Sleep and sleep disorders during pregnancy and postpartum: The Life-ON study.

OBJECTIVE: to prospectively assess sleep and sleep disorders during pregnancy and postpartum in a large cohort of women. METHODS: multicenter prospective Life-ON study, recruiting consecutive pregnant women at a gestational age between 10 and 15 weeks, from the local gynecological departments. The study included home polysomnography performed between the 23rd and 25th week of pregnancy and sleep-related questionnaires at 9 points in time during pregnancy and 6 months postpartum. RESULTS: 439 pregnant women (mean age 33.7 ± 4.2 yrs) were enrolled. Poor quality of sleep was reported by 34% of women in the first trimester of pregnancy, by 46% of women in the third trimester, and by as many as 71% of women in the first month after delivery. A similar trend was seen for insomnia. Excessive daytime sleepiness peaked in the first trimester (30% of women), and decreased in the third trimester, to 22% of women. Prevalence of restless legs syndrome was 25%, with a peak in the third trimester of pregnancy. Polysomnographic data, available for 353 women, revealed that 24% of women slept less than 6 h, and 30.6% of women had a sleep efficiency below 80%. Sleep-disordered breathing (RDI≥5) had a prevalence of 4.2% and correlated positively with BMI. CONCLUSIONS: The Life-ON study provides the largest polysomnographic dataset coupled with longitudinal subjective assessments of sleep quality in pregnant women to date. Sleep disorders are highly frequent and distributed differently during pregnancy and postpartum. Routine assessment of sleep disturbances in the perinatal period is necessary to improve early detection and clinical management.

Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals.

BACKGROUND: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. METHODS: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. RESULTS: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ±â€¯2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ±â€¯0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. CONCLUSIONS: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.

Slow wave oscillations in Schizophrenia First-Degree Relatives: A confirmatory analysis and feasibility study on slow wave traveling.

Abnormal sleep oscillations have recently been proposed as endophenotypes of schizophrenia. However, optimization of methodological approaches is still necessary to standardize analyses of their microstructural characteristics. Additionally, some relevant features of these oscillations remain unexplored in pathological conditions. Among others, slow wave traveling is a promising proxy for diurnal processes of brain connectivity and excitability. The study of slow oscillations propagation appears particularly relevant when schizophrenia is conceptualized as a dys-connectivity syndrome. Given the rising knowledge on the neurobiological mechanisms underlying slow wave traveling, this measure might offer substantial advantages over other approaches in investigating brain connectivity. Herein we: 1) confirm the stability of our previous findings on slow waves and sleep spindles in FDRs using different automated algorithms, and 2) report the dynamics of slow wave traveling in FDRs of Schizophrenia patients. A 256-channel, high-density EEG system was employed to record a whole night of sleep of 16 FDRs and 16 age- and gender-matched control subjects. A recently developed, open source toolbox was used for slow wave visualization and detection. Slow waves were confirmed to be significantly smaller in FDRs compared to the control group. Additionally, several traveling parameters were analyzed. Traveled distances were found to be significantly reduced in FDRs, whereas origins showed a different topographical pattern of distribution from control subjects. In contrast, local speed did not differ between groups. Overall, these results suggest that slow wave traveling might be a viable method to study pathological conditions interfering with brain connectivity.

Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives.

Sleep spindles and slow waves are the main brain oscillations occurring in non-REM sleep. Several lines of evidence suggest that spindles are initiated within the thalamus, whereas slow waves are generated and modulated in the cortex. A decrease in sleep spindle activity has been described in Schizophrenia (SCZ), including chronic, early course, and early onset patients. In contrast, slow waves have been inconsistently found to be reduced in SCZ, possibly due to confounds like duration of illness and antipsychotic medication exposure. Nontheless, the implication of sleep spindles and slow waves in the neurobiology of SCZ and related disorders, including their heritability, remains largely unknown. Unaffected first-degree relatives (FDRs) share a similar genetic background and several neurophysiological and cognitive deficits with SCZ patients, and allow testing whether some of these measures are candidate endophenotypes. In this study, we performed sleep high-density EEG recordings to characterise the spatiotemporal features of sleep spindles and slow waves in FDRs of SCZ probands and healthy subjects (HS) with no family history of SCZ. We found a significant reduction of integrated spindle activity (ISAs) in FDRs relative to HS, whereas spindle density and spindle duration were not different between groups. FDRs also had decreased slow wave amplitude and slopes. Altogether, our results suggest that ISAs deficits might represent a candidate endophenotype for SCZ. Furthermore, given the slow wave deficits observed in FDRs, we propose that disrupted cortical synchronisation increases the risk for SCZ, but thalamic dysfunction is necessary for the disorder to fully develop.

Chronobiology, sleep-related risk factors and light therapy in perinatal depression: the "Life-ON" project.

BACKGROUND: Perinatal depression (PND) has an overall estimated prevalence of roughly 12 %. Untreated PND has significant negative consequences not only on the health of the mothers, but also on the physical, emotional and cognitive development of their children. No certain risk factors are known to predict PND and no completely safe drug treatments are available during pregnancy and breastfeeding. Sleep and depression are strongly related to each other because of a solid reciprocal causal relationship. Bright light therapy (BLT) is a well-tested and safe treatment, effective in both depression and circadian/sleep disorders. METHODS: In a 3-year longitudinal, observational, multicentre study, about 500 women will be recruited and followed-up from early pregnancy (10-15 gestational week) until 12 months after delivery. The primary aim of the present study is to systematically explore and characterize risk factors for PND by prospective sleep assessment (using wrist actigraphy, polysomnography and various sleep questionnaires) and bloodbased analysis of potential markers during the perinatal period (Life-ON study). Secondary aims are to explore the relationship between specific genetic polymorphisms and PND (substudy Life-ON1), to investigate the effectiveness of BLT in treating PND (substudy Life-ON2) and to test whether a short term trial of BLT during pregnancy can prevent PND (substudy Life-ON3). DISCUSSION: The characterization of specific predictive and risk factors for PND may substantially contribute to improve preventive medical and social strategies for the affected women. The study results are expected to promote a better understanding of the relationship between sleep disorders and the development of PND and to confirm, in a large sample of women, the safety and efficacy of BLT both in prevention and treatment of PND. TRIAL REGISTRATION: ClinicalTrials.gov NCT02664467 . Registered 13 January 2016.

Antiepileptic drugs in Rett Syndrome.

PURPOSE: We investigated drugs most often used to treat epilepsy in Rett Syndrome and their efficacy in a large cohort of Italian patients. METHODS: This is a multi-centre retrospective study. Data of 165 Rett subjects were collected from the patients' files, and hospital charts. The efficacy of antiepileptic drugs (AEDs) was classified as follows: not effective; decrease in seizure frequency ≥50% for at least 6 months; seizure-free for at least 2 years. Phenotypic and genetic categorization of patients was performed and it was considered in AEDs efficacy evaluation. RESULTS: There were 130 epileptic patients.Sodium valproate (VPA) was the most commonly administered AED (44.3%) at seizure onset, followed by Carbamazepine (CBZ) (25.4%) and Phenobarbital (PB) (13%). Monotherapy was the first treatment option in most patients. VPA and CBZ proved to be equally effective in Rett patients who presented seizures within the typical age range (4-5 years), while Lamotrigine (LTG) was effective for patients in whom epilepsy started later. Overall, the frequency of side effects was low and the most often observed ones were restlessness and somnolence. CONCLUSION: Our study suggests that LTG, VPA and CBZ can be used as drugs of first choice in Rett Syndrome. The association of four drugs should be avoided since it did not result in any significant clinical improvement.

Epilepsy in Rett syndrome: clinical and genetic features.

Epilepsy often occurs in Rett syndrome and is considered a major problem. The aim of this study was to define the clinical features of epilepsy and the correlation between seizures and both genotype and clinical phenotype in the Rett population. One hundred sixty-five patients with Rett syndrome referred to four Italian centers were recruited. All patients underwent video/EEG monitoring and molecular analysis of the MECP2 gene or, in negative cases, of the CDKL5 and FOXG1 genes. The frequency of epilepsy was 79%. Drug-resistant epilepsy occurred in 30% of all our patients with Rett syndrome and in 38% of those with epilepsy. Our findings demonstrate that epilepsy differs among the various phenotypes and genotypes with respect to age at onset, drug responsiveness, and seizure semiology. The Hanefeld and preserved speech variants represent the extremes of the range of severity of epilepsy: the preserved speech variant is characterized by the mildest epileptic phenotype as epilepsy is much less frequent, starts later, and is less drug resistant than what is observed in the other phenotypes. Another important finding is that seizure onset before 1 year of age and daily frequency are risk factors for drug resistance. Thus, this study should help clinicians provide better clinical counseling to the families of patients with Rett syndrome.