Marco Filardi

Actigraphic assessment of sleep/wake behavior in central disorders of hypersomnolence

OBJECTIVE To evaluate the reliability of actigraphy to distinguish the features of estimated daytime and nighttime sleep between patients with central disorders of hypersomnolence and healthy controls. METHODS Thirty-nine drug-naïve patients with Narcolepsy Type 1, twenty-four drug-naïve patients with Idiopathic Hypersomnia, and thirty age- and sex- matched healthy controls underwent seven days of actigraphic and self-report monitoring of sleep/wake behavior. The following variables were examined: estimated time in bed (eTIB), estimated total sleep time, estimated sleep latency (eSOL), estimated sleep efficiency, estimated wake after sleep onset, number of estimated awakenings (eAwk), number of estimated awakenings longer than 5 minutes, estimated sleep motor activity (eSMA), number of estimated naps, mean duration of the longest estimated nap (eNapD), and daytime motor activity. RESULTS All actigraphic parameters significantly differentiated the three groups, except eTIB and eSOL. A discriminant score computed combining actigraphic parameters from nighttime (eSMA, eAwk) and daytime (eNapD) periods showed a wide area under the curve (0.935) and a good balance between positive (95%) and negative predictive (87%) values in Narcolepsy Type 1 cases. CONCLUSION Actigraphy provided a reliable objective measurement of sleep quality and daytime napping behavior able to distinguish central disorders of hypersomnolence and in particular Narcolepsy Type 1. The nycthemeral profile, combined with a careful clinical evaluation, may be an ecological information, useful to track disease course.

Effects of sleep timing, sleep quality and sleep duration on school achievement in adolescents

OBJECTIVE The aim of this study was to examine the effects of sleep timing, quality and duration on school achievement in adolescents. METHODS Thirty-six Italian students (mean age: 18.14 ± 0.49 years) attending their last year of high school participated in the study. They completed the Morningness-Eveningness Questionnaire for Children and Adolescents (MEQ-CA). This was used to determine their ideal sleep timing by computing the total score, with higher scores corresponding to a greater tendency toward morningness. In addition, students underwent two non-consecutive weeks of actigraphy in one-month period to objectively assess: habitual sleep timing through the midpoint of sleep (MS); habitual sleep quality through the parameter of sleep efficiency (SE); and habitual sleep duration through the parameter of total sleep time (TST). Participants also completed the Mini Sleep Questionnaire, which allowed us to assess perceived sleep quality, at the end of each actigraphic-recording week. School performance was assessed using the grades obtained by students in their school leaving exams taken at the end of the school year. RESULTS A significant positive correlation was observed between SE and exam grades, as well as MEQ-CA scores and grades. Multiple regression analysis showed that only SE was significantly and positively related to the final grade. CONCLUSIONS Examining objective and ecological measures, SE (indicator of sleep quality) had the strongest effect on school achievement in adolescents.

The difference between in bed and out of bed activity as a behavioral marker of cancer patients: A comparative actigraphic study.

The current study was conducted to provide normative data on actigraphic dichotomy index (I < O) (the percentage of in bed activity counts that are less than the median of out of bed counts) in healthy population and to assess whether the I < O could be an effective index in discriminating the circadian motor activity of cancer patients from healthy controls. In this retrospective study, we recovered 408 actigraphic records from two databases: healthy controls (n = 182; 79 males; mean age 38.7 ± 12.6) and patients with metastatic colorectal cancer (n = 226; 149 males; mean age 58.4 ± 11.4). Beside the usual actigraphic sleep parameters (time in bed, sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, number of awakenings, and mean motor activity), we also computed the dichotomy index and number of actigraphic wake parameters, namely, diurnal motor activity, diurnal total sleep time, number of sleep episodes, and the mean duration of the longest diurnal sleep episode. Using the Youden index, we calculated the cut off value that performed the best for I < O and actigraphic wake parameters. Finally, we created Receiver Operator Characteristic curves to test the efficacy of each actigraphic parameter to discriminate cancer patient from healthy controls. Mean I < O was 99.5% (SD, 0.48%) in the healthy group, as compared to 96.6% (SD, 3.6%) in the cancer group (p < 0.0001). Important age-related effects appeared unlikely after performing both the main analysis with age as a covariate, and a subset analysis in 104 subjects matched for age and sex. In the main analysis, all actigraphic parameters, except total sleep time, significantly differentiated the two groups of participants. However, the I < O was the one that clearly performed best. Here, we provide the first large dataset on I < O in healthy subjects, we confirm the relevance of this circadian index for discriminating advanced stage colorectal cancer patients from healthy subjects, and we lay the grounds for further investigations of this circadian index in patients with other chronic diseases.

Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy.

STUDY OBJECTIVES Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls. METHODS Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm. RESULTS Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption. CONCLUSIONS Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1.

The association between higher body mass index and poor school performance in high school students

This study aimed to examine the association between body mass index (BMI) and school performance in high school students by controlling for relevant mediators such as sleep quality, sleep duration and socioeconomic status.

In-Field Assessment of Sodium Oxybate Effect in Pediatric type 1 Narcolepsy: An Actigraphic Study

Study Objectives Sodium oxybate (SXB) is a GABAergic agent widely used as off-label treatment in pediatric type 1 narcolepsy (NT1). Here, we aimed at analyzing by wrist actigraphy the sleep/wake profile of NT1 children and adolescents in drug-naïve condition and after 1 year of SXB treatment. As secondary aim, we investigated changes on sleepiness, cataplexy, and childrens anthropometric profile after 1 year of SXB treatment. Methods Twenty-four drug-naïve NT1 children underwent 7 days of actigraphy during the school week. Information on sleepiness, narcolepsy symptoms, and anthropometric features were collected during the same week with questionnaires and semistructured clinical interview. Children started SXB treatment and underwent a second evaluation encompassing actigraphy, clinical interview, questionnaires, and anthropometric assessment after 1 year of stable treatment. Results Actigraphy effectively documented an improvement of nocturnal sleep quality and duration coupled with a reduction of diurnal total sleep time, nap frequency, and duration at 1 year follow-up. Reduction of sleepiness, cataplexy frequency and severity, and weight loss, mainly in obese and overweight NT1 children, were also observed at the 1 year follow-up. Conclusions Actigraphy objectively documented changes in nocturnal sleep quality and diurnal napping behavior after 1 year of SXB treatment, thus representing a valid approach to ecologically assess SXB treatment effect on NT1 childrens sleep/wake profile. NT1 symptoms severity and childrens anthropometric features also changed as expected. Actigraphy offers the possibility to longitudinally follow up children and has potential to become a key tool to tailor treatment in pediatric patients.

Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiency

Background Attentional complaints are common in narcolepsy patients and can overlap with daytime sleepiness features. Few studies attempted to characterize attentional domains in narcolepsy leading to controversial results. We aimed to assess the impact of hypocretin deficiency on attentional functioning by comparing performances on the attention network test (ANT) of narcoleptic patients with hypocretin deficiency (narcolepsy type 1—NT1) versus patients without hypocretin deficiency (narcolepsy type 2—NT2) and healthy controls. We also addressed frequency and severity of psychopathological symptoms and their influence on performances on ANT. Methods Twenty-one NT1 patients, fifteen NT2 patients and twenty-two healthy controls underwent the ANT, which allows assessing three separate attentional processes (alerting, orienting and executive control), and a psychometric assessment including questionnaires on attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, anxiety and depression symptoms. Results NT1 and NT2 patients presented with slower reaction times compared to controls. NT1 patients exhibited an impairment of alerting network relative to NT2 and healthy controls, while orienting and executive control networks efficiency were comparable between groups. NT1 and NT2 displayed higher severity of ADHD inattentive domain than controls, NT1 patients also displayed higher severity of ADHD hyperactive domain and depressive symptoms. In NT1, ADHD and depressive symptoms were positively correlated. Conclusions Despite a shared slowing of reaction times in both NT1 and NT2, a selective impairment of alerting network was present only in hypocretin deficient patients. Clinicians should carefully consider attentional deficits and psychopathological symptoms, including ADHD symptoms, in the clinical assessment and management of patients with narcolepsy.

Non-24-Hour Sleep-Wake Rhythm Disorder and Melatonin Secretion Impairment in a Patient With Pineal Cyst

ABSTRACT We report the case of a 14-year-old girl with a wide non-compressive pineal cyst, associated with the inability to control her sleep-wake schedule. Actigraphic monitoring showed a 24-hour free-running disorder (tau 26.96 hours). A 24-hour serum melatonin curve assay, with concomitant video-polysomnographic and body-core temperature monitoring, was performed. Melatonin curve showed a blunted nocturnal peak, lower total quantity of melatonin, and prolonged melatonin secretion in the morning, with normal temperature profile and sleep parameters. Treatment with melatonin up to 14 mg at bedtime was initiated with complete realignment of the sleep-wake rhythm (tau 23.93 hours). The role of the pineal cyst in the aforementioned alteration of melatonin secretion and free-running disorder remains controversial, but our case supports the utility of monitoring sleep/wake, temperature, and melatonin rhythms in the diagnostic work-up of pineal cysts associated with free-running disorder.

Relationship between sleep time preference of adolescents and their parents

This study aimed to explore the relationship between sleep time preference of adolescents and their parents, considering gender separately. To this end, 912 adolescents (501 females) from 10 to 17 years were administered the Morningness–Eveningness Questionnaire for Children and Adolescents and their parents filled in the Morningness–Eveningness Questionnaire. To assess sleep time preference, the ideal midpoint of sleep was computed. A mathematical function was developed in order to correct the evolution of the ideal midpoint of sleep over time. The actual values were adjusted on the basis of those provided by the function for a specific age and gender and then reclassified into a new ordinal variable, with five categories, according to the interval where difference between actual and predicted values lies. This variable is informative as to the degree and magnitude of the ideal midpoint of sleep dispersion regarding/compared to the average value for a certain age and sex, represented by estimated function. The correlations between actual values of the ideal midpoint of sleep of adolescents and actual values of their parents, separately for gender of both, were not significant. The “corrected” ideal midpoint of sleep of daughters resulted significantly correlated with those “corrected” of mothers and fathers; furthermore, these correlation values were significantly higher than those detected between daughters and unrelated parents, highlighting the fact that such a privileged relationship between daughters and both parents is not due to chance.

Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease

BACKGROUND Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course. METHODS Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses. RESULTS The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4+ terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4+ terminally differentiated effector memory T cells and an increased frequency of NK CD56bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4+ terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls. CONCLUSIONS Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology.