Sleep disturbances in SCN8A-related disorders

Abstract

Objectives: People with neurodevelopmental disorders frequently experience sleep disturbances, negatively impairing their quality of life. We aimed to determine the prevalence and nature of sleep disturbances in patients with SCN8A‐related disorders.

Methods: Through a collaborative network of caregivers and clinicians, we collected data about epilepsy, cognitive/motor abilities, medications, and relevant comorbidities of patients harboring a pathogenic SCN8A variant. The Sleep Disturbance Scale for Children (SDSC), the Children's Sleep Habits Questionnaire (CSHQ‐22‐items), and the Pediatric Daytime Sleepiness Scale (PDSS) were distributed and evaluated by factor scores and Composite Sleep Index. Video‐EEG‐polysomnographic recordings were performed.

Results: We enrolled 47 patients (age range: 2–39 years), whose phenotypes ranged from SCN8A‐DEE to intellectual disability without epilepsy. In the majority of them (82%), sleep disturbances were reported and/or observed at the SDSC. The most frequent were difficulty in initiating and maintaining sleep (64%), followed by sleep breathing disorder (43%), sleep–wake transition disorder (34%), and daytime sleepiness (34%). Sleep disturbances were more frequent in patients with severe DEE (96%) and ongoing seizures (93%) and were more severe in patients with sleep‐related seizures. The CSHQ and PDSS confirmed difficulty in initiating and maintaining sleep. Polysomnographic recordings (9 patients/20 nights) showed an altered sleep structure in 95%, with frequent arousals, mainly not seizure related.

Significance: More than 80% of patients with SCN8A‐related disorders presented with sleep disturbances, primarily consisting of sleep instability with difficulty of initiating and maintaining sleep. Animal studies showed sleep disturbances in SCN8A‐ and SCN1A‐Dravet Syndrome mice models, suggesting a role for voltage‐gated sodium channels in the regulation of sleep. Understanding the effects of SCN8A dysfunction on sleep stability may guide future therapeutic efforts to alleviate this often distressing symptom also in seizure‐free SCN8A patients.

Plain language summary: In this study, we analyzed sleep disturbances in patients with disorders related to a genetic mutation in the gene SCN8A. We found that the majority of the patients experienced sleep disturbances, mainly consisting in difficulty of initiating and maintaining sleep. Sleep disturbances were more frequent in patients with severe cognitive impairment and active epilepsy and more severe in patients with seizures during sleep.

Keywords: SCN8A; developmental and epileptic encephalopathy (DEE); epilepsy; sleep disorders.

FIGURE 1

Abnormal SDSC score across different age groups and phenotypes. AGE GROUPS. The SDSC scores show DIMS as the most represented sleep disturbance in all the age groups, SBD with higher percentage in adults, DA observed in small percentages mainly in adolescents and adults, SWTD reported in all the age groups, DOES described in children and adolescents and SHY in infants and children. SEIZURE FREQUENCY. The SDSC scores reveal higher percentages of sleep disturbances in all the items in patients with persistent seizures compared to patients seizure free, without a significant difference in seizure frequency (frequent versus rare) in patients with ongoing seizures. COGNITIVE IMPAIRMENT. The SDSC scores reveal higher percentages of sleep disturbances in patients with severe ID except for SWTD that is represented in a high percentage of patients without ID. MOTOR IMPAIRMENT. The SDSC scores reveal higher percentages of sleep disturbances in patients with severe motor impairment. DA, disorders of arousal; DIMS, disorders of initiating or maintaining sleep; DOES, disorders of excessive somnolence; ID, intellectual disability; SBD, sleep breathing disorders; SDSC, sleep disturbance scale for children; SHY, sleep hyperhidrosis; SWTD, sleep–wake transition disorders; TOT, total score.

FIGURE 2

Sleep polygraphic recordings. The EEG of a patient with intermediate phenotype, characterized by focal epilepsy well controlled by the ASM and mild cognitive impairment, showing different stages of wakefulness and sleep (NREM 1, 2, 3 and REM). The background activity is represented in wakefulness state and it disappears in the transition between wakefulness and NREM 1. Vertex spikes and sleep spindles and K complex are represented in stage NREM 1 and 2 respectively. High amplitude slow delta activity is represented in NREM 3 sleep stage and faster EEG activity with lower muscular tone is present in REM stage. ECG, electrocardiogram; Mylo, mylohyoideus; NREM, non rapid eye movement; REM, rapid eye movement; Spl. Capitis, splenius capitis; Tib ant, tibialis anterior.

FIGURE 3

Hypnograms and sleep fragmentation. The figure shows the hypnograms of four overnight polygraphic recordings in three different patients (see the supplementary Table for clinical details). The red lines represent the time points of seizures captured during the overnight polygraphic recordings. Patient 1 has severe DEE and persistent seizures; eight seizures were recorded. The sleep is disrupted by the presence of many awakenings, only a minority of whom were seizure‐related. The percentage of REM sleep is decreased and NREM 3 sleep is not represented. Patient 25, with intermediate focal epilepsy and mild cognitive impairment, was seizure‐free at the time of recordings. The hypnogram shows the representation of all the stages of sleep with an increased percentage of WASO. Patient 39 has focal epilepsy with drug‐resistant seizures and moderate cognitive impairment. Three seizures were recorded during the first night and no seizure occurred during the second night of polysomnographic recordings. The hypnograms show sleep fragmentation with many awakenings in both registrations but higher WASO in the night with recorded seizures. DEE, development epileptic encephalopathy; NREM, non rapid eye movement; Pt, patient; REM, rapid eye movement.