Melatonin use in managing insomnia in children with autism and other neurogenetic disorders - An assessment by the international pediatric sleep association (IPSA).

Though it is widely prescribed for improving sleep of children with autism and other neurogenetic disorders, there is a need for practical guidance to clinicians on the use of melatonin for managing insomnia in this population. Because data were either lacking or inconclusive, a task force was established by the International Pediatric Sleep Association (IPSA) to examine the literature based on clinical trials from 2012 onwards. A summary of evidence pertaining to melatonin's utility and potential side effects, practice-related caveats, and insights for use are published herewith.

Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome.

OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults. METHODS: Participants (n = 1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n = 697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n = 2107). A 5% false discovery rate was used to assess significance. RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index. CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Increased incidence of pediatric narcolepsy following the 2009 H1N1 pandemic: a report from the pediatric working group of the sleep research network.

This study was aimed to evaluate the yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multicenter retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and its relationship to historical H1N1 influenza data. A total of 950 participants were included in the analysis; 487 participants were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6  ±â€… 3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (p  <  .0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (p  <  .05). Cross-correlation analysis demonstrated a significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (p  =  .397, p  <  .0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. 1: We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). 2: We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). 3: We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). 4: We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). 5: We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). 6: We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). 7: We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). 8: We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). 9: We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 10: We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 11: We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 12: We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 13: We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). 14: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). 15: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 16: We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 17: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 18: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 19: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). 20: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). 21: We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). 22: We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

INTRODUCTION: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS: The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.

Brain tumours result in sleep disorders in children and adolescents.

BACKGROUND AND OBJECTIVES: Sleep disturbances are frequently reported in children with brain tumours. The objective of our cross-sectional study was to systematically examine sleep in these children. We hypothesised that children with tumours involving the sleep-wake-regulatory areas have an altered sleep-wake-regulation. METHODS: Sixty-one patients aged 0-18 years and with a diagnosis of a primary brain or cervical medullary tumour were included. They were categorised based upon tumour location into two groups - those affecting the sleep-wake regulatory regions, i.e. brain stem, basal forebrain, hypothalamus, thalamus, and posterior fossa compressing the brain stem and those that did not. Sleep history, questionnaire surveys, polysomnography, and multiple sleep latency test were used, as indicated clinically. Surveys included Pediatric Daytime Sleepiness Scale, Children's Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. RESULTS: Patients with tumours involving the sleep-wake regulatory areas were sleepier/more fatigued (p = 0.03). Sleep apnoea was observed in 86% of all the patients and comorbid narcolepsy in 8%, without group differences (p ≥ 0.12). Patients with tumours involving the sleep-wake-regulatory areas had more emotional problems (p = 0.04), were more affected by mental health problems (p < 0.001), and had poorer quality of life (p ≤ 0.03). CONCLUSIONS: Many children with brain tumours suffer from disturbed sleep, poor mental health, and low quality of life. We recommend that systematic sleep evaluation is included in their routine care along with psychological and social support.

The influence of antidepressants and actigraphy-derived sleep characteristics on pediatric multiple sleep latency testing.

STUDY OBJECTIVES: Research evaluating the influence of rapid eye movement suppressing antidepressants (REMS-AD) on multiple sleep latency test (MSLT) results and the value of performing actigraphy prior to this test in children and adolescents is lacking. We examined the impact of REMS-AD and actigraphy parameters on mean sleep latency (MSL) and sleep-onset REM episodes (SOREMs) on MSLT in a pediatric clinical sample. METHODS: This was a retrospective chart review at a quarternary referral center. We identified 164 MSLTs conducted in patients aged less than 18 years between 2014 and 2017. Correlations between REMS-AD, self-reported sleep duration, actigraphy parameters, and each of the outcomes (MSL and SOREMs) were examined. Regression analyses accounting for clinical characteristics were performed. RESULTS: Mean age of the sample was 11.9 ± 4.19 years, 62% were female, 28 (17%) were on REMS-AD (48% of whom were able to discontinue these medications prior to MSLT), and mean pediatric daytime sleepiness score was 21.7 ± 6.1. MSL was 11.27 ± 5.77 min and mean number of SOREMs 0.55 ± 1.04. Patients on a REMS-AD at initial assessment had fewer SOREMs compared to those not taking these medications (0.17 ± 0.19 vs 0.62 ± 0.09; P = .04); no difference was noted in MSL (10.36 ± 1.10 vs 11.47 ± 0.50; P = .36). Increased time in bed on actigraphy correlated with a longer MSL and fewer SOREMs (r = .23; P = .04 and r = .316; P = .004, respectively). Following regression analyses, use of REMS-AD continued to remain associated with fewer SOREMs; greater time in bed on actigraphy, but not self-reported sleep duration, was associated with a longer MSL (all P < .05). CONCLUSIONS: Clinicians should account for the use of REMS-AD and utilize actigraphy to determine time in bed while interpreting the results of a pediatric MSLT. CITATION: Mansukhani MP, Dhankikar S, Kotagal S, Kolla BP. The influence of antidepressants and actigraphy-derived sleep characteristics on pediatric multiple sleep latency testing. J Clin Sleep Med. 2021;17(11):2179-2185.

Specialist approaches to prognostic counseling in isolated REM sleep behavior disorder.

OBJECTIVES/BACKGROUND: Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling. PATIENTS/METHODS: We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics. RESULTS: Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient's and family's mental health. CONCLUSIONS: Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients' values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling.

Autonomic dysfunction in childhood hypersomnia disorders.

OBJECTIVE: Orthostatic intolerance (OI) is a common manifestation of autonomic dysfunction. It is characterized by light-headedness and palpitations in the upright position, with relief when supine. It can affect the quality of life. Other symptoms that may accompany OI include headache, fatigue, nausea, palpitations and abdominal pain. The prevalence and characteristics of autonomic symptoms in childhood hypersomnia disorders of childhood has not been examined, and hence were studied. METHODS: The medical records of children and adolescents with hypersomnia disorders were reviewed. Subjects had been diagnosed with narcolepsy types 1 or 2 (NT1 or NT2), idiopathic hypersomnia (IH) or the KLS, or hypersomnia related to medical conditions, were under 18 years of age at sleep diagnosis, and had been evaluated at our sleep center between 2000 and 2018. Those with comorbidities such as obstructive sleep apnea and major depression were excluded. The medical records were reviewed for symptoms at initial presentation suggestive of autonomic dysfunction, such as orthostatic intolerance, headache, fatigue, nausea, palpitations and abdominal pain. If these symptoms had been recorded, the chart was examined further to determine if an autonomic reflex screen (ARS) battery had been conducted. The ARS battery examines both sympathetic and parasympathetic function. It is composed of a tilt table test, heart rate and blood pressure responses to the Valsalva maneuver and deep breathing, a quantitative sudomotor axon reflex test and beat-to-beat blood pressure measurements during the Valsalva maneuver. Results of the ARS battery were interpreted by an autonomic neurology specialist (WS), who was not otherwise involved in the care of the patients. Medications taken at the time of autonomic testing were recorded. RESULTS: There were 89 patients with hypersomnia disorders. Forty six patients had NT1, 17 had NT2, 18 had IH, 1 with KLS, and 7 had hypersomnia associated with medical disorders. Thirty three of 89 subjects (37%) had the symptom of OI at initial presentation, hence had undergone autonomic reflex screen testing. The median age at diagnosis of hypersomnia in the 33 subjects with the OI symptom was 14.5 years (interquartile range 12-16) and similar (14.5 years, interquartile range 11.5-16) in the 56 subjects without OI. In the group with OI, 25/33 had not received medications for treating hypersomnia at the time of autonomic testing. OI was not related to the degree of sleepiness- the mean sleep latency in the subjects with OI was 5.3 ± 2.9 min while in those without OI it was 4.5 ± 3.8 min. The symptom of OI was not more likely to occur in any specific type of hypersomnia. OI however tended to occur predominantly in females - the female: male ratio in the OI subgroup was 2:1 (n = 33) while in the subgroup without OI, it was 1: 2.1 (n = 56; p = 0.0015). Additional symptoms recorded in the OI subgroup included lightheadedness in 25/33, palpitations in 6/33, nausea and vomiting in 4/33, fatigue in 25/33, headache in 15/33 and constipation in 3/33. The symptoms of OI were reproduced during the tilt table test in 17/33 subjects; 5 of these patients had a rise in heart rate consistent with postural orthostatic tachycardia syndrome (POTS). CONCLUSION: In this retrospective sample, one third of children with hypersomnia disorders exhibited the symptom of OI at initial presentation, with female predominance. A smaller subgroup met criteria for POTS. Screening for autonomic symptoms in children with hypersomnia is important because the former seems to be a treatable co-morbidity that impacts the sense of well-being.

Secondary Narcolepsy in Children.

Secondary narcolepsy occurs as a consequence of lesions involving the hypothalamic region that subserve wakefulness. Although observations on the characteristics of secondary narcolepsy have been published in adults, information on this topic in children is sparse. This is a retrospective study of characteristics and outcome of secondary narcolepsy in children. The medical records of 10 children with this condition at Mayo Clinic, Rochester, were reviewed. Characteristics of the underlying neurologic disorder, narcolepsy subtype, multiple sleep latency tests, medications used and outcome were extracted. Age at diagnosis of narcolepsy was between 6 and 17 years. Five of 10 patients had onset of excessive sleepiness within 1 year of diagnosis of the primary neurologic disorder. Six of 10 patients had type 1 narcolepsy (with cataplexy) whereas 4/10 had type 2 (without cataplexy). The clinical course was variable, with 8/10 continuing to require treatment for sleepiness at a mean period 6.6±6.2 years after diagnosis. One patient with narcolepsy type 1 due to Niemann Pick type C disease had died. One patient with narcolepsy type 2 due to craniopharyngioma had spontaneous remission of sleepiness. The 5/10 patients surviving with narcolepsy type 1 have continued to require pharmacotherapy for both sleepiness and cataplexy. This study draws attention to an important chronic sequel of childhood brain lesions that has variable, etiology-specific outcome. The rare occurrence of spontaneous resolution of childhood narcolepsy symptoms, not previously described, is also discussed.

Restless sleep in children: A systematic review.

This systematic review assessed the prevalence of restless sleep in children, documented the association of restless sleep with other conditions, and summarized the existing evidence regarding whether restless sleep should be considered a distinct sleep disorder. A comprehensive search of electronic databases was performed using the broad search term "restless sleep" in all fields. Of the 266 articles retrieved, 107 were retained for inclusion in this review. The majority (n = 93) were observational studies. The studies were grouped under several pathologic/condition categories: sleep-disordered breathing (n = 19); adenotonsillectomy (n = 7); respiratory disorders, otitis media, and smoke exposure (n = 12); sleep-related movement disorders and restless sleep disorder (n = 11); neurologic or psychiatric disorders (n = 7); Down syndrome/other neurodevelopmental disorders (n = 10); sleep-related bruxism and other sleep disorders (n = 7); and restless sleep in the general population/mixed clinical samples (n = 18). A high prevalence of restless sleep was found in children with many of these underlying conditions, likely related to associated inherent sleep disruption and frequent awakenings (e.g., apnea and periodic limb movements), pain, sleep instability, and caregiver perception. The majority of studies identified restless sleep as reported by the caregiver, only 34 studies attempted to define restless sleep further. Four studies provided supportive evidence for designating restless sleep as an independent sleep disorder, restless sleep disorder (RSD). This review highlights the fact that the prevalence, etiology and sequelae (including daytime impairments) of restless sleep in children are important topics deserving of further research and that clinical definitions based on empirical evidence need to be developed. The designation of "primary" versus "secondary" restless sleep may be a useful construct, especially with regard to developing clinical trials and treatment algorithms.

Sleep and Breathing After Nusinersen Therapy in a Child With Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) type 3 is an autosomal recessive neurological disorder associated with a deletion/mutation in the survival motor neuron gene, with gradually progressive degeneration of the motor neurons of the spinal cord and brainstem, which causes muscle weakness responsible for impairment of swallowing, breathing, and mobility. REPORT OF CASE: We report an 11-year-old girl with SMA type 3 with moderate to severe obstructive sleep apnea (OSA) syndrome refractory to adenotonsillectomy and noninvasive ventilatory support. She was started on nusinersen, which is a novel disease modifying therapy for SMA. This new treatment led to improvement of the OSA in a short period, likely from better respiratory muscle function. CONCLUSIONS: The improvement in OSA supports the role of nusinersen in sleep-related upper respiratory muscle function in SMA type 3.

Consensus diagnostic criteria for a newly defined pediatric sleep disorder: restless sleep disorder (RSD).

BACKGROUND: Restless sleep is a frequent complaint in clinical practice and has been reported in the medical literature since the 1970s. Most often, it has been described in association with specific sleep or medical conditions. However, more recently, publications have emerged that describe a disorder characterized by restless sleep as the core feature. To assess this further, the International Restless Legs Syndrome Study Group (IRLSSG) appointed a task force composed of international sleep experts. METHODS: A committee of 10 sleep clinicians developed a set of 16 consensus questions to review, conducted a comprehensive literature search, and extensively discussed potential diagnostic criteria. The committee recommendations were reviewed and endorsed by the IRLSSG Executive Committee. RESULTS: Based on the medical literature and expert clinical experience, the task force found sufficient evidence to formulate diagnostic criteria for a clinical entity designated "restless sleep disorder" (RSD). Eight essential criteria were agreed upon, which include a complaint of restless sleep, observed large body movements during sleep, video-polysomnographic documentation of 5 or more large body movements/hour, occurrence at least three times a week for at least three months, clinically significant impairment, and differentiation from other conditions that might secondarily cause restless sleep. However, the current evidence limits application to ages 6-18 years. Diagnostic coding, addition to existing diagnostic nosologies, and name selection are discussed. CONCLUSIONS: Consensus diagnostic criteria for RSD have been developed, which are intended to improve clinical practice and promote further research.

Expanded genetic insight and clinical experience of DNMT1-complex disorder.

OBJECTIVE: To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder. METHODS: Neurophysiologic testing, imaging, and genetic findings were summarized in clinical context for 5 cases with DNMT1-complex disorder. RESULTS: We identified 2 novel DNMT1 mutations (p.E510K and p.P1546A) by whole-exome sequencing (WES). Case 1 (p.E510K) presented with childhood ataxia, treatment-refractory seizures, and rapid cognitive decline in his 50s. Case 2 also had childhood onset and presented with seizures, language regression, hearing loss, narcolepsy with cataplexy symptoms, optic atrophy, sensory neuropathy, and hypogammaglobulinemia requiring IV immunoglobulin. Case 2 (p.P1546A) was identified with a de novo and the first mutation residing outside the targeting sequence domain. Case 3 (p.A570V) had paralytic asymmetric onset attacks triggered by emotionality and lasting sometimes for weeks. Neuropsychological testing showed executive dysfunction localizing to frontosubcortical and frontoparietal structures. He gradually developed left predominant brain atrophy. MRI showed T2 hyperintense lesions that enhanced on T1 postgadolinium images, and brain PET showed hypometabolism in atrophied regions. Case 4 (p.T497P) underwent left cochlear implant, resulting in significant hearing improvements at all tested frequencies (250-6,000 Hz). Case 5 (p.Y511H) had profound gait ataxia with posterior column atrophy of the spinal cord and abnormal evoked potentials primarily affecting the fasciculus gracilis. CONCLUSIONS: Broader application of WES further expands genotype-phenotype correlations of DNMT1-complex disorder. Two mutations are identified with early childhood onsets. The expanded new phenotypes include asymmetric brain hemiatrophy with parenchymal gadolinium enhancement, spinal cord atrophy, prolonged cataplectic spells, and hypogammaglobulinemia. Hearing loss treatment by cochlear implantation is helpful and should be considered.

Iron Deficiency and Its Role in Sleep Disruption in Patients With Angelman Syndrome.

OBJECTIVE: To determine if Angelman syndrome patients with sleep complaints have an increased risk of iron deficiency, and if iron therapy improves their sleep difficulties. BACKGROUND: About two-thirds of Angelman syndrome patients experience sleep difficulties, which are likely multifactorial. Because iron deficiency can contribute toward restlessness in sleep, we investigated whether it might be a contributing factor in this special population. METHODS: This retrospective study involved medical record review of Angelman syndrome patients <18 years old who had attended our multidisciplinary Angelman syndrome clinic and had sleep complaints. Serum ferritin levels were compared to age- and sex-matched controls. Sleep history and nocturnal polysomnogram findings of the Angelman syndrome patients were also characterized. RESULTS: Nineteen Angelman syndrome patients (9 female, mean age 6.2±4.4 years) were identified. All 19 reported sleep difficulties. The mean serum ferritin level was 19.9±8.5 µg/L, while that in controls was 27.8±17.8 µg/L (P value .13). The odds ratio of iron deficiency in Angelman syndrome compared to controls was 4.17 (95% confidence interval 1.23-14.10), using normal serum ferritin level of 24 µg/L based on literature. Fifteen Angelman syndrome patients underwent nocturnal polysomnogram with 9/15 showing an elevated periodic limb movement index (overall mean 9.8±10.4). Seventeen of 19 received iron therapy. Twelve had follow-up after iron therapy, with parents reporting improved sleep quality. Eight had serum ferritin levels rechecked after iron therapy, showing a mean increase of 24±5.1 µg/L. CONCLUSIONS: Sleep difficulties in Angelman syndrome, though multifactorial, may in part be related to iron deficiency. Treatment with iron improved sleep to a modest degree in this population.

Intracranial Epidural Abscess in a 9-Year-Old Boy With Precocious Puberty and Use of Continuous Positive Airway Pressure.

Intracranial extension of rhinosinusitis is rare in children. We report a 9-year-old immunocompetent boy with central precocious puberty and obstructive sleep apnea-hypopnea syndrome who developed an intracranial epidural abscess secondary to rhinosinusitis while on continuous positive airway pressure (CPAP) treatment. A retrospective review of the medical record and imaging studies was performed. MEDLINE and Cochrane databases were searched for reports of epidural abscess developing in patients receiving CPAP treatment or in patients with precocious puberty. Intracranial extension of frontal rhinosinusitis is more common during puberty probably because of the active growth of the frontal sinuses and their rich blood supply. Controlled studies show no increase with rhinosinusitis in adults on CPAP; no published studies assess intracranial extension of rhinosinusitis in CPAP use. Patients with unexplained, severe headache and fever following CPAP use may require neuroimaging (magnetic resonance imaging [MRI] / contrast computed tomography) to rule out intracranial extension of sinusitis.

Physician and patient determinants of prognostic counseling in idiopathic REM sleep-behavior disorder.

OBJECTIVES/BACKGROUND: Prognostic counseling about the risk for developing overt neurodegenerative disorders for patients with idiopathic REM sleep-behavior disorder (iRBD) and isolated REM sleep without atonia (iRSWA) is difficult, given lack of disease-modifying interventions and uncertainty in accurate prognostication for individuals. We aimed to analyze patient and physician characteristics associated with documented prognostic discussions for patients with iRBD and iRSWA. PATIENTS/METHODS: We retrospectively reviewed the medical records for 138 (112 iRBD and 26 iRSWA) patients seen at the Mayo Clinic between 2012 and 2015. We analyzed physician and patient demographics, initial complaint, and other information discussed during office visits. We then comparatively analyzed the impact of physician and patient characteristics on documented prognostic discussions using Chi Square or Fischer's exact test. RESULTS: Mean iRBD patient age was 65.0 ± 13.0, and mean iRSWA age was 58 ± 15 years. Seventy-eight (69.6%) iRBD and 22 (84.6%) iRSWA patients were men. Sixty-two (55%) iRBD and three (12%) iRSWA patients received prognostic counseling about phenoconversion risk. iRBD was a secondary complaint in 67 (59.8%). Patients over age 60 years and those having iRBD as a chief complaint more frequently received prognostic discussions than those with opposite characteristics (all p < 0.05). Patient sex and antidepressant use were not associated with counseling. Sleep neurologists disclosed prognostic information most frequently, with male more likely than female clinicians to disclose prognoses. CONCLUSIONS: Several patient and physician characteristics appear to influence documented prognostic counseling for iRBD/RSWA patients. Future studies of iRBD/RSWA patients' preferences are needed to clarify ethically appropriate physician-patient communication concerning prognosis.