Feasibility of Actigraphy for Evaluating Sleep and Daytime Physical Activity in Children with Autism Spectrum Disorder.

This research evaluated the feasibility of actigraphy to measure sleep and physical activity in children (ages 2-8 years) with autism spectrum disorder (ASD). We also explored associations between sleep and physical activity. Validated screening measures established eligibility. Questionnaires, diaries, and 5 days and 5 nights of actigraphy monitoring were used to collect data. Of the 32 children enrolled, 27 (84.4%) completed actigraphy monitoring. Based on the median steps per day, children with high physical activity had lower total sleep time and more disruptive behaviors than children with low physical activity. Findings support the feasibility of using actigraphy to measure sleep and physical activity in children with ASD. Larger studies are needed to evaluate interactions of physical activity on sleep in this population.

Sleep in children and adolescents with Angelman syndrome: association with parent sleep and stress.

BACKGROUND: Sleep concerns are common in children with Angelman syndrome, with 20-80% of individuals having a decreased sleep need and/or abnormal sleep-wake cycles. The impact of these sleep behaviours on parental sleep and stress is not known. METHOD: Through the use of standardised questionnaires, wrist actigraphy and polysomnography, we defined the sleep behaviours of 15 children/adolescents with Angelman syndrome and the association of the child/adolescents sleep behaviours on parental sleep behaviours and parental stress. RESULTS: Both children/adolescents and their parents exhibited over 1 h of wake time after sleep onset and fragmented sleep. Prolonged sleep latency in the child was associated with parent insomnia and daytime sleepiness. Additionally, variability in child total sleep time was associated with parental stress. CONCLUSIONS: Poor sleep in children/adolescents with Angelman syndrome was associated with poor parental sleep and higher parental stress. Further work is warranted to identify the underlying causes of the poor sleep, and to relate these findings to daytime functioning, behaviour and the family unit.

Characterizing sleep disorders in an autism-specific collection of electronic health records.

OBJECTIVE/BACKGROUND: Sleep problems are common in people on the autism spectrum. This study reviews one detailed approach to querying the electronic health record (EHR) in a large tertiary care center. PATIENTS/METHODS: We developed methods for identifying people on the autism spectrum and defined their sleep problems using the key words, "sleep" or "melatonin", or International Classification of Diseases (ICD) codes. We examined treatment responses of these individuals to melatonin supplementation. RESULTS: Sleep problems were documented in 86% of patients with ages ranging from 6 to 30 years old. Our specific keyword search yielded more patients with sleep diagnoses than ICD codes alone. About two-thirds of patients who received melatonin supplementation reported benefit from its use. CONCLUSIONS: Our study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in people on the autism spectrum. Using specific keywords could be helpful in future work that queries the EHR.

Sleep patterns and daytime sleepiness in adolescents and young adults with Williams syndrome.

BACKGROUND: Sleep disorders are common in individuals with neurodevelopmental disorders and may adversely affect daytime functioning. Children with Williams syndrome have been reported to have disturbed sleep; however, no studies have been performed to determine if these problems continue into adolescence and adulthood. METHODS: This study examined overnight sleep patterns and daytime sleepiness in 23 adolescents and adults with Williams syndrome age 25.5 (8.0) years [mean (SD)]. Interviewer-administered sleep questionnaires were used to evaluate nighttime sleep behaviours and daytime sleepiness. Wrist actigraphy was used to evaluate sleep patterns. RESULTS: Although individuals in our sample averaged 9 h in bed at night, daytime sleepiness and measures of sleep disruption were common and comparable to those of other populations with neurodevelopmental disorders. These measures included reduced sleep efficiency [74.4 (7.0)%] with prolonged sleep latency [37.7 (37.3) min], increased wake time after sleep onset [56.1 (17.6) min], and an elevated movement and fragmentation index [14.3 (4.6)]. CONCLUSION: Adolescents and young adults with Williams syndrome were found to be sleepy despite averaging 9 h in bed at night. Implications are discussed for associated causes of sleep disruption and future polysomnographic evaluation.

Characterizing Sleep in Adolescents and Adults with Autism Spectrum Disorders.

We studied 28 adolescents/young adults with autism spectrum disorders (ASD) and 13 age/sex matched individuals of typical development (TD). Structured sleep histories, validated questionnaires, actigraphy (4 weeks), and salivary cortisol and melatonin (4 days each) were collected. Compared to those with TD, adolescents/young adults with ASD had longer sleep latencies and more difficulty going to bed and falling asleep. Morning cortisol, evening cortisol, and the morning-evening difference in cortisol did not differ by diagnosis (ASD vs. TD). Dim light melatonin onsets (DLMOs) averaged across participants were not different for the ASD and TD participants. Average participant scores indicated aspects of poor sleep hygiene in both groups. Insomnia in ASD is multifactorial and not solely related to physiological factors.

Cultured cells as a screen for novel treatments of Alzheimer's disease.

Two easily measured abnormal properties of fibroblasts from patients with Alzheimer's disease have been utilized to develop an in vitro test system for screening novel therapeutic agents for Alzheimer's disease. The abnormal properties selected for study were increased isoproterenol-stimulated cyclic adenosine monophosphate production and decreased pH (measured by the weak-acid distribution method). L-Carnitine was tested as a potential therapeutic agent, since it has been used to treat a variety of experimental metabolic encephalopathies. The addition of L-carnitine normalized both of these properties in the Alzheimer cells. Tissue culture may aid as a preliminary screen for identifying novel approaches to the treatment of Alzheimer's disease.

Neuralgic amyotrophy in association with radiation therapy for Hodgkin's disease.

We describe 4 patients with Hodgkin's disease who developed neuralgic amyotrophy in the setting of radiation therapy. In contrast to tumor progression or radiation plexopathy, the symptom onset was abrupt and occurred within days to weeks of receiving radiation treatments. There is an association between Hodgkin's disease, radiation therapy, and neuralgic amyotrophy.

Carbamazepine withdrawal: effects of taper rate on seizure frequency.

We prospectively investigated the effects of rate of carbamazepine (CBZ) withdrawal and CBZ level on seizure type and frequency in 12 epilepsy patients withdrawn completely from antiepileptic drugs prior to entering an investigational monotherapy trial. Patients withdrawn from CBZ rapidly (over 4 days) experienced significantly more generalized tonic-clonic seizures (GTCSs) and GTCS clusters than did those withdrawn slowly (over 10 days). Complex partial seizure (CPS) frequency did not differ between the two groups. CPSs preceded GTCSs, with GTCSs occurring in the majority of patients after CBZ had been discontinued, at subtherapeutic or absent CBZ levels. Two of six patients who had been tapered rapidly and all six patients who had been tapered slowly were able to enter the investigational monotherapy trial.

Usefulness of polysomnography in epilepsy patients.

We reviewed the records of 63 adult epilepsy patients who underwent polysomnograms in our laboratory since 1985 to determine the indications for polysomnography and the results of testing. Reasons for referral included excessive daytime sleepiness, suspected obstructive sleep apnea (OSA), and characterization of nocturnal spells. The most common polysomnographic diagnosis was OSA, although we also found narcolepsy, insufficient sleep syndrome with possible idiopathic hypersomnolence, and previously unrecognized nocturnal seizures. We treated OSA with continuous positive airway pressure in 28 patients, 15 of whom were using the device at follow-up appointments. The majority of patients treated for OSA or other disorders reported an improvement in sleepiness or seizure control. Polysomnography, when indicated, is beneficial in epilepsy patients.

Obstructive sleep apnea is common in medically refractory epilepsy patients.

BACKGROUND: Previous reports have documented the coexistence of obstructive sleep apnea (OSA) and epilepsy and the therapeutic effects of treatment on seizure frequency and daytime sleepiness. The authors' objective was to determine the prevalence of OSA and its association with survey items in a group of patients with medically refractory epilepsy undergoing polysomnography (PSG). METHODS: Thirty-nine candidates for epilepsy surgery without a history of OSA underwent PSG as part of a research protocol examining the relationship of interictal epileptiform discharges to sleep state. Subjects also completed questionnaires about their sleep, including validated measures of sleep-related breathing disorders (Sleep Apnea Scale of the Sleep Disorders Questionnaire [SA/SDQ]) and subjective daytime sleepiness (Epworth Sleepiness Scale [ESS]). RESULTS: One-third of subjects had OSA, defined by a respiratory disturbance index (RDI) > or = 5. Five subjects (13%) had moderate to severe OSA (RDI > 20). Subjects with OSA were more likely to be older, male, have a higher SA/SDQ score, and more likely to have seizures during sleep than those without OSA (p < 0.05). Seizure frequency per month, the number or type of antiepileptic drugs (AED) prescribed, the localization of seizures (temporal versus extratemporal), and the ESS were not statistically different between the two groups. CONCLUSIONS: In our sample, previously undiagnosed obstructive sleep apnea was common, especially among men, older subjects, and those with seizures during sleep. The impact of treating OSA on seizure frequency and daytime sleepiness in medically refractory epilepsy patients warrants further controlled study.

Effects of vagus nerve stimulation on respiration during sleep: a pilot study.

BACKGROUND: Vagus nerve stimulation (VNS) is associated with respiratory effects such as hoarseness, dyspnea, and laryngeal irritation. The effects of VNS on sleep-related breathing in humans have not been reported previously. METHODS: Four epilepsy patients underwent polysomnography (PSG) before and after 3 months of treatment with VNS. Two of the four patients also underwent follow-up PSG to assess the effects of changing stimulus parameters on sleep-related breathing. RESULTS: All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas. Apneas and hypopneas were more frequent during VNS activation than during nonactivation. Apnea-hypopnea index (AHI) for three subjects during VNS treatment PSG was <5 apneas and hypopneas/hour. In one patient with obstructive sleep apnea (OSA) before VNS treatment, AHI rose from 4 (pretreatment) to 11.3 (treatment). In this patient and in another patient without clinically significant OSA, lowering stimulus frequency, but not stimulus intensity, pulse width, or on-time, ameliorated VNS-related apneas and hypopneas. CONCLUSIONS: VNS is associated with adverse changes in respiration during sleep. In patients without preexisting OSA, this VNS effect is probably not clinically significant. In patients with preexisting OSA, VNS should be administered with care. Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA.

Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients.

BACKGROUND: Given that vagal afferents project to brainstem regions that promote alertness, the authors tested the hypothesis that vagus nerve stimulation (VNS) would improve daytime sleepiness in patients with epilepsy. METHODS: Sixteen subjects with medically refractory seizures underwent polysomnography and multiple sleep latency tests (MSLT) and completed the Epworth Sleepiness Scale (ESS), a measure of subjective daytime sleepiness, before and after 3 months of VNS. Most subjects (>80%) were maintained on constant doses of antiepileptic medications. RESULTS: In the 15 subjects who completed baseline and treatment MSLT, the mean sleep latency (MSL) improved from 6.4 +/- 4.1 minutes to 9.8 +/- 5.8 minutes (+/- SD; p = 0.033), indicating reduced daytime sleepiness. All subjects with stimulus intensities of < or =1.5 mA showed improved MSL. In the 16 subjects who completed baseline and treatment ESS, the mean ESS score decreased from 7.2 +/- 4.4 to 5.6 +/- 4.5 points (p = 0.049). Improvements in MSLT and ESS were not correlated with reduction in seizure frequency. Sleep-onset REM periods occurred more frequently in treatment naps as compared to baseline naps (p < 0.008; Cochran-Mantel-Haenszel test). The amount of REM sleep or other sleep stages recorded on overnight polysomnography did not change with VNS treatment. CONCLUSIONS: Treatment with VNS at low stimulus intensities improves daytime sleepiness, even in subjects without reductions in seizure frequency. Daytime REM sleep is enhanced with VNS. These findings support the role of VNS in activating cholinergic and other brain regions that promote alertness.

Sleep deprivation does not affect seizure frequency during inpatient video-EEG monitoring.

OBJECTIVE: To determine whether acute sleep deprivation facilitates seizures during inpatient monitoring in a controlled protocol. METHODS: Eighty-four patients with medically refractory partial epilepsy undergoing inpatient monitoring were assigned in consecutive blocks to either sleep deprivation every other night or to normal sleep. In both groups, subjects were requested to stay awake during the day, from 6 AM to 10 PM. In the sleep deprivation group, patients also stayed awake between 10 PM and 6 AM every other night beginning with Day 2. Patients were removed from sleep deprivation if they had two or more secondarily generalized seizures within 24 hours. Patients were removed from the normal sleep group and were sleep deprived if they did not have a complex partial or secondarily generalized seizure by Day 6 of monitoring. In these patients removed from sleep deprivation or from normal sleep, data were analyzed up to and including the day of removal from the protocol. RESULTS: The sleep deprivation and normal sleep subjects did not differ in age, sex, seizure localization, or percent dosage reduction in antiepileptic drugs from baseline at days 1 to 3 of monitoring. Protocol duration was 6.5 +/- 2.4 days (mean +/- SD) for the sleep deprivation group and 5.8 +/- 2.0 days for the normal sleep group. Seizures per day for complex partial, secondarily generalized, and combined complex partial and secondarily generalized, calculated from admission until end of protocol, did not differ significantly between the two groups. CONCLUSION: Acute sleep deprivation did not affect seizure frequency during inpatient monitoring in our patients with intractable complex partial seizures with secondary generalization.

Anticonvulsant withdrawal-emergent psychopathology.

We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.

A direct comparison of PET activation and electrocortical stimulation mapping for language localization.

Mapping eloquent language cortex in presurgical patients typically is accomplished using highly invasive direct cortical stimulation techniques. Functional imaging during language activation using positron emission tomography (PET) is a promising, noninvasive alternative that requires validation. In seven patients undergoing surgical evaluation for intractable epilepsy, we performed both direct cortical stimulation and PET activation mapping of language cortex using identical tasks. MRI, PET, and CT scans were coregistered to directly compare the location of language centers determined by cortical stimulation versus activation PET. We found that cortical regions that showed increased cerebral blood flow during both visual and auditory naming tasks were located in the same regions as subdural electrodes which disrupted language during electrical stimulation. Cortical regions underlying electrodes that did not disrupt language also showed no consistent changes in regional cerebral blood flow during PET activation. Used cautiously, PET activation produces language maps similar to those obtained with direct cortical stimulation, with more complete brain coverage and considerably less invasion.

Seizures and arousals from sleep--which comes first?

Epileptic seizures may be associated with arousals from sleep. The temporal sequence of seizures and arousals is often uncertain and it may be impossible to determine their relationship by surface electroencephalogram (EEG) recordings alone. We describe a 28-year-old right-handed man with medically refractory partial epilepsy in whom seizure onset appeared to follow arousal from stage 2 nonrapid eye movement sleep based on the surface EEG. Inspection of simultaneously recorded intracranial EEG, however, demonstrated that the seizure onset preceded the arousal. This study illustrates the limitations of surface EEG and the utility of intracranial electrode recordings in investigating the relationship between arousals and seizures.

Predictors of sleepiness in epilepsy patients.

Sleepiness, a common complaint of epilepsy patients, is frequently attributed to antiepileptic medications. To determine predictors of subjective sleepiness in epilepsy patients, we gave self-administered, validated surveys of sleepiness [Epworth sleepiness scale (our major outcome measure)] and sleep apnea [sleep apnea scale of the sleep disorders questionnaire (SA/SDQ)] to 158 epilepsy patients and 68 neurology patients without epilepsy (controls). An elevated Epworth score (>10) was more likely in epilepsy patients compared to controls after controlling for age and gender (p < 0.05). When Epworth scores were adjusted for SA/SDQ scores and restless legs symptoms (RLS), however, epilepsy patients showed only a nonsignificant trend toward elevated Epworth scores compared to controls (p = 0.08). SA/SDQ scores (p < 0.005) and RLS (p < 0.007) were significant predictors of elevated Epworth score in both epilepsy patients and controls. Among the epilepsy patients, the number or type of antiepileptic medication, seizure frequency, epilepsy syndrome (partial vs. generalized), and the presence of sleep-related seizures were not significant predictors (p > 0.10) of elevated Epworth score. Before attributing sleepiness in epilepsy patients to antiepileptic medications or uncontrolled seizures, clinicians should consider the possibility of a coexisting sleep disorder.

Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy.

Since its introduction, the multiple sleep latency test (MSLT) has played a major role in the diagnosis of narcolepsy. We assessed its diagnostic value in a series of 2,083 subjects of whom 170 (8.2%) were diagnosed with narcolepsy. The sensitivity of the combination of two or more sleep onset rapid eye movement (REM) periods (SOREMPs) with a mean sleep latency of < 5 minutes on an initial MSLT was 70% with a specificity of 97%, but 30% of all subjects with this combination of findings did not have narcolepsy. In some narcoleptics who had more than one MSLT, the proportion of naps with SOREMPs varied substantially from the initial MSLT to the follow-up test. The highest specificity (99.2%) and positive predictive value (PPV) (87%) for MSLT findings was obtained with the criteria of three or more SOREMPs combined with a mean sleep latency of < 5 minutes, but the sensitivity of this combination was only 46%. The combination of a SOREMP with a sleep latency < 10 minutes on polysomnography yielded a specificity (98.9%) and PPV (73%) almost equal to those obtained from combinations of MSLT findings, but the sensitivity was much lower. Our results suggest that the MSLT cannot be used in isolation to confirm or exclude narcolepsy, is indicated only in selected patients with excessive daytime sleepiness, and is most valuable when interpreted in conjunction with clinical findings.

Hippocampal sleep spindles revisited: physiologic or epileptic activity?

OBJECTIVE: Few reports have described sleep spindles in intracranial electrode recordings from human hippocampus. Controversy exists regarding whether hippocampal spindles represent a physiologic or epileptic phenomenon. METHODS: We reviewed hippocampal recordings in 8 subjects to characterize events resembling sleep spindles. RESULTS: In 6 subjects, events occurred exclusively during non-rapid eye movement (NREM) sleep, were similar in morphology to surface spindles, occurred simultaneously or independently of surface spindles, and did not show a consistent relationship to the epileptic region. In an additional subject, a proportion of the hippocampal activity recorded differed slightly in morphology from surface spindles, was present during both NREM and rapid eye movement (REM) sleep, occurred in the same channels as isolated interictal epileptiform discharges, attenuated just prior to seizures, and occurred postictally as repetitive discharges. This activity occurred simultaneously or independently of surface spindles, but differed from surface spindles by both visual and signal analysis measures. CONCLUSIONS: Most examples of hippocampal activity resembling spindles are probably physiologic, originating within the hippocampus or propagated from neighboring regions. However, in one subject, spindle activity and epileptiform discharges may have coincided, supporting experimental evidence that neurophysiological processes associated with spindle generation and NREM sleep contribute to the activation of epileptiform discharges.

Felbamate monotherapy has stimulant-like effects in patients with epilepsy.

The objective of this study was to assess the psychiatric effects of the antiepileptic drug (AED) felbamate (FBM) in patients with epilepsy. FBM is a new AED with a novel putative (antiglutaminergic) mechanism. Older AEDs such as carbamazepine and valproate have psychotropic properties, but the psychiatric effects of FBM and other new antiglutamatergic AEDs remain to be determined. Thirty inpatients with refractory epilepsy were openly tapered off all AEDs in conjunction with intensive presurgical monitoring prior to a two week randomized double-blind parallel trial of FBM monotherapy versus placebo, followed by open FBM therapy. Psychopathology was rated with weekly psychiatric rating scales. Anxiety, depression and seizures increased significantly with AED discontinuation. Acute blind FBM monotherapy yielded antiepileptic and stimulant-like effects (insomnia, anorexia, and anxiety), but failed to influence AED withdrawal-emergent psychopathology. Restarting original AEDs resolved such pathology in FBM drop outs. Chronic open FBM also had stimulant-like effects, with half of the patients displaying psychiatric deterioration and the other half modest improvement compared to baseline therapies. Baseline insomnia and anxiety may be markers for poorer psychiatric responses to chronic open FBM. FBM had stimulant-like effects, lacked anxiolytic effects, and failed to attenuate AED withdrawal-emergent psychopathology. Baseline insomnia or anxiety may predict poorer psychiatric responses to FBM. Further studies are required to assess whether the novel psychiatric effects observed with FBM also occur with other new antiglutamatergic AEDs.