Unexpected Fat Distribution in Adolescents With Narcolepsy

Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.info:eu-repo/semantics/publishedVersio

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers

Effects of Vagus Nerve Stimulation and Ketogenic Diet on Quality of Life and Changes in EEG and Sleep

When anti-epileptic drugs fail, and epilepsy surgery is found unfeasible or ineffective, there remains a group of at least 25% of children with epilepsy in whom seizure control cannot be achieved. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy. It is an implantable, multi-programmable pulse generator that delivers current electrical stimulation to the vagus nerve for the purpose of suppressing and reducing the frequency and/or severity of epileptic seizures. Ketogenic diet (KD) is a high fat, low carbohydrate and low protein diet that has been used for childhood therapy resistant epilepsy since the1920s. It was developed to mimic the ketotic state of starvation. The general aim of this thesis was to evaluate effects of VNS on epileptiform activity, deltapower and sleep characteristics and to correlate these to clinical aspects on behaviour, mood and QOL in children with therapy resistant epilepsy. Initially, and after three and nine months of VNS-treatment, 15 children were investigated. Sleep characteristics and clinical correlations were also evaluated after 3 and 12 months in 18 children with KD. A diary of seizure frequency and the National Hospital Seizure Severity Scale (NHS3) were collected. In the first study (paper I) cognitive functioning was recorded, a Visual Analogue Scale for validating QOL, Child Behaviour Checklist (CBCL) for quantifying behaviour problems, Dodrill Mood Analogue Scale and Birleson Depression Self-Rating Scale were used. Six of fifteen children showed a 50% or more reduction in seizure frequency; one of these became seizure-free. Two children had a 25-50% seizure reduction. Two children showed increased seizure frequency. In 13 of 15 children there was an improvement in NHS3. The parents reported shorter duration of seizure and recovery phase. There were no changes in cognitive functioning. Twelve children showed an improvement in QOL. Eleven of these also improved in seizure severity and mood and 5 also in depressive parameters. In the second study (paper II) 24 hours ambulatory EEG monitoring for spike detection were used. This study shows that VNS reduces interictal epileptiform discharges (IEDs), especially in rapid eye movements (REM) and slow wave sleep, and the number of electrographic seizures. It also shows a concordance between reduction in IEDs and electrographic seizures. There was no correlation between the extent of improvement in clinical data and the degree of spike reduction. In the third and forth study (paper III and IV) children with VNS and KD were examined with ambulatory polysomnographic recordings. Sleep parameters, and in VNS, movement times (MTs), used to account for arousals were estimated. Our findings indicate that VNS counteracts known adverse effects of epilepsy on sleep and increases slow wave sleep. This possibly contributes to the reported improvement in wellbeing. We also see an increase in MTs. This arousal effect seems to be of minor importance for QOL and could possibly be related to the antiepileptic mechanisms in VNS. KD decreases night sleep and improves sleep quality. The improvement in sleep quality, with increased REM sleep, seems to contribute to the improvement in QOL. In the fifth study (paper V) the 24 hours ambulatory EEG monitoring were used to study immediate effects of VNS stimulation on epileptiform activity, arousals and background frequency in EEG. The findings lend no support to earlier studies suggesting immediate VNS stimulation related changes in IEDs och IEIs. There were no VNS stimulation related changes in background EEG frequency despite the significant increase in the number of MTs immediately related to the VNS stimulation periods

Long term effects on epileptiform activity with vagus nerve stimulation in children.

Purpose: We report tong-term effects of vagus nerve stimulation (VNS) on epileptiform activity in 15 children, and how these changes are related to activity stage and to clinical effects on seizure reduction, seizure severity (NHS3) and quality of life (QOL). Methods: Initially, and after 3 and 9 months of VNS-treatment, 15 children were investigated with 24 h ambulatory EEG monitoring for spike detection. The number of interictal epiteptiform discharges (IEDs) and the inter spike intervals (ISIs) were analysed during 2 h in the awake state, and 1 h of rapid eye movement (REM)-, spindle- and delta-steep, respectively. Total number and duration of electrographic seizure episodes were also analysed. Results: At 9 months the total number of IEDs was significantly reduced (p = 0.04). There was a tendency of reduction in all activity stages, and significantly so in delta-steep (p = 0.008). Total etectrographic seizure number was significantly reduced in the 24 h EEG at 3 and 9 months (p = 0.03, 0.05). There was a significant concordance in direction of changes in epileptiform activity and etectrographic seizures at 9 months (p = 0.04). Concordance in direction of changes was seen in 9 of 15 children between clinical seizures and IED (p > 0.3), in 10 of 15 children between QOL and IED (p = 0.3) and in 8 of 15 children between NHS3 and IED (p > 0.3). There was no direct correlation between the extent of improvement in these clinical data and the degree of spike reduction. Conclusion: This study shows that VNS reduces IEDs especially in REM and delta steep, as well as the number of electrographic seizures. It also shows a concordance between reduction in IEDs and etectrographic seizures

Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy

PURPOSE: The purpose was to quantify changes of epileptiform activity during ketogenic diet (KD) treatment in children with therapy resistant epilepsy, and evaluate how these changes are related to activity stage and to clinical effects on seizure frequency, seizure severity, attentional behaviour, quality of life (QOL), and beta-hydroxybutyrate (betaOHb). METHODS: Eighteen children were investigated with 24h ambulatory EEG monitoring 1 week prior to KD initiation and, after 3 months of KD treatment. Epileptiform activity was evaluated by automated spike detection. This data was compared with data presented in a previous study published in Epilepsia 2006, on sleep structure and different activity stages, clinical data on seizure frequency, seizure severity, QOL and attentional behaviour on the same children [Hallbook, T., Lundgren, J., Rosen, I., 2007. Ketogenic diet improves sleep quality in children with therapy resistant epilepsy. Epilepsia 48, 59-65]. RESULTS: After 3 months of KD treatment the number of interictal epileptiform discharges (IEDs) was significantly reduced (p<0.001). When considering the four activity stages separately, the reduction was significant during non-rapid eye movement sleep stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep (p=0.001, 0.001, 0.002), and not significantly so during awake (p=0.07). Beta-hydroxybutyrate was significantly increased (p<0.001). There was a significant correlation between the reduction in IEDs and clinical seizures (Spearman r=0.6, p=0.005) and between improvement in attentional behaviour and the increase in betaOHb (Spearman r=0.5, p=0.03). There was no significant correlation between changes in attentional behaviour and IEDs or clinical seizures. CONCLUSION: This study shows that KD reduces the number of IEDs, especially during sleep. It shows a correlation between reduction in epileptiform activity and clinical seizures. There were no correlations between reduction in epileptiform activity and clinical seizures and improvement in QOL or attention. The increase in betaOHb correlated with improvement in attention

Vagus nerve stimulation in 15 children with therapy resistant epilepsy; its impact on cognition, quality of life, behaviour and mood.

PURPOSE: Vagus nerve stimulation (VNS) is a neurophysiologic treatment for patients with refractory epilepsy. There is growing evidence of additional quality of life (QOL) benefits of VNS. We report the effects of VNS on seizure frequency and severity and how these changes are related to cognitive abilities, QOL, behaviour and mood in 15 children with medically refractory and for surgery not eligible epilepsy. METHODS: Initially, and after 3 and 9 months of VNS-treatment, 15 children were investigated with Bayley Scales of Infant Development (BSID), Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R), Wechlser Intelligence Scales for Children (WISC-III) depending on the child's level of functioning, a Visual Analogue Scale for validating QOL, Child Behaviour Checklist (CBCL) for quantifying behaviour problems, Dodrill Mood Analogue Scale and Birleson Depression Self-Rating Scale, and the National Hospital Seizure Severity Scale (NHS3). A diary of seizure frequency was collected. RESULTS: Six of 15 children showed a 50% or more reduction in seizure frequency; one of these became seizure-free. Two children had a 25-50% seizure reduction. Two children showed increased seizure frequency. In 13 of 15 children there was an improvement in NHS3. The parents reported shorter duration of seizure and recovery phase. There were no changes in cognitive functioning. Twelve children showed an improvement in QOL. Eleven of these also improved in seizure severity and mood and five also in depressive parameters. CONCLUSION: This study has shown a good anti-seizure effect of VNS, an improvement in seizure severity and in QOL and a tendency to improvement over time regarding behaviour, mood and depressive parameters. The improvement in seizure severity, QOL, behaviour, mood and depressive parameters was not related to the anti-seizure effect

Ketogenic diet improves sleep quality in children with therapy-resistant epilepsy. Epilepsia

T. Hallböök 2 Purpose The study purpose was to evaluate sleep structure during ketogenic diet (KD) treatment in children with therapy resistant epilepsy and to correlate possible alterations with changes in clinical effects on seizure reduction, seizure severity, quality of life (QOL) and behaviour. Methods Eighteen children were examined with ambulatory polysomnographic recordings initially and after three months of KD treatment. Eleven children continued with the KD and were also evaluated after 12 months. Sleep parameters were estimated. Seizure frequency was recorded in a diary and seizure severity in the National health seizure severity scale (NHS3). QOL was assessed with a visual analogue scale. Child Behaviour Checklist and Ponsford and Kinsella&apos;s Rating-Scale of Attentional Behaviour were used. Results KD induced a significant decrease in total sleep (p=0.05) and total night sleep (p=0.006). Slow wave sleep was preserved, rapid eye movement (Bailey and Bremer) sleep increased (p=0.01), sleep stage two decreased (p=0.004) and sleep stage one was unchanged. Eleven children continued with the KD and were also evaluated after 12 months. They showed a significant decrease in daytime sleep (p=0.01) and a further increase in REM sleep (p=0.06). Seizure frequency (p=0.001, p=0.003), seizure severity (p&lt;0.001, p=0.005) and QOL (p&lt;0.001, p=0.005) were significantly improved at three and twelve months. Attentional behaviour was also improved, significantly so at three months (p=0.003). There was a significant correlation between increased REM sleep and improvement in QOL (Spearman r= 0.6, p=0.01) at three months. The basis for the improvement in both seizure control and behaviour is still unclear. There are different theories of the anti epileptic mechanisms of ketogenic diet. Increased cerebral energy reserves with decreased ictal excitability, decreased rate of glutamate transamination to aspartate and, possibly, enhancement in the rate of glutamate decarboxylation to GABA, may be some of the important mechanisms behind the increased resistance to seizures in ketotic brain tissue in response to starvation or KD (Schwartzkroin, 1999, Stafstrom and The study purpose was to evaluate sleep structure following KD in children with therapy resistant epilepsy and to correlate possible alterations with changes in clinical effects on seizure reduction, seizure severity, QOL, attention and behaviour. This study includes all children put on KD from December 1999. The first 18 children are presented in this study. Ketogenic Diet All children were admitted to the hospital and started gradually on the diet following a 12-hour out patient fast. The children were started on the classical KD. Fifteen received a 4:1 and three a 3.5:1 ratio implying 4 g or 3.5 g of fat to 1 g of combined protein and carbohydrates. Sixteen children were kept stable and two more changed from ratio 4:1 to 3.5:1 during the first three months and were then kept stable. The children also received the recommended daily intake of vitamins and minerals and were supplemented with calcium, magnesium, phosphorous, potassium and carnitine. The children were closely monitored to exclude intake of extra carbohydrates. In two children the diet was introduced via a gastrostomy tube, using Ketocal and a soy milk based ketogenic formula. were treated together as SWS. Monitoring During three months before KD initiation, a diary of seizure frequency and severity was collected together with clinical data. The severity of the seizures was scored with the National Hospital Seizure Severity Scale (NHS3), a further development of the Chalfont Seizure Severity Scale described by O&apos;Donoghue et al (O&apos;Donoghue et al., 1996). QOL was assessed with a visual analogue scale and parents&apos; perception of the children&apos;s general behaviour and attention were quantified by using the total score of the Child Behaviour Checklist (CBCL) Statistical Evaluation Wilcoxon signed rank test was used for comparison of data from the hypnogram. SWS was preserved, REM sleep increased (p=0.01) ( Median and range of the beta hydroxybutyrate levels initially and after three and 12 months in the two groups are also shown in Monitoring At three months there was a significant reduction in seizure frequency (p=0.001). Eight children (44%) showed 90% or more reduction in seizure frequency, four (22%) became seizure free, four (22%) had a 50-90% seizure reduction, five (28%) less than 50% seizure reduction and one (6%) increased in seizure frequency. Eleven children (61%) continued with the diet. They were also evaluated after 12 months. They had a significant reduction in seizure frequency (p=0.003). Four (36%) had a 90% or more reduction of seizures, two (18%) were seizure free, four (36%) had a 50-90% seizure reduction and three (27%) less than 50% seizure reduction. Seizure severity and QOL were significantly improved at three and twelve months (p&lt;0.001, p=0.005). Attentional behaviour was also improved, significantly so at three months (p=0.006, p=0.08). Changes in sleep parameters were compared with clinical seizure reduction, improvement in seizure severity, attentional behaviour and QOL. There was a T. Hallböök 10 significant correlation between increased REM sleep and improvement in QOL at three months (Spearman r= 0.6, p=0.01). No other significant correlations were seen. The three children that continued KD despite less than 50% seizure reduction described an improvement in seizure severity, a decrease in total sleep and an improvement in attentional behaviour and QOL. One of the three children that stopped the KD despite good antiepileptic effect experienced ataxia and lethargy. These side effects overweighed the antiepileptic effect. In the other two there were problems with compliance. T. Hallböök 11 Discussion In this study we saw decreased total sleep (TS) and total night sleep (TNS) and at 12 months a decreased total daytime sleep (TDS). REM sleep increased, sleep stage two decreased and SWS was preserved. We also saw an improvement in seizure frequency, seizure severity, attentional behaviour and QOL. To avoid first night laboratory effects the recordings were performed ambulatory with the children in their natural surroundings. PSG was performed on the left side. In a few children the right side was used because of artifacts from a lose lead or because of abundant epileptiform activity. All PSG recordings were interpretable with the Somnologica automatic sleep scoring hypnogram with necessary corrections manually for overestimated SWS and underestimated REM sleep. AED were kept stable throughout the study. The good antiepileptic effect and a slight fall off in efficacy during the study could justify this. On the other hand, despite a good antiepileptic effect or even seizure freedom we did not reduce or taper the AED until 12 months. This is in accordance with the recommendations after epilepsy surgery, where AED are kept stable for at least one year. The changes in sleep parameters cannot solely be explained by age dependent changes. Total sleep time does not change with age from early childhood to adolescence. It is related to environmental factors rather than biologic changes. At birth the amount of REM and non REM sleep is about equal. The amount of REM sleep gradually decreases to 20-25% before the age of five. There are no significant changes in REM sleep with age from 5 years of age or older. SWS decreases during childhood and this continues steadily until old age. The amount of sleep stage two increases with age from early childhood Sleep is also known to have both precipitating and protecting effects on seizures. Generalized tonic-clonic or myoclonic convulsions occur mainly during non REM sleep and ¨drowsy wakefulness