Relationship Between Sleep Characteristics and Sudden Unexplained Death Risk in Epilepsy.

BACKGROUND: Sleep disorders and disturbances are generally underestimated in patients with epilepsy. The aim of this study is to determine the frequency of sleep disturbances and the comorbidity of sleep disorders in people with epilepsy without any complaints about sleep and their relation of sudden unexplained death in epilepsy (SUDEP) risk. METHODS: Sleep complaints and the presence of sleep disorders were assessed with 4 questionnaires in 139 patients with epilepsy. Subjective sleep features were evaluated with Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Berlin Questionnaire for sleep apnea, and restless legs syndrome with International Restless Legs Syndrome Study Group (IRLSSG) severity scale. The presence of rapid eye movement/nonrapid eye movement parasomnia was asked to the patients and their relatives who share the same house. The patients' SUDEP-7 scores were also determined and associations with sleep problems were investigated statistically. RESULTS: Ninety-two patients with focal and 47 patients with generalized epilepsy were evaluated after their consent. The daily sleep quality was poor in 34 (24.5%) patients with PSQI. Daily sleepiness was present in 7 (5%) patients with ESS. Twenty-five patients (18%) had severe sleep apnea risk with the Berlin Questionnaire. Mild or severe RLS was detected in 24 patients (17.2%). There were no significant differences between focal or generalized epilepsy groups' scores. No statistically significant relationship was identified between SUDEP-7 scores and sleep quality or sleep-related disorders. CONCLUSION: Our results emphasized a remarkable magnitude of the comorbidity of sleep disorders in patients with epilepsy, even for those who do not have complaints about sleep. As SUDEP cases are frequently seen during sleep, it is important to evaluate sleep in patients with epilepsy.

Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.

IMPORTANCE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder. OBJECTIVE: To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. DESIGN, SETTINGS, AND PARTICIPANTS: In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. MAIN OUTCOMES AND MEASURES: Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity. RESULTS: Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP. CONCLUSIONS AND RELEVANCE: This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.