Summary
Objective
To describe treatment and outcome of epilepsy in children with tuberous sclerosis complex (TSC).
Methods
Seventy‐one children with TSC and epilepsy treated at the ENCORE TSC ...Expertise Center between 1988 and 2014 were included. Patient characteristics and duration and effectiveness of antiepileptic treatments were extracted from our clinical database. Correlations were made between recurrence of seizures after response to treatment, and several patient characteristics.
Results
Median age at time of inclusion was 9.4 years (range 0.9–18.0). Seizure history showed that 55 children (77%) of 71 became seizure‐free for longer than 1 month, and 21 (30%) of 71 for longer than 24 months. Remission of seizures was associated with higher IQ, and a trend was observed between seizure remission and age at onset of seizures. A total of 19 antiepileptic drugs (AEDs) were used. Valproic acid, vigabatrin, levetiracetam, and carbamazepine were used most frequently. Nonpharmacologic therapies (ketogenic diet, epilepsy surgery, and vagus nerve stimulation) were used 13 times. Epilepsy surgery was most effective, with four of five children becoming seizure‐free. AEDs prescribed as first and second treatment were most effective. Valproic acid was prescribed most frequently as first and second treatment, followed by vigabatrin. Thirty‐one children had infantile spasms, preceded by focal seizures in 18 children (58%). Vigabatrin was used by 29 children (94%), and was first treatment in 15 (48%). Vigabatrin was more effective than other AEDs when prescribed as first treatment.
Significance
We showed that, although 77% of children with epilepsy due to TSC reached seizure remission, usually after their first or second AED, this was sustained for at least 24 months in only 38%. Almost half of those with 24 months of remission later had relapse of seizures. Our results support vigabatrin as first choice drug, and show the need for better treatment options for these children.
Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly ...among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood.
For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided.
Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk.
We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings.
This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the ...Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2‐q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow‐up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family.
DNA double‐strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling ...processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS‐like disorder. Here, we report a long‐term follow‐up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient‐derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient‐derived fibroblasts and provided evidence for a markedly reduced radiation‐induced AT‐mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.
Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous ...entities have been grouped as PIK3CA‐Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low‐level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient‐specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi‐system and often complex medical issues seen with PROS. In March 2019, macrocephaly‐capillary malformation (M‐CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M‐CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.
XXX.
Objective
Guillain‐Barré syndrome (GBS) is an acute postinfectious immune‐mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in ...some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross‐reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case‐control study.
Methods
We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198).
Results
Anti–M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti‐GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti‐GalC‐positive patients showed more‐frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti‐GalC antibodies correlated with anti–M. pneumoniae antibodies (p < 0.001) and cross‐reacted with different M. pneumoniae strains. Anti‐GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti‐GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006).
Interpretation
M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti‐GalC antibodies, of which specifically anti‐GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566–580
Aim
To identify meaningful outcomes of children and their caregivers attending a paediatric brain centre.
Method
We compiled a long list of outcomes of health and functioning of children with ...brain‐related disorders such as cerebral palsy, spina bifida, (genetic) neurodevelopmental disorders, and acquired brain injury. We incorporated three perspectives: patients, health care professionals, and published outcome sets. An aggregated list was categorized using the International Classification of Functioning, Disability, and Health: Children and Youth version in a patient validation survey for children and parent‐caregivers to prioritize outcomes. Outcomes were considered meaningful when ranked ‘very important’ by 70% or more of the participants.
Results
We identified 104 outcomes from the three perspectives. After categorizing, 59 outcomes were included in the survey. Thirty‐three surveys were completed by children (n = 4), caregivers (n = 24), and parent‐caregivers together with their child (n = 5). Respondents prioritized 27 meaningful outcomes covering various aspects of health and functioning: emotional well‐being, quality of life, mental and sensory functions, pain, physical health, and activities (communication, mobility, self‐care, interpersonal relationships). Parent‐caregiver concerns and environmental factors were newly identified outcomes.
Interpretation
Children and parent‐caregivers identified meaningful outcomes covering various aspects of health and functioning, including caregiver concerns and environmental factors. We propose including those in future outcome sets for children with neurodisability.
What this paper adds
Outcomes that children with brain‐related disorders and their parent‐caregivers consider to be the most meaningful cover a wide range of aspects of functioning.
Involving these children and their parent‐caregivers resulted in the identification of important outcomes that were not covered by professionals and the literature.
Parent‐caregiver‐related factors (coping, burden of care) and environmental factors (support, attitudes, and health care services) were identified as meaningful.
What this paper adds
Outcomes that children with brain‐related disorders and their parent‐caregivers consider to be the most meaningful cover a wide range of aspects of functioning.
Involving these children and their parent‐caregivers resulted in the identification of important outcomes that were not covered by professionals and the literature.
Parent‐caregiver‐related factors (coping, burden of care) and environmental factors (support, attitudes, and health care services) were identified as meaningful.
Meaningful outcomes in children and their caregivers with brain‐related disorders (such a cerebral palsy, brain injury and genetic neurodevelopmental disorders) were identified using a online patient validation survey assessing salient outcomes. The survey was based on the integrated outcomes from the perspectives of families, health‐care professionals and literature.
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This original article is commented on by Geboers on pages 1419–1420 of this issue.
There is a letter to the editor on this original article by Oakeshott et al. on page 1531
To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis ...complex (TSC).
In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.
Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.
Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.
NCT01730209.
This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.
Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants ...in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.
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•Mutations in SCN3A (NaV1.3) associate with perisylvian polymicrogyria•Pathogenic SCN3A mutations increase persistent sodium current•SCN3A is expressed during human fetal development in progenitors and neurons•Mutated SCN3A alters cortical folding pattern in the ferret brain
Smith et al. define a role for sodium channel SCN3A (NaV1.3) in the developing human cerebral cortex, as well as a cortical malformation that can result from NaV1.3 dysfunction.
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