Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination

Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients' CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research.Peer reviewe

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'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<0.001, p=0.005) and QOL (p<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'Donoghue et al (O'Donoghue et al., 1996). QOL was assessed with a visual analogue scale and parents' perception of the children'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<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

Cortical excitability measured with transcranial magnetic stimulation in children with epilepsy before and after antiepileptic drugs

Aim To evaluate cortical excitability with transcranial magnetic stimulation (TMS) in children with new-onset epilepsy before and after antiepileptic drugs (AEDs). Method Fifty-five drug-naive patients (29 females, 26 males; 3-18y), with new-onset epilepsy were recruited from 1st May 2014 to 31st October 2017 at the Child Neurology Department, Queen Silvias Childrens Hospital, Gothenburg, Sweden. We performed TMS in 48 children (23 females, 25 males; mean [SD] age 10y [3y], range 4-15y) with epilepsy (27 generalized and 21 focal) before and after the introduction of AEDs. We used single- and paired-pulse TMS. We used single-pulse TMS to record resting motor thresholds (RMTs), stimulus-response curves, and cortical silent periods (CSPs). We used paired-pulse TMS to record intracortical inhibition and facilitation at short, long, and intermediate intervals. Results There were no differences in cortical excitability between children with generalized and focal epilepsy at baseline. After AED treatment, RMTs increased (p=0.001), especially in children receiving sodium valproate (p=0.005). CSPs decreased after sodium valproate was administered (p=0.050). As in previous studies, we noted a negative correlation between RMT and age in our study cohort. Paired-pulse TMS could not be performed in most children because high RMTs made suprathreshold stimulation impossible. Interpretation Cortical excitability as measured with RMT decreased after the introduction of AEDs. This was seen in children with both generalized and focal epilepsy who were treated with sodium valproate, although it was most prominent in children with generalized epilepsy. We suggest that TMS might be used as a prognostic tool to predict AED efficacy.Funding Agencies|Drottning Silvias Jubileums Foundations</p

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.Funding Agencies|Research Council of South East Sweden [FORSS-480551]; Knut and Alice Wallenberg foundation [KAW 2013.0076]</p

Corrigendum: Altered Brain Microstate Dynamics in Adolescents With Narcolepsy (vol 10, 369, 2016)

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