleles of the MAO-A promoter VNTR polymorphism (χ2 TDT =7.124, 1 df P=0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.

Restless legs in Tourette syndrome.

Restless legs syndrome (RLS) and Tourettes syndrome (TS) share some common features, including the phenomenology of sensations relieved by movements, but few studies have examined the links between RLS and TS. We examined RLS and other TS comorbidities in 144 probands with TS or chronic tics and their parents. RLS was present in 10% of probands and 23% of parents with no gender differences. RLS in probands was linked significantly to maternal RLS but not paternal RLS, suggesting that a maternal RLS factor may contribute to the variable expression of TS.

Association of Intronic Variants of the BTBD9 Gene With Tourette Syndrome

OBJECTIVE To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. DESIGN Case-control association study. SETTING Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. MAIN OUTCOME MEASURES Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. RESULTS The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (chi(2) = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (chi(2) = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. CONCLUSION Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Association between 7q31 markers and tourette syndrome

Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e‐TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele‐wise TDT χ2 = 12.61, 4 df, P = 0.013, genotype‐wise TDT χ2 = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype‐wise (χ2 = 10.68, 4 df, P = 0.03 and χ2 = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele‐wise TDT χ2 = 18.37, 7 df, P = 0.01 and genotype‐wise TDT χ2 = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity‐free subgroup (genotype‐wise TDT χ2 = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype‐wise TDT χ2 = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.

Nocturnal polysomnographic sleep across the menstrual cycle in premenstrual dysphoric disorder

OBJECTIVES Women with premenstrual dysphoric disorder (PMDD) experience disturbed mood, altered melatonin circadian rhythms, and frequent reports of insomnia during the luteal phase (LP) of their menstrual cycle. In this study we aimed to investigate nocturnal polysomnographic (PSG) sleep across the menstrual cycle in PMDD women and controls. METHODS Seven PMDD women who indicated insomnia during LP, and five controls, spent every third night throughout a complete menstrual cycle sleeping in the laboratory. RESULTS In PMDD and controls progesterone and core body temperature (BT(core)) were elevated during LP compared to the follicular phase (FP). Stage 2 sleep showed a significant main effect of menstrual phase and was significantly increased during mid-LP compared to early-FP in both groups. Rapid eye movement (REM) sleep for both groups was decreased during early-LP compared to early-FP. Slow wave sleep (SWS) was significantly increased, and melatonin significantly decreased, in PMDD women compared to controls. CONCLUSIONS PMDD women who experience insomnia during LP had decreased melatonin secretion and increased SWS compared to controls. The sleep and melatonin findings in PMDD women may be functionally linked. Results also suggest an altered homeostatic regulation of the sleep-wake cycle in PMDD, perhaps implicating melatonin in the homeostatic process of sleep-wake regulation.

Pilot Investigation of the Circadian Plasma Melatonin Rhythm across the Menstrual Cycle in a Small Group of Women with Premenstrual Dysphoric Disorder

Women with premenstrual dysphoric disorder (PMDD) experience mood deterioration and altered circadian rhythms during the luteal phase (LP) of their menstrual cycles. Disturbed circadian rhythms may be involved in the development of clinical mood states, though this relationship is not fully characterized in PMDD. We therefore conducted an extensive chronobiological characterization of the melatonin rhythm in a small group of PMDD women and female controls. In this pilot study, participants included five women with PMDD and five age-matched controls with no evidence of menstrual-related mood disorders. Participants underwent two 24-hour laboratory visits, during the follicular phase (FP) and LP of the menstrual cycle, consisting of intensive physiological monitoring under “unmasked”, time-isolation conditions. Measures included visual analogue scale for mood, ovarian hormones, and 24-hour plasma melatonin. Mood significantly (P≤.03) worsened during LP in PMDD compared to FP and controls. Progesterone was significantly (P = .025) increased during LP compared to FP, with no between-group differences. Compared to controls, PMDD women had significantly (P<.05) decreased melatonin at circadian phases spanning the biological night during both menstrual phases and reduced amplitude of its circadian rhythm during LP. PMDD women also had reduced area under the curve of melatonin during LP compared to FP. PMDD women showed affected circadian melatonin rhythms, with reduced nocturnal secretion and amplitude during the symptomatic phase compared to controls. Despite our small sample size, these pilot findings support a role for disturbed circadian rhythms in affective disorders. Possible associations with disrupted serotonergic transmission are proposed.

Postural control anomalies in children with Tourette syndrome.

The goal of the present study was to determine whether postural control is affected in Gilles-de-la-Tourette syndrome (TS). Center of pressure (COP) displacements were recorded in children with TS and unaffected siblings in three conditions using a force platform: (1) Eyes-Open, (2) Eyes-Closed, (3) One-Leg standing with eyes open. The COP range and velocity were higher in children with TS than in unaffected siblings in all conditions. These differences could not be attributed to age, present tic severity, comorbidities (hyperactivity and compulsions) or medication. The data suggest that sub-clinical postural control anomalies are present in TS.

Genome-wide TDT analysis in French-Canadian families with Tourette syndrome.

Tourette syndrome (TS) is a complex neurodevelopmental disorder with an estimated prevalence of 1%1 that is characterized by motor and vocal tics as well as psychiatric comorbidities, such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD).2-4 Despite a strong genetic contribution,5,6 no common variants have been clearly associated with the disorder, possibly because of allelic and non-allelic genetic heterogeneity. Several candidate genes involved in dopaminergic neurotransmission have been analyzed based on the observation that neuroleptics are used to treat TS patients. Positive association results between TS and some of these genes have been reported.7-9 However, because other studies failed to replicate these results, the role played by dopaminergic in TS remains unclear.10-12 Founder populations are known to offer several advantages for the gene-mapping of complex traits, as the reduced genetic heterogeneity of population isolates is thought to simplify the genetic background of complex traits and higher frequencies of specific mutations inherited from a common ancestor may be observed. Moreover, even if the number of implicated genes is not decreased, the allelic heterogeneity is decreased and the presence of a common haplotype that segregates among patients is more probable than within a heterogeneous population.13 For instance, the G2019S substitution in the LRRK2 gene accounts for 20–40% of NorthAfrican Arab and Ashkenazi patients with Parkinson disease.14,15 In the French-Canadian (FC) population, founder mutations in the BRCA1 and BRCA2 genes were identified in 40% of patients from families with a high risk of breast and ovarian cancer.16 For several reasons, the FC population of Quebec displays all the characteristics of a population isolate. An estimated 2,600 pioneers who settled in Quebec before 1680 account for two thirds of the modern FC gene pool and a vast majority of FC people have, as ancestors, approximately 7,000 individuals who immigrated to Quebec before 1760. Given that these founders rarely mixed with other immigrants over three centuries and that there was a sustained demographic growth in the FC population, the ~6 million FC individuals currently living in Quebec inherited most of their genes from a relatively small pool of founders.17 Based on a cohort of 217 FC trios (father, mother and proband) presenting with TS, the goal of this study was to assess the presence of frequent and highly penetrant alleles predisposing to TS in the FC population. Affected individuals and their relatives were recruited through the Montreal General Genome-Wide TDTAnalysis in French-Canadian Families with Tourette Syndrome