Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.

OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.

Correlates of general quality of life are different in patients with primary insomnia as compared to patients with insomnia and psychiatric comorbidity.

Chronic insomnia is known to have a negative influence on quality of life (QOL). To date, most studies on chronic insomnia have focused on health-related aspects of QOL. General QOL, which is a different construct, has not been studied in detail. Moreover, it is not known which factors are associated with general QOL in insomnia, and whether the presence of mental disorders, a condition known as comorbid insomnia, affects these variables. The present study focused on identifying sleep and psychosocial variables that might be associated with general QOL in primary and comorbid insomnia. Personality traits, coping variables, anxiety and depressive symptoms, fatigue and subjective sleep variables were assessed in 218 consecutive well-characterized patients with primary and comorbid insomnia, referred to a third line centre for sleep medicine. In primary insomnia, higher extraversion and lower discrepancies in social support were associated with higher QOL. Surprisingly, insomnia severity was not significantly associated with QOL in this group. However, lower fatigue, which can be seen as an important daytime consequence of insomnia was correlated with higher QOL in patients with primary insomnia. In both insomnia groups, low anxiety and depressive symptoms and low fatigue were associated with higher general QOL. In contrast with the primary insomnia group, lower insomnia severity was correlated with higher QOL in patients with comorbid insomnia. These results stress the importance of assessing and treating daytime fatigue in insomnia. In primary insomnia, improving social support might be an important treatment goal. Furthermore, this study supports the concept that treatment of insomnia should not be neglected in patients with comorbid insomnia. Indeed, both insomnia and indices of psychiatric disease are strongly associated with general QOL in this condition.

Diagnostic accuracy of audio-based seizure detection in patients with severe epilepsy and an intellectual disability.

UNLABELLED: We evaluated the performance of audio-based detection of major seizures (tonic-clonic and long generalized tonic) in adult patients with intellectual disability living in an institute for residential care. METHODS: First, we checked in a random sample (n=17, 102 major seizures) how many patients have recognizable sounds during these seizures. In the second part of this trial, we followed 10 patients (who had major seizures with recognizable sounds) during four weeks with an acoustic monitoring system developed by CLB ('CLB-monitor') and video camera. In week 1, we adapted the sound detection threshold until, per night, a maximum of 20 sounds was found. During weeks 2-4, we selected the epilepsy-related sounds and performed independent video verification and labeling ('snoring', 'laryngeal contraction') of the seizures. The video images were also fully screened for false negatives. In the third part, algorithms in the CLB-monitor detected one specific sound (sleep-related snoring) to illustrate the value of automatic sound recognition. RESULTS: Part 1: recognizable sounds (louder than whispering) occurred in 23 (51%) of the 45 major seizures, 20 seizures (45%) were below this threshold, and 2 (4%) were without any sound. Part 2: in the follow-up group (n=10, 112 major seizures; mean: 11.2, range: 1-30), we found a mean sensitivity of 0.81 (range: 0.33-1.00) and a mean positive predictive value of 0.40 (range: 0.06-1.00). All false positive alarms (mean value: 1.29 per night) were due to minor seizures. We missed 4 seizures (3%) because of lack of sound and 10 (9%) because of sounds below the system threshold. Part 3: the machine-learning algorithms in the CLB-monitor resulted in an overall accuracy for 'snoring' of 98.3%. CONCLUSIONS: Audio detection of major seizures is possible in half of the patients. Lower sound detection thresholds may increase the proportion of suitable candidates. Human selection of seizure-related sounds has a high sensitivity and moderate positive predictive value because of minor seizures which do not need intervention. Algorithms in the CLB-monitor detect seizure-related sounds and may be used alone or in multimodal systems.

Psychiatric comorbidity and aspects of cognitive coping negatively predict outcome in cognitive behavioral treatment of psychophysiological insomnia.

Cognitive behavioral treatment is the gold standard treatment for insomnia, although a substantial group does not respond. We examined possible predictors for treatment outcome in psychophysiological insomniacs, with a focus on the presence of clearly defined psychiatric comorbidity. This was a longitudinal uncontrolled case series study comprising 60 patients with chronic psychophysiological insomnia consecutively referred to a tertiary sleep medicine center, to receive cognitive behavioral treatment for insomnia (CBT-I). Remission of insomnia was defined as a posttreatment Insomnia Severity Index score below 8. As an alternative outcome, we used a clinically relevant decrease on the Insomnia Severity Index (drop of > 7 points). Personality, coping, and social support questionnaires were assessed before the start of the treatment and were compared between treatment responders and nonresponders. To examine whether these variables were predictive for negative treatment outcome, logistic regression analyses were applied. Treatment nonresponders had a significantly higher prevalence of psychiatric comorbidity. Logistic regression analyses showed that the presence of psychiatric comorbidity was strongly predictive for negative treatment outcome (odds ratios: 20.6 and 10.3 for the 2 outcome definitions). Additionally, higher scores on the cognitive coping strategy called "refocus on planning" were associated with worse CBT-I outcome. Current psychiatric comorbidity is strongly predictive for negative treatment outcome. The presence of a psychiatric disorder must therefore be one of the leading arguments in the choice of treatment modalities that are being proposed to patients with insomnia.

Validation of the Dutch translation of the Paris Arousal Disorders Severity Scale for non-REM parasomnias in a 1-year and 1-month version.

STUDY OBJECTIVES: We created a Dutch version of the Paris Arousal Disorders Severity Scale (PADSS), which assesses non-rapid eye movement (NREM) parasomnia symptoms over the past year (PADSS-year). This questionnaire was previously validated in patients with sleep walking and/or sleep terrors (SW/ST). We validated the questionnaire in SW/ST patients, and in a broader population, including patients with confusional arousals, comorbidities, and medication users ("other NREM parasomnias"). Furthermore, we introduced a version covering the past month (PADSS-month), with the potential purpose of evaluating symptom evolution and treatment response. METHODS: We compared PADSS scores among 54 SW/ST patients, 34 age-matched controls, and 23 patients with other NREM parasomnias. We evaluated discriminative capacity, internal consistency, and construct validity. Furthermore, we assessed the test-retest reliability and treatment response of PADSS-month. RESULTS: Healthy controls scored significantly lower than both patient groups. We found an excellent diagnostic accuracy (area under the curve PADSS-year 0.990, PADSS-month 0.987) and an acceptable internal consistency. Exploratory factor analysis identified 3 components: "behaviors outside the bed," "behaviors in/around the bed," and "violent behaviors," with the former 2 factors reflecting the distinction between SW and ST. PADSS-month showed an acceptable test-retest reliability (0.75). Additionally, PADSS-month significantly decreased after pharmaceutical and/or behavioral treatment. This change was correlated with the clinical impression of the caregiver, implying that PADSS-month is sensitive to treatment effects. CONCLUSIONS: The Dutch PADSS questionnaire can be used as a screening tool in a broad population of patients with NREM parasomnia, not only SW/ST. Furthermore, we validated a PADSS-month version to assess the evolution of symptoms and treatment effect. CITATION: van Mierlo P, Hermans L, Arnulf I, Pijpers A, Overeem S, van Gilst M. Validation of the Dutch translation of the Paris Arousal Disorders Severity Scale for non-REM parasomnias in a 1-year and 1-month version. J Clin Sleep Med. 2022;18(4):1135-1143.

Effect of treatment on cognitive and attention problems in children with narcolepsy type 1.

STUDY OBJECTIVES: To ascertain the presence of cognitive and attention problems in treatment naïve children with narcolepsy type 1 (NT1) and to explore whether children recently diagnosed with NT1 improve with respect to cognition and attention problems 1 year after regular treatment for NT1. METHODS: A total of 15 treatment naïve children (7-15 years) with recently diagnosed NT1 were recruited from three sleep medicine centers in the Netherlands. The control group consisted of 15 healthy children, being frequency matched on age and gender. Both groups were investigated at baseline to examine intelligence profile (Wechsler Intelligence Scale for Children [WISC] III), attention problems, and processing speed (Bourdon Vos and sustained attention to respond task [SART]). These tests were repeated in children with NT1 1 year after regular (behavioral and medication) treatment for NT1. RESULTS: Children with NT1 scored significantly lower on the verbal scale and processing speed subscale of the WISC III, showed more fluctuations in reaction time of the Bourdon Vos and made more mistakes during the SART than the healthy control group at baseline. Children with NT1 significantly improved on total IQ score, and on the WISC indices processing speed, and perceptual organization 1 year after treatment. At follow-up, test scores of treated children were largely comparable to those of the control group at baseline. CONCLUSIONS: Children with NT1 show improvement in several cognitive domains 1 year after start of treatment. Our findings stress the need for early detection and treatment of narcolepsy in childhood.

Modeling sleep onset misperception in insomnia.

OBJECTIVES: To extend and validate a previously suggested model of the influence of uninterrupted sleep bouts on sleep onset misperception in a large independent data set. METHODS: Polysomnograms and sleep diaries of 139 insomnia patients and 92 controls were included. We modeled subjective sleep onset as the start of the first uninterrupted sleep fragment longer than Ls minutes, where parameter Ls reflects the minimum length of a sleep fragment required to be perceived as sleep. We compared the so-defined sleep onset latency (SOL) for various values of Ls. Model parameters were compared between groups, and across insomnia subgroups with respect to sleep onset misperception, medication use, age, and sex. Next, we extended the model to incorporate the length of wake fragments. Model performance was assessed by calculating root mean square errors (RMSEs) of the difference between estimated and perceived SOL. RESULTS: Participants with insomnia needed a median of 34 minutes of undisturbed sleep to perceive sleep onset, while healthy controls needed 22 minutes (Mann-Whitney U = 4426, p < 0.001). Similar statistically significant differences were found between sleep onset misperceivers and non-misperceivers (median 40 vs. 20 minutes, Mann-Whitney U = 984.5, p < 0.001). Model outcomes were similar across other subgroups. Extended models including wake bout lengths resulted in only marginal improvements of model outcome. CONCLUSIONS: Patients with insomnia, particularly sleep misperceivers, need larger continuous sleep bouts to perceive sleep onset. The modeling approach yields a parameter for which we coin the term Sleep Fragment Perception Index, providing a useful measure to further characterize sleep state misperception.

Publisher Correction: Enhanced food-related responses in the ventral medial prefrontal cortex in narcolepsy type 1.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Impaired social functioning in children with narcolepsy.

Study Objectives: To explore impairments in social functioning in children with narcolepsy compared to healthy children. Methods: Parents of 53 pediatric patients with narcolepsy type 1 and 64 matched healthy children completed the Social Responsiveness Scale (SRS) and the Child Behavior Checklist 6-18 (CBCL 6-18). Results: Patients scored significantly higher on the total score of the SRS (median 56, interquartile range [IQR] 23.5) compared to controls (median 44.5, IQR 8.5, U = 797.0, p < 0.001). Patients also scored higher on the sum of the CBCL 6-18 subscales indicative of social functioning (Withdrawn/Depressed, Social Problems, and Thought Problems; median 183, IQR 30.5) compared to controls (median 155, IQR 13, U = 500.0, p < 0.001). A total of 24 patients (45.3%) reported at least mild-to-moderate difficulties in social functioning compared to seven controls (10.9%, χ2 = 17.165, p < 0.001). Eleven patients (20.8%) and only one control (1.6%) had T scores above 75, which points to severely impaired social functioning (χ2 = 11.602, p = 0.001). Within the patient group, girls reported mild-to-moderate difficulties in social functioning significantly more often compared to boys on the SRS (77.8% versus 28.6%, χ2 = 17.560, p < 0.001). Conclusions: Impaired social functioning is common in children with narcolepsy type 1, especially in girls. Questionnaires such as the SRS and the CBCL 6-18 may help in early detection of social problems in pediatric narcolepsy. Recognition of these problems could be valuable in the management of young people with narcolepsy.

Enhanced food-related responses in the ventral medial prefrontal cortex in narcolepsy type 1.

Narcolepsy type 1 is a chronic sleep disorder caused by a deficiency of the orexin (hypocretin) neuropeptides. In addition to sleep regulation, orexin is important for motivated control processes. Weight gain and obesity are common in narcolepsy. However, the neurocognitive processes associated with food-related control and overeating in narcolepsy are unknown. We explored the neural correlates of general and food-related attentional control in narcolepsy-type-1 patients (n = 23) and healthy BMI-matched controls (n = 20). We measured attentional bias to food words with a Food Stroop task and general executive control with a Classic Stroop task during fMRI. Moreover, using multiple linear regression, we assessed the relative contribution of neural responses during Food Stroop and Classic Stroop to spontaneous snack intake. Relative to healthy controls, narcolepsy patients showed enhanced ventral medial prefrontal cortex responses and connectivity with motor cortex during the Food Stroop task, but attenuated dorsal medial prefrontal cortex responses during the Classic Stroop task. Moreover, the former activity but not the latter, was a significant predictor of spontaneous snack intake. These findings demonstrate that narcolepsy, characterized by orexin deficiency, is associated with decreased dorsal medial prefrontal cortex responses during general executive control and enhanced ventral medial prefrontal cortex responses during food-driven attention.

Validation of the System One RemStar Auto A-Flex for Obstructive Sleep Apnea Treatment and Detection of Residual Apnea-Hypopnea Index: A European Randomized Trial.

STUDY OBJECTIVES: Autotitrating continuous positive airway pressure (CPAP) devices adjust pressure in response to changes in airflow and are an alternative to attended in-laboratory titration polysomnography (PSG) to determine optimal pressure levels. The aim of this study was to compare the performance of the System One RemStar Auto A-Flex (Philips Respironics, Murrysville, PA, USA) automatically adjusted positive airway pressure (APAP) mode to manually titrated, fixed pressure CPAP and to validate the device's breathing event detection capabilities against attended in-laboratory PSG. METHODS: Sixty-one patients investigated in five centers for moderate to severe obstructive sleep apnea between May 2012 and June 2013 were invited to participate. Participants underwent two full-night attended polysomnograms in random order with manually titrated, fixed pressure CPAP versus APAP. RESULTS: Fifty-three participants with a mean apnea-hypopnea index (AHI) of 45.9 ± 23 completed two sleep studies and were included in the analysis. There were significant but not clinically relevant differences between APAP and CPAP respectively: Apnea index [1.0 (2.8 ± 0.8), median (mean ± standard deviation)] versus [1.8 (5.3 ± 11.5)], p = 0.004; percentage of N1 sleep [12.3 (15.9 ± 0.5)] versus [14.3 (18.9 ± 12.7)], p = 0.028. AHI values differed between PSG [2.8 (5.5. ± 9.3)] and device [3.7 (6.0 ± 8.6)], p = 0.003). Regarding residual events detection, intraclass correlation coefficients for AHI were strong (0.956, p < 0.001) and the area under the curve was 0.988 (AHI cut-off value of 10). CONCLUSIONS: The new APAP modality was effective and residual apnea-hypopnea indices calculated by the device strongly correlated to those assessed by PSG. COMMENTARY: A commentary on this article appears in this issue on page 167.

Aberrant Food Choices after Satiation in Human Orexin-Deficient Narcolepsy Type 1.

STUDY OBJECTIVES: Besides influencing vigilance, orexin neurotransmission serves a variety of functions, including reward, motivation, and appetite regulation. As obesity is an important symptom in orexin-deficient narcolepsy, we explored the effects of satiety on food-related choices and spontaneous snack intake in patients with narcolepsy type 1 (n = 24) compared with healthy matched controls (n = 19). In additional analyses, we also included patients with idiopathic hypersomnia (n = 14) to assess sleepiness-related influences. METHODS: Participants were first trained on a choice task to earn salty and sweet snacks. Next, one of the snack outcomes was devalued by having participants consume it until satiation (i.e., sensory-specific satiety). We then measured the selective reduction in choices for the devalued snack outcome. Finally, we assessed the number of calories that participants consumed spontaneously from ad libitum available snacks afterwards. RESULTS: After satiety, all participants reported reduced hunger and less wanting for the devalued snack. However, while controls and idiopathic hypersomnia patients chose the devalued snack less often in the choice task, patients with narcolepsy still chose the devalued snack as often as before satiety. Subsequently, narcolepsy patients spontaneously consumed almost 4 times more calories during ad libitum snack intake. CONCLUSIONS: We show that the manipulation of food-specific satiety has reduced effects on food choices and caloric intake in narcolepsy type 1 patients. These mechanisms may contribute to their obesity, and suggest an important functional role for orexin in human eating behavior. CLINICAL TRIALS REGISTRATION: Study registered at Netherlands Trial Register. URL: www.trialregister.nl. Trial ID: NTR4508.

Quantitative Motor Performance and Sleep Benefit in Parkinson Disease.

STUDY OBJECTIVES: Many people with Parkinson disease experience "sleep benefit": temporarily improved mobility upon awakening. Here we used quantitative motor tasks to assess the influence of sleep on motor functioning in Parkinson disease. DESIGN: Eighteen Parkinson patients with and 20 without subjective sleep benefit and 20 healthy controls participated. Before and directly after a regular night sleep and an afternoon nap, subjects performed the timed pegboard dexterity task and quantified finger tapping task. Subjective ratings of motor functioning and mood/vigilange were included. Sleep was monitored using polysomnography. RESULTS: On both tasks, patients were overall slower than healthy controls (night: F2,55 = 16.938, P < 0.001; nap: F2,55 = 15.331, P < 0.001). On the pegboard task, there was a small overall effect of night sleep (F1,55 = 9.695, P = 0.003); both patients and controls were on average slightly slower in the morning. However, in both tasks there was no sleep*group interaction for nighttime sleep nor for afternoon nap. There was a modest correlation between the score on the pegboard task and self-rated motor symptoms among patients (rho = 0.233, P = 0.004). No correlations in task performance and mood/vigilance or sleep time/efficiency were found. CONCLUSIONS: A positive effect of sleep on motor function is commonly reported by Parkinson patients. Here we show that the subjective experience of sleep benefit is not paralleled by an actual improvement in motor functioning. Sleep benefit therefore appears to be a subjective phenomenon and not a Parkinson-specific reduction in symptoms.

The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency.

BACKGROUND: Narcolepsy is often not recognized or accurately diagnosed. This may be due to the fact that cataplexy, a core symptom which is virtually 100% specific, can-in practice-only be diagnosed based on the patient's history. However, the current definition of cataplexy is not very precise and the common distinction between "typical" and "atypical" cataplexy is not well codified. METHODS: We aimed to provide a detailed description of the phenotypic variability of cataplexy. We included 109 patients with a definite history of cataplexy and a proven hypocretin-1 deficiency. The questionnaire contained 37 items to broadly cover the clinical aspects of cataplexy, including triggers, pattern and duration of muscle weakness, associated aspects such as sensory phenomena, and limitations in daily life due to cataplexy. RESULTS: "Laughing" only listed in place 11th of most frequent triggers. "Laughing excitedly" was much more potent, showing that a certain intensity of the emotion is important for a "cataplectogenic" effect. Anger was the highest ranking "non-humorous" trigger, followed by "unexpectedly meeting someone well known." About 60% of patients also had spontaneous cataplectic attacks. Forty-five percent of patients experienced both partial and complete attacks and 30% only partial cataplexy. Fifteen percent of complete attacks were reported to last longer than 2 min. An abrupt return of muscle function was an important feature. The jaw and the face were most often involved in partial attacks, even more than the knee or the leg. CONCLUSIONS: Cataplexy presents with a large phenotypical diversity, so the current "typical" versus "atypical" distinction may be difficult to hold. We propose that grading cataplexy with different levels of diagnostic confidence may be more useful.