Associating executive dysfunction with behavioral and socioemotional problems in children with epilepsy. A systematic review.

As children with epilepsy may have a number of learning and behavioral problems, it is important that insight into the underlying neurocognitive differences in these children, which may underlie these areas of challenge is gained. Executive function (EF) problems particularly are associated with specific learning abilities as well as behavioral problems. We aim to review systematically the current status of empirical studies on the association between EF problems and behavior and socioemotional problems in children with epilepsy. After search, 26 empirical studies were identified, most of them of moderate quality. Overall, attention problems were the most reported cognitive deficit in test assessment and the most reported problem by parents. In 54% of the studies, children with epilepsy scored below average compared to controls/normative samples on different aspects of EF. Most studies reported behavior problems, which ranged from mild to severe. Forty-two percent of the studies specifically reported relationships between EF deficits and behavioral problems. In the remaining studies, below average neuropsychological functioning seemed to be accompanied by above average reported behavioral problems. The association was most pronounced for cognitive control and attention in relation to externalizing behavior problems. This cognitive control is also associated with social functioning. Relevant epilepsy variables in this relationship were early age at onset and high seizure frequency.Future research should distinguish specific aspects of EF and take age into account, as this provides more insight on the association between EF and behavior in pediatric epilepsy, which makes it possible to develop appropriate and early intervention.

Prevalence of sleep disturbances in people with epilepsy and the impact on quality of life: a survey in secondary care.

PURPOSE: Studies in adults with epilepsy, mainly in specialized epilepsy clinics, have shown that sleep disturbances were twice as prevalent in people with epilepsy as in healthy controls. Our aim was to determine the prevalence of sleep disturbances in people with epilepsy treated in district hospitals, as well as the impact of it on Quality of Life. METHOD: Adults with epilepsy, attending outpatient clinics in three district hospitals were invited to participate. Those who accepted (N = 122) provided their own controls matched for age and sex. Both groups completed four questionnaires (Groningen Sleep Quality Scale (GSQ), Medical Outcomes Study-Sleep scale (MOSS), Sleep Diagnosis List (SDL) and Epworth Sleepiness Scale) to measure their sleep over different periods and the 36-Item Short Form Health Survey (SF-36) to measure Quality of Life (QoL). The prevalence of sleep disturbances and scores on QoL were compared between both groups. RESULTS: Sleep quality, measured by the SDL, was in the pathological range 50% more often in the epilepsy group than in controls. This was confirmed by the MOSSINDEX and GSQ. People with epilepsy experienced excessive daytime sleepiness more often than controls. The lowest scores on nearly all domains of the SF-36 were seen in people with epilepsy and associated sleep disturbances. CONCLUSION: We confirmed the higher prevalence of sleep disturbances in people with epilepsy compared to controls as previously reported from specialized settings. The (co-morbid) sleep disturbances result in lower QoL scores, in both people with epilepsy and in controls, but more in people with epilepsy.

Sleep-Related Breathing Disorders in Young Adults With Prader-Willi Syndrome: A Placebo-Controlled, Crossover GH Trial.

CONTEXT: Sleep-related breathing disorders (SRBD) are common in people with Prader-Willi syndrome (PWS). Young adults with PWS benefit from GH continuation after attaining adult height by maintaining the improved body composition obtained during childhood. There are, no studies about the effects of GH on SRBD in young adults with PWS who were treated with GH during childhood. OBJECTIVE: Investigate the effects of GH vs placebo on SRBD in young adults with PWS who were treated with GH during childhood and had attained adult height. DESIGN: Two-year, randomized, double-blind, placebo-controlled, crossover study in 27 young adults with PWS, stratified for sex and body mass index. SETTING: Dutch PWS Reference Center. INTERVENTION: Crossover intervention with GH (0.67 mg/m2/d) and placebo, both over one year. MAIN OUTCOME MEASURES: Apnea hypopnea index (AHI), obstructive apnea index (OAI), central apnea index (CAI), measured by polysomnography. RESULTS: Compared with placebo, GH did not increase AHI, CAI, or OAI (P > 0.35). The effect of GH vs placebo was neither different between men and women, nor between patients with a deletion or maternal uniparental disomy/imprinting center defect. After two years, there was no difference in AHI, CAI, or OAI compared with baseline (P > 0.18). Two patients (7%) fulfilled the criteria of obstructive sleep apnea regardless of GH or placebo. CONCLUSIONS: GH compared with placebo does not cause a substantial increase in AHI, CAI, or OAI in adults with PWS who were treated with GH during childhood and have attained adult height. Our findings are reassuring and prove that GH can be administered safely.

Safety and efficiency of medication withdrawal at home prior to long-term EEG video-monitoring.

PURPOSE: Long-term video-EEG monitoring (LTM) is frequently used for diagnostic purposes and in the workup of epilepsy surgery to determine the seizure onset zone. Different strategies are applied to provoke seizures during LTM, of which withdrawal of anti-epileptic drugs (AED) is most effective. Remarkably, there is no standardized manner of AED withdrawal. For instance, the majority of clinics taper medication during clinical admission, whereas we prefer to taper medication at home prior to admission. Our aim was to study the advantages (efficiency and diagnostic yield) and disadvantages (safety and complication rates) of predominantly tapering of medication at home. METHOD: We report a retrospective observational cohort of 273 patients who had a LTM at our tertiary epilepsy center from 2005 until 2011. Provocation methods to induce seizures were determined on individual basis. Success rate (duration of admittance, time to first seizure, efficiency and diagnostic yield) and complications and serious adverse events were assessed. RESULTS: AED were tapered in 180 (66%) patients, in 93 (24%) of these patients with additional (partial) sleep deprivation. In all of these patients tapering started at home one to four weeks prior to admission. In the other patients, only (partial) sleep deprivation or none provocation method at all was applied. Seizure recordings were successful in 79,9% of patients. Complications occurred in 19 patients (10.9%) of which 3 had (1.7%) serious adverse events (status epilepticus (SE)) with AED withdrawal. These complications only occurred during admittance, not at home. CONCLUSIONS: AED withdrawal at home prior to LTM is an efficient and convenient method to increase the diagnostic yield of LTM and appears relatively safe.

Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation.

This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. Even though both siblings showed a typical CDKL5 phenotype, their presentation is different. From birth, the oldest daughter had a severe developmental delay, feeding problems, and hypotonia and experienced daily refractory seizures. The youngest daughter appeared to be normal until age 3 months. At that age seizures started, deterioration and regression became evident, and an epileptic encephalopathy developed. This report of familial recurrence, with suspected germline mosaicism in a healthy parent, has important consequences for genetic counseling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased.

Effectiveness of cognitive behavioral therapy for insomnia: influence of slight-to-moderate depressive symptom severity and worrying.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) is a well-known, effective treatment for primary insomnia. However, the majority of sleeping problems occur in the presence of another medical or psychiatric disorder. Depression and general anxiety disorder (with a main feature of excessive generalized worrying) are disorders that frequently co-occur with insomnia. The purpose of this study is to evaluate whether depressive symptom severity or worrying influences the subjective effectiveness of CBT-I. METHODS: Patients with a complaint of insomnia received CBT-I. At the beginning of the therapy, patients completed a sleep evaluation list, the Beck Depression Inventory (BDI-II-NL, N = 92), and the Penn State Worry Questionnaire (PSWQ, N = 119). Based on the BDI and the PSWQ, the sample was divided into different groups: patients with low versus high depression scores, low worriers versus high worriers, and patients without depressive symptoms who were also classified as low worriers and patients with depressive symptoms who were also classified as high worriers. The sleep evaluation list was completed directly after the treatment and 6 months later. RESULTS: Sleep evaluation scores, subjective total sleep time, subjective sleep onset latency, and subjective wake after sleep onset all changed in a positive way after CBT-I and remained that way over the next 6 months for all patients. These positive effects of CBT-I did not differ between the subgroups. CONCLUSIONS: Results suggest that CBT-I improves subjective sleep experiences, regardless of depressive symptom severity or worrying.

[Nocturnal choking sensation]. / Stikgevoelens in de nacht.

There are many different types of sleep disorders. The majority of sleep-related breathing disorders can be attributed to sleep apnoea syndrome. Nocturnal choking sensation is a different symptom, for which we present two cases. Nocturnal choking sensation is a terrifying symptom for the patient and the diagnostic approach can be challenging. Aside from sleep choking syndrome, this symptom may appear with nocturnal laryngospasm, insular epilepsy and nocturnal gastro-oesophageal reflux. A thorough patient history and observation of the nocturnal event, sometimes supported by EEG findings, may provide the clue to the diagnosis. These kinds of nocturnal symptoms are best analyzed in a clinic specialized in both epilepsy and sleep disorders.

Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene.

AIM: In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations. METHOD: In four genetically confirmed female patients with CDKL5 mutations (age range 2-15 y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). RESULTS: The Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4/h. When awake, central apnoeas were present in two of the four female children (central AHI 28/h and 41/h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%). INTERPRETATION: Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas/seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances.

Effects of daytime secondarily generalized epileptic seizures on sleep during the following night.

Nocturnal seizures may disturb sleep, but the effect of an epileptic seizure during daytime on sleep during the next night has been under investigated. In this proof-of-principle study, the sleep of 425 patients with epilepsy, who underwent long-term video-electroencephalography recordings, was analyzed. The sleep recordings were retrospectively divided into two groups: Seizure Free, no seizure occurred at least 24 h before the start of the night sleep recording, and Daytime Seizure, at least one (secondarily) generalized seizure occurred during the day before. In Daytime Seizure, longer time in bed and latency to first REM and more NREM II were seen as well as a decrease of deep sleep and REM sleep compared to Seizure Free. As many participants underwent long-term recordings over a period longer than 48 h, we had the opportunity to compare in individual patients the sleep architecture during nights with and without seizures on the day before the recording. Time in bed and WASO were longer, and sleep efficiency was less in the nights after a seizure on the day before the recording. These differences were statistically significant, but their clinical relevance is doubtful.

Morningness and eveningness: when do patients take their antiepileptic drugs?

Almost one-third of epilepsy patients continue to have seizures despite adequate drug treatment. Chronotherapy (based on dynamic changes in drug pharmacology and disease-related processes) could be a promising treatment option. We aimed to explore whether different circadian types adjust administration times of anti-epileptic drugs (AEDs) as a step in exploring chronotherapeutic possibilities. We performed a questionnaire-based study to compare behavior of different circadian types in relation to times of taking drugs. Circadian type was determined by the Morningness-Eveningness Questionnaire. Results clearly show that morning types are taking their AEDs significantly earlier than do evening types on free days. Times of taking AEDs in the morning on work days also differ significantly between morning and evening types. Regardless of circadian type, drugs on free days are taken later than on working days. In conclusion, our study shows that patients adapt times of taking medication to their circadian type.

Timing of temporal and frontal seizures in relation to the circadian phase: a prospective pilot study.

There is strong evidence that epileptic seizures occur in diurnal or 24-h patterns. A study in rat models of partial epilepsy showed circadian seizure patterns, and in humans circadian rhythmicity in interictal discharges has been found, suggesting that circadian rhythm may play a role in epilepsy. Circadian influences on human seizure patterns have not been investigated. We performed a pilot study to ascertain influences of the circadian rhythm on seizure occurrence. We prospectively outlined circadian rhythms of patients admitted for long term EEG and video monitoring, using measurement of the dim light melatonin onset (DLMO). Seizures during admission were recorded with continuous EEG and video monitoring. The DLMO ranged from 18:46h to 23:13h (mean 21:22h). One hundred and twenty-four seizures of 21 patients were analysed. Seizures of temporal lobe origin occurred mainly between 11:00 and 17:00h and frontal seizures were seen mostly between 23:00 and 05:00h. When correlating seizure timing to the individual's circadian phase as measured by the DLMO, the following was seen: temporal seizures occurred most frequently in the 6h before DLMO and frontal seizures mainly in 6-12h after the DLMO. The results of this pilot study suggest that temporal and frontal seizures occur in a non-random fashion synchronized to a hormonal marker of the circadian timing system.

[Staring episodes in children with developmental disorders: epilepsy or behaviour?]. / Kinderen met ontwikkelingsproblemen die staren: epilepsie of gedrag?

Behavioural episodes of staring in children are difficult to distinguish from epileptic seizures, especially in children with developmental disorders such as ADHD, autism spectrum disorders and intellectual disabilities. We discuss two patients with staring episodes who were using anti-epileptic drugs. In both patients, EEG with video monitoring showed that the staring was non-epileptic. The first is an 8-year-old boy, who developed severe motor problems and ataxia during treatment with valproate. His staring episodes were behavioural, caused by his intellectual disability, and the motor problems resolved after discontinuation of valproate. The second patient is a 10-year-old boy with known autism, ADHD and infantile seizures, who developed staring for which he was using valproate. Again, video-EEG monitoring during staring showed no abnormalities and in this case the staring was caused by his intellectual disability and autism. We discuss the differential diagnosis of staring episodes in children with developmental disorders and present the pitfalls of the diagnostic process.

Sleep disturbances in people with epilepsy; prevalence, impact and treatment.

The interaction between epilepsy and sleep is thoroughly studied and is very complex. This review focuses on prevalence, impact on quality of life and effects of treatment of sleep disorders on the course of epilepsy. Self-reported sleep disturbances in people with epilepsy are about twice as prevalent as in healthy controls. People with epilepsy with sleep disturbances have a significant impairment of quality of life compared to those with no sleep disturbances. In children with epilepsy, sleep problems may lead to detrimental effects on daytime behavior and cognition. Most is known about obstructive sleep apnea syndrome (OSAS). Co-morbidity of epilepsy and OSAS is shown to be far higher than expected by chance. Treatment of OSAS significantly improves seizure control in people with epilepsy. More studies on the prevalence of other sleep disorders in people with epilepsy and the effect of treatment are required. Reports on the effect of treatment for other sleep disorders are scarce and not unequivocal.

Chronotypes and subjective sleep parameters in epilepsy patients: a large questionnaire study.

Accumulating evidence suggests epilepsy and seizures may influence circadian rhythms and that circadian rhythms may influence epilepsy. It is also conceivable that seizure timing influences the timing of daily activities, sleeping, and wakefulness (i.e., chronotype). Only one group has studied the distribution of chronotypes of epileptics, showing significant differences between the diurnal activity patterns in two groups of patients with different epilepsy syndromes. The authors performed a questionnaire-based study of 200 epilepsy patients to compare the distribution of chronotypes and subjective sleep parameters of sleep duration and time of mid-sleep on free days to the distribution in the general population (n = 4042). Within this large group of epilepsy patients, we also compared the chronotypes of subsamples with well-defined epilepsy syndromes, i.e., temporal lobe epilepsy [TLE; n = 46], frontal lobe epilepsy [FLE; n = 30], and juvenile myoclonic epilepsy [JME; n = 38]. In addition, 27 patients who had had surgery for TLE were compared with those with TLE who had not had surgery. Both the Morningness-Eveningness Questionnaire and Munich Chronotype Questionnaire were used to determine chronotypes and subjective sleep parameters. Significant differences in morningness/eveningness distribution, timing of mid-sleep (corrected for sleep duration), and total sleep time on free days were found between epileptics and healthy controls. Those with epilepsy were more morning oriented, had earlier mid-sleep on free days, and longer sleep duration on free days (p < .001). However, distributions of chronotypes and sleep parameters between the groups of people with TLE, FLE, and JME did not differ. Persons who had surgery for TLE had similar morningness-eveningness parameters and similar sleep durations compared to those without surgery, but mid-sleep on free days was earlier in operated patients (p = .039). In conclusion, this is the first large study focusing on chronotypes in people with epilepsy. We show that the distribution of chronotypes and subjective sleep parameters of epileptics, in general, is different from that of healthy controls. Nevertheless, no differences are observed between patients with specified epilepsy syndromes, although they exhibit seizures with different diurnal patterns. Our results suggest that epilepsy, itself, rather than seizure timing, has a significant influence on chronotype behavior and subjective sleep parameters.

[Recognition of temporal lobe epilepsy in adults]. / Herkennen van temporaalkwabepilepsie bij volwassenen.

Temporal lobe epilepsy has a subtle and diverse symptomatology, and therefore temporal lobe seizures can initially be misdiagnosed. Here we discuss 3 patients with this type of epilepsy, but with completely different presentations. The first, a 67-year-old woman suffered from episodes of confusion, and later she developed tonic-clonic seizures. The second patient, a 58-year-old man, had auras followed by impaired consciousness and oral automatisms and also developed a type of seizure resembling panic attacks. The third patient, a 65-year-old man, presented with isolated auras. A few years later he developed tonic-clonic seizures, and the diagnosis 'temporal lobe epilepsy' was made. This article discusses differences in presentation between limbic and neocortical temporal lobe epilepsy, as well as the results of EEG and MRI investigations.

Diurnal rhythms in seizures detected by intracranial electrocorticographic monitoring: an observational study.

Few studies have evaluated human seizure occurrence over the 24-hour day, and only one group has employed intracranial electrocorticography monitoring to record seizures. Circadian patterns in seizures may have important implications in diagnosis and therapy and provide opportunities in research. We have analyzed spontaneous seizures in 33 consecutive patients with long-term intracranial EEG and video monitoring. Several aspects of seizures were noted, including time of day, origin, type, and behavioral state (sleeping/awake). We recorded 450 seizures that showed an uneven distribution over the day, depending on lobe of origin: temporal lobe seizures occurred preferentially between 1100 and 1700 hours, frontal seizures between 2300 and 0500 hours, and parietal seizures between 1700 and 2300 hours. In the awake state, larger proportions of clinical seizures were seen from 0500 to 1100 hours and from 1700 to 2300 hours. During sleep, larger proportions occurred from 1100 to 1700 hours and from 2300 to 0500 hours. Our results suggest that seizures from different brain regions have a strong tendency to occur in different diurnal patterns.

The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi syndrome.

BACKGROUND: The annual death rate of patients with Prader-Willi syndrome (PWS) is high (3%). Many deaths of children are sudden and unexplained. Sleep apneas have been suggested to play a role in sudden deaths. Recently, we discovered that 60% of patients with PWS suffer from central adrenal insufficiency (CAI) during stress. OBJECTIVE: The aim was to study the relationship between CAI and sleep-related breathing disorders. DESIGN: In 20 children with PWS who underwent a metyrapone test (30 mg/kg at 2330 h), sleep-related breathing was evaluated by polysomnography before the metyrapone test. In addition, we recorded sleep-related breathing in 10 children with PWS during their metyrapone test. CAI was diagnosed when ACTH levels during the metyrapone test were below 33 pmol/liter at 0730 h. All tests were performed during healthy condition. SETTING: The study was conducted in a pediatric intensive care unit and specialized sleep center. RESULTS: Median (interquartile range) age was 8.4 yr (6.5-10.2). After metyrapone administration, median (interquartile range) central apnea index (number/hour) increased significantly from 2.2 (0.4-4.7) to 5.2 (1.5-7.9) (P = 0.007). The increase tended to be higher in children with CAI [2.8 (2.0-3.9) vs. 1.0 (-0.2 to 2.6); P = 0.09]. During polysomnography before the metyrapone test, sleep-related breathing was worse in children with CAI, who had a significantly higher central apnea index and tended to have a lower minimum oxygen saturation compared to those without CAI (P = 0.03 and P = 0.07). CONCLUSIONS: In children with PWS, the central apnea index increased significantly after metyrapone administration, particularly in those with CAI during stress. In addition, children with CAI had a higher central apnea index compared to those without several months before the metyrapone test.

Temporal distribution of clinical seizures over the 24-h day: a retrospective observational study in a tertiary epilepsy clinic.

PURPOSE: Very few studies have evaluated seizure occurrence in humans over the 24-h day; data from children are particularly scarce. Circadian patterns in seizure occurrence may be of importance in epilepsy research and may have important implications in diagnosis and therapy. METHODS: We have analyzed clinical seizures of 176 consecutive patients (76 children, 100 adults) who had continuous electroencephalography (EEG) and video monitoring lasting more than 22 h. Several aspects of seizures were noted, including classification, time of day, origin, and sleep stage. RESULTS: More than 800 seizures were recorded. Significantly more seizures were observed from 11:00 to 17:00 h, and from 23:00 to 05:00 h significantly fewer seizures were seen. The daytime peak incidences were observed in seizures overall, complex partial seizures (in children and adults), seizures of extratemporal origin (in children), and seizures of temporal origin (in adults). Incidences significantly lower than expected were seen in the period 23:00 to 05:00 h in seizures overall, complex partial seizures (in children and adults), and in tonic seizures (in children). In addition, significantly fewer seizures of temporal (in children and adults) and extratemporal origin (in children) were observed in this period. DISCUSSION: The results suggest that certain types of seizures have a strong tendency to occur in true diurnal patterns. These patterns are characterized by a peak during midday and a low in the early night.

Cognition and behavior in pre-pubertal children with Prader-Willi syndrome and associations with sleep-related breathing disorders.

Prader-Willi syndrome (PWS) is characterized by hypotonia, hypogonadism, obesity, and short stature. Neurobehavioral abnormalities, cognitive impairment, and sleep-related breathing disorders (SRBD) are common. In the general population associations between neurobehavioral and cognitive abnormalities and SRBD have been found. We investigated cognition, behavior, and SRBD in children with PWS. Thirty-one pre-pubertal PWS children were evaluated (5 with paternal deletion, 14 with maternal disomy, 4 with imprinting-center mutation, and in 8 the defect was not specified). Cognition was assessed by Wechsler scale subtests, and behavior by parent-questionnaires. Polysomnography was performed. Cognition, behavior, and associations with SRBD were evaluated. All cognitive subtests were significantly below O SDS, with the lowest median (interquartile range) scores for the Block design subtest (-2.7 SDS (-3.0 to -0.3)). In 60%, verbal subtests were less affected than performance subtests. Parents reported problem behavior related to "emotions/behavior not adapted to the social situation" and "insensitivity to social information." All children had SRBD, with an Apnea Hypopnea Index of 4.1/hr (2.6-7.9). One performance subtest score was significantly higher in children with better sleep efficiency, and daytime sleepiness was associated with more autistic-like social impairment. In contrast to our expectations, behavior was worse in children with better sleep-related breathing. In pre-pubertal PWS children, cognition is impaired. Neurobehavioral abnormalities are common, particularly autistic-like social impairment. Sleep efficiency was associated with better performance on one of the performance subtests, and neurobehavioral abnormalities were associated with daytime sleepiness. In contrast, we could not confirm a positive association of neurobehavioral abnormalities with SRBD in PWS.