Marie-Claire Y. de Wit

Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

BACKGROUND Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months. METHODS In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8-16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20-40 mg per day in months 3-12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150. FINDINGS We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo -1·3 IQ points [95% CI -3·8 to 1·3]; p=0·33), attention problems (-1·6 T-score points [-4·3 to 1·0]; p=0·23), and internalising behavioural problems (-0·1 T-score points [-3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively. INTERPRETATION 12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20-40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended. FUNDING The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).

Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations.

BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in TSC1 and TSC2. Conventional DNA diagnostic screens identify a TSC1 or TSC2 mutation in 75 - 90% of individuals categorised with definite TSC. The remaining individuals either have a mutation that is undetectable using conventional methods, or possibly a mutation in another as yet unidentified gene.MethodsHere we apply a targeted Next Generation Sequencing (NGS) approach to screen the complete TSC1 and TSC2 genomic loci in 7 individuals fulfilling the clinical diagnostic criteria for definite TSC in whom no TSC1 or TSC2 mutations were identified using conventional screening methods.ResultsWe identified and confirmed pathogenic mutations in 3 individuals. In the remaining individuals we identified variants of uncertain clinical significance. The identified variants included mosaic changes, changes located deep in intronic sequences and changes affecting promoter regions that would not have been identified using exon-only based analyses.ConclusionsTargeted NGS of the TSC1 and TSC2 loci is a suitable method to increase the yield of mutations identified in the TSC patient population.

Sirolimus for epilepsy in children with tuberous sclerosis complex A randomized controlled trial

Objective: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). Methods: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8–10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5–10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. Results: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] −69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI −86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. Conclusions: We describe a randomized controlled trial for a non–antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. Classification of evidence: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.

Incidental Findings on Brain Imaging in the General Pediatric Population

Brain MRI in 3966 children from the population-based Generation R Study (mean age, 10.1 years) revealed incidental findings in 25.6%. Most findings did not require neurosurgical intervention, but 7 children (0.18%) had suspected primary brain tumors.

Tuberous sclerosis complex: Concerns and needs of patients and parents from the transitional period to adulthood

INTRODUCTION Transitioning into adulthood and from pediatric services to adult healthcare are both challenging processes for young adults with rare chronic disorders such as tuberous sclerosis complex (TSC) and their parents. Adult healthcare systems are often less family-oriented and lack multidisciplinary care and experience with TSC, which can result in increased health risks and morbidity. Patient-driven data on care needs are necessary to optimize support for this vulnerable patient group. AIM The aim of this study was to explore the concerns and care needs of young adult patients with TSC in medical, psychological, and socioeconomical domains. METHOD A qualitative study was performed using semistructured interviews with 16 patients (median age: 21years; range: 17 to 30) and 12 parents. Concerns and care needs were organized using the International Classification of Functioning, Disability, and Health (ICF). RESULTS Main concerns involved mental and physical health, participation, self-management skills, family planning, and side effects of medications. Patients expressed the need for multidisciplinary care that is well-informed, easily accessible, and focused on the patient as a whole, including his/her family. Parents reported high stress levels. CONCLUSION The current study provides patient-driven information, allowing recommendations to facilitate the (transition of) care for young adults with TSC. In addition to seizures, tumor growth, and TSC-associated neuropsychiatric disorders (TAND), more attention is needed for concerns and care needs specific to the transitional period, participation, and environmental factors. Adult healthcare providers should offer expert multidisciplinary care for adult patients with TSC, including attention for parental stress.

Within-subject consistency of paired associative stimulation as assessed by linear mixed models.

Paired associative stimulation (PAS) is a frequently used TMS paradigm that induces long-term potentiation in the human cortex. However, little is known about the within-subject consistency of PAS-induced effects. We determined PAS-induced effects and their consistency in healthy volunteers between two PAS sessions. Additionally, we assessed the benefit of applying linear mixed models (LMMs) to PAS data. Thirty-eight healthy volunteers underwent two identical PAS sessions with a >1 week interval. During each session, motor evoked potentials (MEPs) were assessed once before PAS induction and 3 times after at 30 min intervals. We did not detect any significant potentiation of MEP size after PAS induction. However, MEP size during PAS induction showed significant potentiation over time in both sessions (LR(1)=13.36, p<0.001). Nevertheless, there was poor within-subject consistency of PAS-induced effects both during (ICC=0.15) and after induction (ICC=0.04-0.09). Additionally, statistical model selection procedures demonstrate that a LMM with an unstructured covariance matrix better estimated PAS-induced effects than one with a conventional compound symmetry matrix (LR(34)=214.73, p<0.001). While our results are supportive of a high intra-individual variability of PAS-induced effects, the generalizability of our results is unclear, as we were only partially successful in replicating results from previous PAS studies typically showing potentiation of MEPs during and after PAS induction. We do, however, demonstrate that linear mixed models can improve the reliability of PAS-induced effects estimation.

Antibody responses to GalC in severe and complicated childhood Guillain-Barré syndrome: Letter to the Editor

We recently presented a case series of seven children who developed severe and complicated Guillain-Barre syndrome (GBS) after infection with M. pneumoniae (Mp) (Meyer Sauteur et al., 2015). The disease was rapidly progressive and severe: one died, four had clinically defined central nervous system (CNS) involvement, and five required mechanical ventilation.

Author response: Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial

We thank Drs. Zou and Liu for their comment on our article,1 and for alerting us to an interesting Chinese study.2 In the open-label uncontrolled study of 52 young children with TSC, 56% of participants showed a seizure response of 50% or more on treatment with sirolimus.2 This effect size is in line with, but larger than, the effect size in our study and that of Krueger et al.1,3 This may be due to the younger age of the participants, but is difficult to assess. Without a control group, further conclusions regarding effectiveness remain uncertain. The results of the EXIST-3 study recently showed a statistically significant effect of everolimus on seizure control in a large group of 366 patients with a response rate of up to 40% of participants (children under the age of 2 years were not included).4 From the combination of these studies, a positive effect pattern emerges of both rapalogs on intractable epilepsy, with an effect size that our study was too underpowered to detect. We agree that it is important to investigate which patients may benefit from these therapies and at what point of treatment therapies will be most beneficial.

Motor nerve excitability after childhood Guillain-Barré syndrome

Residual motor nerve dysfunction after pediatric Guillain‐Barré syndrome (GBS) was determined in an observational cross‐sectional cohort study in patients who previously developed GBS during childhood (<18 years). Ulnar motor nerve dysfunction was defined by compound motor action potential (CMAP) scan in patients after a follow up of at least 1 year compared with age‐matched healthy controls, in relation to clinical course and outcome. A total of 37 persons previously diagnosed with GBS in childhood were included with a mean age at current examination of 20.6 years (4–39 years). The median time between diagnosis and follow‐up was 11 years (range: 1–22 years). CMAP scanning indicated ulnar motor nerve dysfunction in 25 (68%) participants. The most frequent abnormality was a reduction in nerve excitability observed both in those with residual limb weakness and in the majority of those with complete recovery. CMAP scan characteristics were not related to prognostic factors or outcome. In conclusion, GBS in childhood results in residual motor nerve excitability disturbances, even in those completely recovered, probably reflecting altered physiology of regenerated peripheral nerves.

Behandelingen voor genetische neurocognitieve aandoeningen

Eén op de vijftig kinderen wordt geboren met een verstandelijke beperking. Van oudsher wordt zo’n aangeboren verstandelijke beperking gezien als een onomkeerbaar probleem van de hersenontwikkeling. Echter, recent onderzoek laat zien dat veelal een genetisch defect ten grondslag ligt aan een ernstige verstandelijke handicap. Met het groeiende inzicht in de rol van deze genen in het functioneren van de hersenen, beginnen we ons ook te realiseren dat de visie van onomkeerbaarheid mogelijk niet altijd opgaat. Deze hypothese wordt besproken aan de hand van de genetische syndromen neurofibromatose type 1 (NF1) en tubereuze sclerose complex (TSC). Veel patiënten met NF1 hebben een lichte verstandelijke beperking, waarvoor ze bijvoorbeeld extra hulp nodig hebben op school. Bij TSC is de variatie van de verstandelijke ontwikkeling veel groter. Sommige patiënten hebben een normaal IQ, anderen hebben extra hulp nodig of zitten op speciaal onderwijs, terwijl weer anderen nooit leren praten of lopen.