Amerins Weijenberg

RCTs with new antiepileptic drugs in children : A systematic review of monotherapy studies and their methodology

Few randomised controlled trials (RCTs) have been performed in which a second-generation antiepileptic drug (AED) used as monotherapy was compared with placebo or another AED in children (<18 years of age) with epilepsy. We describe the results of the available studies, assess the validity of these results, and give recommendations for optimal study design for AED monotherapy studies in children with epilepsy. Studies were identified using PubMed (Medline), Embase and the Cochrane Library (January 1990-January 2010). All reports were assessed for methodological quality and results were summarised descriptively. Nine RCTs were included. No difference in efficacy and safety between second-generation AEDs and first-generation AEDs in children was detected. Considerable heterogeneity in study design, inclusion criteria and primary endpoints impaired formal meta-analysis and correct interpretation of results. Follow-up periods were between 2 and 104 weeks; the dosage of the tested AEDs varied between studies, with sometimes use of apparent subtherapeutic dosages; in only two studies the method of randomisation was well described, in only three the power calculations; several studies did not use an intention-to-treat analysis. Although from the available studies first- and second-generation AEDs appear to have similar efficacy and safety in children with epilepsy, these trials are inadequate to provide a sufficient evidence base for decision making. Better trials are needed: AEDs should be studied in optimal paediatric doses, power should be sufficient to detect small but clinically relevant differences, and the follow-up period should be long enough. Most important, primary endpoint to be evaluated should be time to treatment failure or retention rate, since these outcomes combine efficacy and safety.

The efficacy of the modified Atkins diet in North Sea Progressive Myoclonus Epilepsy : an observational prospective open-label study

BackgroundNorth Sea Progressive Myoclonus Epilepsy is a rare and severe disorder caused by mutations in the GOSR2 gene. It is clinically characterized by progressive myoclonus, seizures, early-onset ataxia and areflexia. As in other progressive myoclonus epilepsies, the efficacy of antiepileptic drugs is disappointingly limited in North Sea Progressive Myoclonus Epilepsy. The ketogenic diet and the less restrictive modified Atkins diet have been proven to be effective in other drug-resistant epilepsy syndromes, including those with myoclonic seizures. Our aim was to evaluate the efficacy of the modified Atkins diet in patients with North Sea Progressive Myoclonus Epilepsy.ResultsFour North Sea Progressive Myoclonus Epilepsy patients (aged 7–20 years) participated in an observational, prospective, open-label study on the efficacy of the modified Atkins diet. Several clinical parameters were assessed at baseline and again after participants had been on the diet for 3 months. The primary outcome measure was health-related quality of life, with seizure frequency and blinded rated myoclonus severity as secondary outcome measures.Ketosis was achieved within 2 weeks and all patients completed the 3 months on the modified Atkins diet. The diet was well tolerated by all four patients. Health-related quality of life improved considerably in one patient and showed sustained improvement during long-term follow-up, despite the progressive nature of the disorder. Health-related quality of life remained broadly unchanged in the other three patients and they did not continue the diet. Seizure frequency remained stable and blinded rating of their myoclonus showed improvement, albeit modest, in all patients.ConclusionsThis observational, prospective study shows that some North Sea Progressive Myoclonus Epilepsy patients may benefit from the modified Atkins diet with sustained health-related quality of life improvement. Not all our patients continued on the diet, but nonetheless we show that the modified Atkins diet might be considered as a possible treatment in this devastating disorder.

Changing pattern of anti-epileptic drug prescription in children in the Netherlands

1875 (author A. Guekht) Tables 1, 2 Conclusion: Actovegin improved cognitive outcomes in patients with PSCI, compared with placebo. Disclosure: This study was organized and funded by Takeda Pharmaceuticals. O1205 Circulating endothelial markers in the monogenic small vessel disease retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations N. Pelzer1, R. Bijkerk2, M. Reinders2, A.J. van Zonneveld2, M. Ferrari1, A. van Den Maagdenberg3, J. Eikenboom4, G. Terwindt1 1Neurology, Leiden University Medical Center, Leiden, Netherlands, 2Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands, 3Human Genetics & Neurology, Leiden University Medical Center, Leiden, Netherlands, 4Internal Medicine, Section Thrombosis and Haemostasis and Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands Background and aims: Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is an underdiagnosed monogenic small vessel disease caused by TREX1 mutations. The pathophysiology of RVCL-S is largely unknown, but a systemic endothelial involvement is suggested that leads to pathology in the brain, but also systemically, including retina, liver and kidneys. We investigated circulating levels of endothelial markers to seek confirmation of endothelial involvement in RVCL-S and to identify biomarkers to assess disease activity. Methods: We measured in a cross-sectional study circulating levels of VWF antigen (VWF:Ag), VWF propeptide (VWFpp) and Ang-2 in members of three Dutch RVCL-S families (31 with and 33 without a TREX1 mutation) and 31 age and sex-matched unrelated healthy controls. Results: We found elevated levels of VWF:Ag, VWFpp and Ang-2 in TREX1 mutation carriers compared to family members without a TREX1 mutation and unrelated healthy controls (p<0.001 for all three markers and both control groups). Effects were most pronounced in mutation carriers aged ≥40 years (p<0.001 for all three markers and both control groups). All three markers showed strong correlations with RVCL-S symptoms (Spearman’s rho>0.6). However, levels of VWF:Ag and Ang-2 were already elevated in mutation carriers aged <40 years compared to healthy controls (p=0.02 and p=0.04, respectively). Conclusion: VWF:Ag and Ang-2 may serve as (early) biomarkers of disease activity in RVCL-S. Our findings improve mechanistic insight in the pathophysiology of the monogenic cerebral small vessel disease RVCL-S but also may help to understand common neurovascular disorders, including stroke. Disclosure: This work was supported by grants of the Netherlands Organization for Scientific Research (NWO) [VIDI no. 91711319 to GMT], the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NWO) [CMSB no. 050-060-409 to AvdM], and the European Community (EC) [FP7-EUROHEADPAIN no. 602633 to AvdM & MDF & GMT and FP7-NIMBL no. 241779 to AvdM].

Investigator‐initiated randomized controlled trials in children with epilepsy: Mission impossible?

In children many antiepileptic drugs (AEDs) are prescribed off‐label due to a lack of well‐designed randomized controlled trials (RCTs). We conducted a multicenter RCT in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator‐initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing RCTs in children, and now give recommendations for future studies.

Antiepileptic drug prescription in Dutch children from 2006–2014 using pharmacy-dispensing data

OBJECTIVE In the last two decades several new antiepileptic drugs (AEDs) have become available. The aim of our study was to analyse whether and how AED prescribing patterns in Dutch children have changed during the last decade and whether these changes were supported by guidelines and results from recently available trials. METHODS From a large community pharmacy-dispensing database in the Netherlands, we identified children aged 0-19 years who received at least one prescription for an AED between 2006 and 2014. Children who also received prescriptions for migraine or psychiatric disorders were excluded. We calculated year-prevalences and -incidences of AED use with emphasis on old versus new AEDs, and individual AEDs. We evaluated these results, including the course of AED prescribing. RESULTS During the study period, the prescribing prevalence of old AEDs decreased from 1.61 per 1000 (95% C.I. 1.40-1.82) to 1.39 per 1000 (95% C.I. 1.18-1.60); for new AEDs it increased from 0.58 per 1000 (95% C.I. 0.45-0.71) to 1.35 per 1000 (95% C.I. 1.14-1.56). Valproic acid was the most frequently initiated AED in 2006. From 2010, prescribing of old and new AEDs became equal with levetiracetam as the most often initiated AED since 2012. This drug was recommended for all seizure types in the 2013 Dutch national epilepsy guideline. Only 5.5% of the children used AED combination therapy. Of those on monotherapy, 85.7% remained on the first prescribed AED. CONCLUSIONS In the last 10 years, prescribing of new AEDs increased at the expense of old AEDs. Levetiracetam has replaced valproic acid as the most frequently prescribed first line antiepileptic drug in children since 2012, which is in line with national guidelines.

Ketogenic Diet in Refractory Childhood Epilepsy: Starting With a Liquid Formulation in an Outpatient Setting

Background: Ketogenic diet in children with epilepsy has a considerable impact on daily life and is usually adopted for at least 3 months. Our aim was to evaluate whether the introduction of an all-liquid ketogenic diet in an outpatient setting is feasible, and if an earlier assessment of its efficacy can be achieved. Methods: The authors conducted a prospective, observational study in a consecutive group of children with refractory epilepsy aged 2 to 14 years indicated for ketogenic diet. Ketogenic diet was started as an all-liquid formulation of the classical ketogenic diet, KetoCal 4:1 LQ, taken orally or by tube. After 6 weeks, the liquid diet was converted into solid meals. The primary outcome parameter was time-to-response (>50% seizure reduction). Secondary outcome parameters were time to achieve stable ketosis, the number of children showing a positive response, and the retention rate at 26 weeks. Results: Sixteen children were included. Four of them responded well with respect to seizure frequency, the median time-to-response was 14 days (range 7-28 days). The mean time to achieve stable ketosis was 7 days. The retention rate at 26 weeks was 50%. Of the 8 children who started this protocol orally fed, 6 completed it without requiring a nasogastric tube. Conclusions: Introduction of ketogenic diet with a liquid formulation can be accomplished in orally fed children without major complications. It allowed for fast and stable ketosis.

Teaching NeuroImages: FDG-PET imaging in primary diffuse leptomeningeal gliomatosis

A 50-year-old man presented with progressive tetraparesis and loss of vision. Inflammation and malignancy were considered based on diffuse meningeal enhancement on MRI (figure 1) and CSF content (very high protein, mild pleocytosis, and low to normal glucose). CSF cultures and cytologic examinations, including flow cytometry, were normal. FDG-PET showed increased uptake in the spinal cord and brain (figure 2), matching primary diffuse leptomeningeal gliomatosis (PDLG), leptomeningeal carcinomatosis/lymphoma, or isolated CNS infection.1 A temporal leptomeningeal-cortical biopsy confirmed PDLG.