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.

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.

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.

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.

Sexsomnia in an Adolescent.

ABSTRACT: Sexsomnia has been reported and is well described in 115 prior cases in the literature. There have been associations with other sleep disorders serving as triggers for confusional arousals, thereby worsening sexsomnia episodes. We present a case of an adolescent boy with a history of resected and treated pineoblastoma who later developed sexsomnia marked by multiple episodes of masturbatory events per night. He had additional suspicions of obstructive sleep apnea. Polysomnography confirmed severe obstructive sleep apnea and captured multiple episodes of sexsomnia from both REM and NREM sleep. The patient also had daytime symptoms of severe anxiety and hypersomnia that required pharmacological intervention, cognitive behavioral techniques, and hypnosis. The patient showed improvement with hypnosis along with a multimodal approach to the treatment of sexsomnia.

Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report.

BACKGROUND: Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force to review these studies and provide evidence-based and consensus guidelines for the iron treatment of RLS in adults, and RLS and PLMD in children. METHODS: A literature search was performed to identify papers appearing in MEDLINE from its inception to July 2016. The following inclusion criteria were used: human research on the treatment of RLS or periodic limb movements (PLM) with iron, sample size of at least five, and published in English. Two task force members independently evaluated each paper and classified the quality of evidence provided. RESULTS: A total of 299 papers were identified, of these 31 papers met the inclusion criteria. Four studies in adults were given a Class I rating (one for IV iron sucrose, and three for IV ferric carboxymaltose); only Class IV studies have evaluated iron treatment in children. Ferric carboxymaltose (1000 mg) is effective for treating moderate to severe RLS in those with serum ferritin <300 µg/l and could be used as first-line treatment for RLS in adults. Oral iron (65 mg elemental iron) is possibly effective for treating RLS in those with serum ferritin ≤75 µg/l. There is insufficient evidence to make conclusions on the efficacy of oral iron or IV iron in children. CONCLUSIONS: Consensus recommendations based on clinical practice are presented, including when to use oral iron or IV iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed.

Effect of Obstructive Sleep Apnea Treatment on Lipids in Obese Children.

Obesity in children is associated with several co-morbidities including dyslipidemia. Obstructive sleep apnea (OSA) is commonly seen in obese children. In adults, diagnosis of OSA independent of obesity is associated with cardiometabolic risk factors including dyslipidemia. There is limited data on the impact of treatment of OSA on lipids in children. The objective of the study was to examine the impact of treatment of OSA on lipids in 24 obese children. Methods: Seventeen children were treated with continuous positive airway pressure (CPAP) and five underwent adenotonsillectomy. Mean apnea hypopnea index prior to treatment was 13.0 + 12.1 and mean body mass index (BMI) was 38.0 + 10.6 kg/m². Results: Treatment of OSA was associated with improvement in total cholesterol (mean change = -11 mg/dL, p < 0.001), and low-density lipoprotein cholesterol (mean change = -8.8 mg/dL, p = 0.021). Conclusion: Obese children should be routinely screened for OSA, as treatment of OSA favorably influences lipids and therefore decreases their cardiovascular risk.

Comorbidities in infants with obstructive sleep apnea.

STUDY OBJECTIVE: The clinical characteristics of obstructive sleep apnea (OSA) in infants have been insufficiently characterized. Our aim was to describe identifiable comorbidities in infants with obstructive sleep apnea, which may assist in recognizing these patients earlier in their disease course and help improve management. METHODS: This was a single-center, retrospective study involving infants 0-17 months of age with a diagnosis of OSA on the basis of clinical features and nocturnal polysomnography (PSG) at the Mayo Clinic Center for Sleep Medicine between 2000 and 2011. Patients were excluded if they had central apnea accounting for greater than 50% of respiratory events. OSA severity was determined by the apnea-hypopnea index (AHI). RESULTS: One hundred thirty-nine patients were included. Based upon the AHI, they were subdivided into mild (AHI <5; 30%), moderate (AHI 5-9; 30%), or severe (AHI >10; 40%) categories. Comorbidities included gastroesophageal reflux in 95/139 (68%), periodic limb movements in sleep in 59/139 (42%), craniofacial abnormalities in 52/139 (37%), neuromuscular abnormalities in 47/139 (34%), prematurity in 41/139 (29%), genetic syndromes in 41/139 (29%), laryngomalacia / tracheomalacia in 38/139 (27%), and epilepsy in 23/139 (17%) of subjects. Severity of OSA correlated with prematurity, having a genetic syndrome, or neuromuscular abnormality. Multispecialty evaluation was needed for 119/139 (86%). CONCLUSION: Comorbidities in infants with OSA differ from those of older children. Based upon the comorbidities identified in our study population, it appears that appropriate management of infants with OSA requires a multidisciplinary approach involving genetics, gastroenterology, pulmonology, otolaryngology, neurology, and general pediatrics.

Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose.

OBJECTIVE: An alternative treatment approach is needed for children who cannot tolerate oral iron preparations or when there is a need for rapid replenishment of iron stores. We report on the safety, adverse effects, and efficacy of intravenous iron sucrose in a retrospective sample of children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). METHODS: Sixteen children with RLS/PLMD who received intravenous iron sucrose at our institution between 2005 and 2011 were identified. The diagnosis of RLS/PLMD was established after formal sleep consultation and nocturnal polysomnography (PSG). Serum ferritin was assayed in all 16 subjects prior to iron sucrose infusion and in 14 subjects after infusion. The medical records were reviewed for treatment-related details. RESULTS: The mean age of subjects was 6.6 years (range, 2-16 y; 5/16 girls). The mean periodic limb movement index (PLMI) was 18.2±12.8. Fifteen of the 16 subjects (93.7%) had systemic or neurologic comorbidities. Fourteen of 16 (87.5%) subjects had received prior oral iron supplementation for sleep-related concerns, with the majority of the subjects either having gastrointestinal (GI) side effects or insufficient benefits. Intravenous iron sucrose therefore was provided to these 16 subjects through our outpatient pediatric infusion therapy center. The average dose of intravenous iron sucrose of 3.6 mg/kg was infused over 2 h. The baseline mean serum ferritin was 16.4±6.6 ng/mL. After infusion with intravenous iron sucrose, the mean serum ferritin rose to 45.7±22.4 ng/mL (n=14; [95% confidence interval, 17.2-41.3]; P<.0001). Parental assessment of response to iron sucrose therapy was conducted on follow-up clinic visits or via telephone calls. There was improved sleep in 62.5% (n=10) of subjects and no improvement in 12.5% (n=2) of subjects. No follow-up information was available for 25% (n=4) of subjects. Minor adverse events occurred in 25% (n=4) of subjects--two subjects experienced difficulty with peripheral intravenous catheter placement, while two had transient GI symptoms, such as anorexia, nausea, and vomiting. None of the subjects had anaphylaxis. CONCLUSIONS: Intravenous iron sucrose appears to be a relatively effective therapy for patients with childhood-onset RLS/PLMD and iron deficiency who do not tolerate or respond to oral iron supplements. Side effects were transient. The most common adverse events were difficulty with intravenous line placement and GI disturbance. There is a need for systematic prospective studies on the safety and efficacy of intravenous iron sucrose in RLS/PLMD in children.

The role of nocturnal polysomnography in assessing children with Chiari type I malformation.

OBJECTIVE: To evaluate nocturnal polysomnogram findings in children with suspected symptomatic Chiari type I malformation, correlate them with clinical and magnetic resonance imaging data and to determine if this information has value in clinical decision making process. METHODS: A retrospective review identified 24 children with type I Chiari malformation, presumed symptomatic who had undergone neurological assessment, cranial magnetic resonance imaging and nocturnal polysomnography. Perimedullary subarachnoid space effacement on the magnetic resonance studies and the magnitude of cerebellar tonsillar descent in relation to the McRae line were correlated with frequency of obstructive or central sleep apnea, number of cortical arousals and evidence of impaired vocal mobility on laryngoscopy. The Wilcoxon rank sum test was applied for continuous variables and the Fisher exact test for categorical variables. RESULTS: The median age of the subjects was 6 years. The findings from 16/24 subjects with perimedullary subarachnoid space effacement (effaced group) were compared with those of 8/24 in the non-effaced group. The central apnea index [1.5 (IQR 1-3.5) versus 0.5 (IQR 0-1.5)] and cortical arousal index [12 (IQR 10-19) versus 8 (IQR 6.5-9)] were significantly higher in the effaced group than in the non-effaced group (p=0.0376 and 0.0036 respectively). Greater descent of tonsils as measured by distance from the McRae line to the tonsil tip was associated with significantly higher central apnea index, total arousal index and respiratory event related arousals. Measurements of clivus-canal angle, Klauss index and pB-C2 line did not correlate with abnormalities on polysomnography. CONCLUSION: The central apnea and arousal indices derived from the nocturnal polysomnogram correlate well with magnetic resonance imaging findings of subarachnoid space effacement and degree of tonsillar herniation. In children with Chiari type I malformation, the nocturnal polysomnogram findings provides important information that aids in the decision making process about proceeding with surgical decompression.

Cerebral venous sinus thrombosis in pediatric cancer patients: long-term neurological outcomes.

Cerebral venous sinus thrombosis (CVST) is an uncommon but recognized complication of treatment for leukemia. Our goal was to determine the long-term neurocognitive outcomes in childhood cancer survivors who had CVST during therapy. Nine patients were identified from an institutional database. All had experienced CVST in the setting of L-asparaginase therapy in combination with other chemotherapeutic agents. Four patients completed neuropsychological evaluation. Their neurological examinations were normal. Neuropsychological testing showed that the participants performed well, with average to above-average scores on cognitive and behavioral testing. Three exhibited difficulties on a visual-motor integration task and 1 had difficulty with fine-motor dexterity, nonverbal memory, emotional control, shifting attention, and anxiety. Overall, by patient and parent report, the survivors had few problems. CVST is a known complication associated with treatment for leukemia and non-Hodgkin lymphoma, most commonly observed if asparaginase is used in combination with other chemotherapeutic agents. Although subtle difficulties were noted in survivors on neuropsychological testing, survivors themselves were not aware of the deficits. Further evaluation of leukemia survivors with a history of CVST is needed to assess for deficits and to understand whether further intervention is necessary.

Treatment of dyssomnias and parasomnias in childhood.

OPINION STATEMENT: Dyssomnias are sleep disorders associated with complaints of insomnia or hypersomnia. The daytime sleepiness of narcolepsy is treated by a combination of planned daytime naps, regular exercise medications such as modafinil, or salts of methylphenidate, or amphetamine. Cataplexy that accompanies narcolepsy is treated with anticholinergic agents, selective serotonin reuptake inhibitors, or sodium oxybate. Children with neurodevelopmental disabilities such as autism have sleep initiation and maintenance difficulties on a multifactorial basis, with favorable response to melatonin in some patients. Childhood onset restless legs syndrome is often familial, associated with systemic iron deficiency, and responsive to iron supplementation and gabapentin. Parasomnias are episodic phenomena events which occur at the sleep -- wake transition or by intrusion on to sleep. Arousal parasomnias such as confusional arousals and sleep walking can sometimes be confused with seizures. A scheme for differentiating arousal parasomnias from nocturnal seizures is provided. Since arousal parasomnias are often triggered by sleep apnea, restless legs syndrome, or acid reflux, treatment measures directed specifically at these disorders often helps in resolution. Clonazepam provided in a low dose at bedtime can also alleviate sleep walking and confusional arousals. Obstructive sleep apnea affects about 2 percent of children. Adeno-tonsillar hypertrophy, cranio-facial anomalies, and obesity are common predisposing factors. Mild obstructive sleep apnea can be treated using a combination of nasal corticosteroids and a leukotriene antagonist. Moderate to severe obstructive sleep apnea are treated with adeno-tonsillectomy, positive airway pressure breathing devices, or weight reduction as indicated. This paper provides an overview of the topic, with an emphasis on management steps. Where possible, the level of evidence for treatment recommendations is indicated.

Treatment of childhood obstructive sleep apnea.

OPINION STATEMENT: An array of surgical, medical and orthodontic treatments is available for treating childhood obstructive sleep apnea. Adenotonsillectomy remains the first choice in treatment, with a need for subsequent clinical and polysomnographic reassessment in selected cases to determine residual sleep-disordered breathing. Residual obstructive sleep apnea is more likely in patients with craniofacial abnormalities or obesity. It may require the use of a positive airway pressure breathing device. Topical corticosteroids, leukotriene antagonists, weight reduction, and positional therapy also play a role in ameliorating childhood obstructive sleep apnea. The published evidence for the efficacy of various treatment modalities consists largely of case-controlled studies and case reports.

Obstructive sleep apnea, seizures, and childhood apraxia of speech.

Associations between obstructive sleep apnea and motor speech disorders in adults have been suggested, though little has been written about possible effects of sleep apnea on speech acquisition in children with motor speech disorders. This report details the medical and speech history of a nonverbal child with seizures and severe apraxia of speech. For 6 years, he made no functional gains in speech production, despite intensive speech therapy. After tonsillectomy for obstructive sleep apnea at age 6 years, he experienced a reduction in seizures and rapid growth in speech production. The findings support a relationship between obstructive sleep apnea and childhood apraxia of speech. The rather late diagnosis and treatment of obstructive sleep apnea, especially in light of what was such a life-altering outcome (gaining functional speech), has significant implications. Most speech sounds develop during ages 2-5 years, which is also the peak time of occurrence of adenotonsillar hypertrophy and childhood obstructive sleep apnea. Hence it is important to establish definitive diagnoses, and to consider early and more aggressive treatments for obstructive sleep apnea, in children with motor speech disorders.

Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia.

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.