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Aim: To find proof-of-principle evidence for short-term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1)., Method: This was a double-blind, parallel-group, randomized, placebo-controlled clinical trial (the NF1-EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17  years 6 months. The short-term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention-deficit/hyperactivity problems, and executive functioning., Results: We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete-case analysis showed no effect of lamotrigine on either performance IQ (-0.23, 95% CI -6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (-0.81, 95% CI -1.67 to 0.04)., Interpretation: Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1 +/- mice to a cerebellum-dependent associative learning task, called Pavlovian eyeblink conditioning. Additionally, we assessed general motor function and muscle strength in Nf1 +/- mice. To our surprise, we found that Nf1 +/- mice showed a moderately increased learning rate of conditioned eyeblink responses, as well as improved accuracy in the adaptive timing of the eyeblink responses. Locomotion, balance, general motor function, and muscle strength were not affected in Nf1 +/- mice. Together, our results support the view that cerebellar function in Nf1 +/- mice is unimpaired., (© 2022. The Author(s).)

Objective: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1., Methods: We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS)., Results: The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009)., Conclusions: Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients., Significance: These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance., Methods: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets., Results: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population., Conclusions: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.

Objective: In a worldwide debate on deliberately terminating the lives of newborns, proponents point at newborns with very severe forms of myelomeningocele (MMC) and their assumed suffering, claiming there are no effective means of alleviating their distress. Nevertheless, the degree of discomfort and pain in these newborns has never been assessed in a structured manner., Methods: In a prospective cohort study, 28 consecutive newborns with MMC were included over a 5-year period and were followed up throughout their hospital stay for initial treatment. We created 2 disease severity groups on the basis of the Lorber criteria. The primary outcomes were discomfort and pain, assessed by simultaneously scoring 2 validated scales: the visual analog scale for pain and the Comfort Behavioral Scale for discomfort. These scores were coupled to a validated and evidence-based analgesia algorithm., Results: Overall, discomfort related to pain was measured in 3.3% of the scores. This percentage differed little between the preoperative and postoperative periods and did not significantly differ between newborns with less severe MMC and severe MMC (3.9% vs 2.8%; P = .3). The mean dosage of paracetamol was 35 mg/kg per day (95% confidence interval: 32-39); the mean dosage of morphine was 0.9 μg/kg per hour (95% confidence interval: 0.6 -1.2)., Conclusion: Over the length of their hospital stays for initial treatment, all newborns with MMC presented with low levels of discomfort and pain independent of disease severity and time frame.