mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development: Novel Variants, Topographic Mapping, and Clinical Outcomes.

Background and Objectives: Somatic and germline pathogenic variants in genes of the mammalian target of rapamycin (mTOR) signaling pathway are a common mechanism underlying a subset of focal malformations of cortical development (FMCDs) referred to as mTORopathies, which include focal cortical dysplasia (FCD) type II, subtypes of polymicrogyria, and hemimegalencephaly. Our objective is to screen resected FMCD specimens with mTORopathy features on histology for causal somatic variants in mTOR pathway genes, describe novel pathogenic variants, and examine the variant distribution in relation to neuroimaging, histopathologic classification, and clinical outcomes. Methods: We performed ultra-deep sequencing using a custom HaloPlexHS Target Enrichment kit in DNA from 21 resected fresh-frozen histologically confirmed FCD type II, tuberous sclerosis complex, or hemimegalencephaly specimens. We mapped the variant alternative allele frequency (AAF) across the resected brain using targeted ultra-deep sequencing in multiple formalin-fixed paraffin-embedded tissue blocks. We also functionally validated 2 candidate somatic MTOR variants and performed targeted RNA sequencing to validate a splicing defect associated with a novel DEPDC5 variant. Results: We identified causal mTOR pathway gene variants in 66.7% (14/21) of patients, of which 13 were somatic with AAF ranging between 0.6% and 12.0%. Moreover, the AAF did not predict balloon cell presence. Favorable seizure outcomes were associated with genetically clear resection borders. Individuals in whom a causal somatic variant was undetected had excellent postsurgical outcomes. In addition, we demonstrate pathogenicity of the novel c.4373_4375dupATG and candidate c.7499T>A MTOR variants in vitro. We also identified a novel germline aberrant splice site variant in DEPDC5 (c.2802-1G>C). Discussion: The AAF of somatic pathogenic variants correlated with the topographic distribution, histopathology, and postsurgical outcomes. Moreover, cortical regions with absent histologic FCD features had negligible or undetectable pathogenic variant loads. By contrast, specimens with frank histologic abnormalities had detectable pathogenic variant loads, which raises important questions as to whether there is a tolerable variant threshold and whether surgical margins should be clean, as performed in tumor resections. In addition, we describe 2 novel pathogenic variants, expanding the mTORopathy genetic spectrum. Although most pathogenic somatic variants are located at mutation hotspots, screening the full-coding gene sequence remains necessary in a subset of patients.

The Experience of Parents of Children With Genetically Determined Leukoencephalopathies With the Health Care System: A Qualitative Study.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.

Surgically Remediable Secondary Network Epileptic Encephalopathies With Continuous Spike Wave in Sleep: Lesions May Not Be Visible on Brain Magnetic Resonance Imaging (MRI).

BACKGROUND: Continuous spike wave in sleep (CSWS) is an electroencephalogram (EEG) pattern associated with developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This etiologically heterogeneous syndrome may occur because of genetic factors and congenital or acquired brain lesions. We studied the pattern of clinical presentation and underlying etiologies in patients with DEE-SWAS that respond to resective surgery. METHODS: We reviewed our clinical and research databases for patients who had resolution of CSWS following surgical resection of a focal lesion. RESULTS: We identified 5 patients meeting inclusion criteria. In 3 of 5, an epileptogenic structural abnormality was not apparent on brain magnetic resonance imaging (MRI). In all 3 patients, focal cortical dysplasia was identified through intracranial EEG monitoring. SIGNIFICANCE: DEE-SWAS may be a secondary bilateral network epilepsy syndrome, which can be treated with resection of the inciting focal lesion. In patients with drug-resistant CSWS, clinicians should consider a complete epilepsy presurgical workup, including intracranial EEG monitoring.

Experience of Parents of Children with Genetically Determined Leukoencephalopathies Regarding the Adapted Health Care Services During the COVID-19 Pandemic.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

New interinstitutional, multimodal presurgical evaluation protocol associated with improved seizure freedom for poorly defined cases of focal epilepsy in children.

OBJECTIVE: In an attempt to improve postsurgical seizure outcomes for poorly defined cases (PDCs) of pediatric focal epilepsy (i.e., those that are not visible or well defined on 3T MRI), the authors modified their presurgical evaluation strategy. Instead of relying on concordance between video-electroencephalography and 3T MRI and using functional imaging and intracranial recording in select cases, the authors systematically used a multimodal, 3-tiered investigation protocol that also involved new collaborations between their hospital, the Montreal Children's Hospital, and the Montreal Neurological Institute. In this study, the authors examined how their new strategy has impacted postsurgical outcomes. They hypothesized that it would improve postsurgical seizure outcomes, with the added benefit of identifying a subset of tests contributing the most. METHODS: Chart review was performed for children with PDCs who underwent resection following the new strategy (i.e., new protocol [NP]), and for the same number who underwent treatment previously (i.e., preprotocol [PP]); ≥ 1-year follow-up was required for inclusion. Well-defined, multifocal, and diffuse hemispheric cases were excluded. Preoperative demographics and clinical characteristics, resection volumes, and pathology, as well as seizure outcomes (Engel class Ia vs > Ia) at 1 year postsurgery and last follow-up were reviewed. RESULTS: Twenty-two consecutive NP patients were compared with 22 PP patients. There was no difference between the two groups for resection volumes, pathology, or preoperative characteristics, except that the NP group underwent more presurgical evaluation tests (p < 0.001). At 1 year postsurgery, 20 of 22 NP patients and 10 of 22 PP patients were seizure free (OR 11.81, 95% CI 2.00-69.68; p = 0.006). Magnetoencephalography and PET/MRI were associated with improved postsurgical seizure outcomes, but both were highly correlated with the protocol group (i.e., independent test effects could not be demonstrated). CONCLUSIONS: A new presurgical evaluation strategy for children with PDCs of focal epilepsy led to improved postsurgical seizure freedom. No individual presurgical evaluation test was independently associated with improved outcome, suggesting that it may be the combined systematic protocol and new interinstitutional collaborations that makes the difference rather than any individual test.

DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans.

Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis.

Intravenous Immunoglobulin as a Treatment for Intractable Epilepsy Secondary to Focal Cortical Dysplasia: A Meta-analysis.

BACKGROUND: The observation of a dramatic response to intravenous immunoglobulin (IVIG) by a child from our center with intractable epilepsy due to focal cortical dysplasia prompted us to perform a meta-analysis on the efficiency of IVIG in this condition. Focal cortical dysplasia is a common cause of intractable epilepsy. Microglial activation and upregulation of neuroinflammatory pathways have been documented in brain specimen from surgically treated patients with intractable epilepsy and focal cortical dysplasia. IVIG has been used for decades to treat patients with intractable epilepsy; however, there is little evidence regarding its efficacy, possibly because of the pathophysiological heterogeneity of patients included in most of the published studies. METHODS: A search for studies in patients from 0 to 18 years was performed in databases. We found four observational studies-prospective or retrospective-including patients with focal cortical dysplasia with intractable epilepsy treated with IVIG. The primary outcome was a reduction of seizure frequency by more than 50%. RESULTS: A total of eight patients were included in this meta-analysis. The intravenous immunoglobulin doses ranged from 0.2 to 1 g/kg/day, repeated three to six times over one to 14 months (median: five months). Intravenous immunoglobulin was associated with reduced seizure frequency in six out of eight patients (P < 0.05). Among these six patients, the reduction of seizure frequency lasted for nine months to nine years (median: 3.7 years). There were either no or mild adverse effects of IVIG infusion including postinfusion paresthesia (n = 1) and a transient increase in temperature (n = 1). CONCLUSIONS: Despite obvious limitations, mainly because of the small number of patients, and the selection biases, this study suggests that, based on the available data, IVIG might be effective in the treatment of intractable epilepsy secondary to focal cortical dysplasia. Further therapeutic trials are mandatory to further clarify the efficacy of IVIG in this condition.

Clinical and Radiologic Spectrum of Septo-optic Dysplasia: Review of 17 Cases.

We retrospectively reviewed the clinical and radiologic characteristics of 17 individuals with septo-optic dysplasia (SOD) and attempted to identify correlations between imaging findings, clinical features, and neurodevelopmental outcome. Surprisingly, only 1 (6%) individual was classified as classic SOD (with septum pellucidum/corpus callosum dysgenesis), 3 (18%) as SOD-like (with normal septum pellucidum/corpus callosum) and the majority, 13 (76%), as SOD-plus (with cortical brain malformation). Cortical abnormalities included schizencephaly, polymicrogyria, and gray matter heterotopias. All individuals had optic nerve hypoplasia, 11 (65%) had endocrinologic deficits, and 13 (76%) had abnormal cerebral midlines. Seven individuals (41%) had all 3 features. Neurodevelopmental outcome was abnormal in 13 (78%), ranging from mild to severe developmental delay. Individuals with SOD-plus did not have more severe neurologic deficits than individuals with classic or SOD-like subgroups. Thus, SOD is clinically and radiologically heterogeneous, and cortical abnormalities are very common. Neurodevelopmental deficits are very prevalent, and of wide-ranging severity.

Breaking the cycle: A comparison between intravenous immunoglobulins and high dosage prednisone in the treatment of medically intractable epilepsy in children.

PURPOSE: Because immune mediated mechanisms are suspected in epileptogenesis, IVIg and corticosteroids have been used as alternatives to treat refractory seizures. We present our experience treating intractable epileptic children with IVIg and prednisone. METHODS: Children with intractable epilepsy treated with prednisone or IVIg between 2005-2016 were reviewed retrospectively. Children with infantile spasms and autoimmune epilepsy were excluded. Data analyzed include epilepsy type and etiology, duration of epilepsy prior to treatment, seizure outcome, time to best seizure outcome, and adverse effects. RESULTS: Fifty-one patients were included: 26 received IVIg; 25 received prednisone. Etiologies were similar between cohorts: genetic (13 IVIg; 10 prednisone), lesional (8 IVIg; 7 prednisone), and unknown (5 IVIg; 8 prednisone). In the prednisone cohort, 92.0% had generalized epilepsy compared to 61.5% for IVIg. Among the IVIg treated, 84.6% responded (10 genetic, 4 unknown, and 8 lesional) with mean seizure reduction of 77.3% and mean time to best response of 9.8 weeks. With prednisone, 24.0% responded (2 genetic, 3 unknown, and 1 lesional) with a mean seizure reduction of 95.0% and mean time to best response of 2.7 weeks. Adverse effects occurred in 2 and 16 patients treated with IVIg and prednisone, respectively. The difference in responders and seizure reduction was statistically significant (p<0.0001 and p=0.001, respectively). CONCLUSION: IVIg had greater responders and lower adverse effects and honeymoon effect. This response was independent of epilepsy type, etiology, and duration suggesting different mechanisms of action between prednisone and IVIg and a common, reversible, immune-mediated pathway to intractability.

Somatosensory evoked potentials in neonates with hypoxic-ischemic encephalopathy treated with hypothermia.

OBJECTIVE: Somatosensory evoked potentials (SEPs) are reported to have high positive predictive value (PPV) for neurodevelopmental impairment (NDI) in neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). Our objective was to assess if this predictive value remains high with the use of therapeutic hypothermia. METHODS: A cohort of HIE neonates treated with hypothermia was recruited between September 2008 and September 2010. SEPs were elicited after hypothermia and classified as bilateral absent N19, abnormal N19 (i.e., delayed or unilateral absent), or normal. Qualitative evaluation of MRI was also performed. The primary outcome was moderate or severe NDI around 2 years of age. RESULTS: SEPs were performed after hypothermia in 26 of 34 neonates submitted to hypothermia with adequate follow-up at a median day of life 11 (IQR 9, 13). Twenty-three (88%) had moderate encephalopathy. Eleven neonates (42%) had bilateral absent N19, 4 of whom had NDI, while fifteen neonates (58%) had either abnormal or normal N19, of whom only one had NDI. SEPs thus had a PPV of 0.36 (4/11) and a negative predictive value (NPV) of 0.93 (14/15). Eighteen neonates (69%) had brain injury on MRI. MRI thus had a PPV of 0.28 (5/18) and an NPV of 1.00 (8/8). CONCLUSIONS: Neonates with HIE treated with hypothermia with bilateral absent N19 potentials may have a better prognosis than reported in the pre-hypothermia era. MRI also had a low PPV and high NPV. SEPs should be interpreted with caution in this new population and need to be re-evaluated in larger studies.

De novo deletion of FMN2 in a girl with mild non-syndromic intellectual disability.

We present the case of a child with mild non-syndromic intellectual disability in whom array genomic hybridization revealed a de novo heterozygous deletion involving only one gene, FMN2. FMN2 encodes FORMIN-2, a member of the formin homology family, which is primarily expressed in the developing and mature brain, and has an important role in cytoskeletal organization and actin nucleation. A heterozygous deletion of FMN2 along with 2 other genes has been recently reported in a boy with non-syndromic intellectual disability. This report provides further support for the important role of FMN2 in brain development and cognition.

Homozygous deletion of Tenascin-R in a patient with intellectual disability.

BACKGROUND: TNR encodes Tenascin-R, an extracellular matrix glycoprotein that is primarily expressed in the central nervous system. Loss of TNR impairs cognition, synaptic plasticity and motor abilities in mice, however its role in human neurodevelopment and cognition is less clear. METHODS AND RESULTS: The authors present the case of a child with intellectual disability and transient choreoathetosis. Array genomic hybridisation revealed a homozygous deletion involving only two genes, including TNR. Sequencing TNR in a cohort of 219 patients with intellectual disability did not identify any potential pathogenic mutations. CONCLUSION: This is the first report of a complete loss of TNR associated with intellectual disability. This study provides evidence of the important role of TNR in brain development and cognition in humans.

Gender differences in the developmental outcomes of children with congenital cardiac defects.

OBJECTIVE: This study compares the developmental and functional outcomes at school entry between boys and girls born with a congenital cardiac defect who required early surgical correction. STUDY DESIGN: A prospective cohort of 94 children, including 49 percent boys, were followed up to 5 years of age and assessed for developmental progress. Developmental measures included Wechsler Preschool and Primary Scale of Intelligence - cognitive; Peabody Picture Vocabulary Test - receptive language; Peabody Developmental Motor Scale - motor; and Child Behaviour Checklist - behaviour. Measures of function included the Vineland Adaptive Behavior Scale and Functional Independence Measure for Children (WeeFIM). RESULTS: The mean scores of the boys on the WeeFIM subscales, such as self-care, mobility, cognition, were significantly lower than that of the girls. There was a trend for a greater proportion of boys to have abnormalities on neurological examination (boys 37.5 percent abnormal, girls 19.5 percent abnormal). Verbal, performance, and full scale Intellectual Quotients were 5-7 points lower in boys but did not reach significance (full scale Intellectual Quotient: boys 87.7 plus or minus 22.2; girls 93.9 plus or minus 19.3). Boys were more likely to have fine motor delays (50 percent, 82.7 plus or minus 16.5) compared with girls (28.2 percent, 87.0 plus or minus 15.8). There were no gender differences in receptive language or behavioural difficulties. CONCLUSIONS: Boys born with congenital heart disease requiring early surgical repair appear to be at enhanced risk for neuromotor impairments and activity limitations. Findings support gender differences in the pathogenesis of early brain injury following hypoxic-ischaemic insults. This has implications for neuroprotective strategies to prevent brain injury.

A de novo 2.1-Mb deletion of 13q12.11 in a child with developmental delay and minor dysmorphic features.

We report on a patient with an interstitial deletion at 13q12.11. He had mild developmental delay, craniofacial dysmorphism, a pectus excavatum, narrow shoulders, malformed toes, and café-au-lait spots. Array CGH analysis disclosed a de novo deletion spanning 2.1 Mb,within cytogenetic band 13q12.11.The deletion produces hemizygozity for 16 known genes, among which GJA3, GJB2, GJB6, IFT88, LATS2, and FGF9 have potential clinical significance. The observed phenotype may be due to mutation in one of the 16 genes, or to a combination of deletion and/or mutation in a number of them.

A new look at outcomes of infants with congenital heart disease.

This article provides an overview of a longitudinal study on a cohort of 131 newborns and young infants with congenital heart defects who required open heart surgery. The rationale for the study design is provided as well as a summary of the procedures used to evaluate these children prior to surgery, at discharge after surgery, 12-18 months later, and at 5 years of age. Results demonstrate that a substantial proportion of these infants had neurologic and developmental abnormalities prior to surgical repair. Developmental delays were common in children with both cyanotic and acyanotic heart defects, and these deficits persisted to school entry. A number of medical, surgical, demographic and environmental factors were significantly associated with developmental outcomes suggesting a multifactorial etiology to brain injury. Limited educational and rehabilitation resources for this cohort at early school age suggests that service needs may need to be more carefully planned for this high-risk population. Lessons learnt from this prospective study are highlighted as well as future directions for research and clinical practice.

Sudden cardiac death in association with the ketogenic diet.

The ketogenic diet is a high-fat, low-carbohydrate, adequate-protein diet that is used to decrease the frequency of seizures in patients who have refractory epilepsy. Despite its positive effects in some patients, there are potential adverse effects. Two complications related to the ketogenic diet are selenium deficiency, which has been associated with impaired myocardial function, and QT prolongation as documented on electrocardiography. Reported here are two cases of death in a child on the ketogenic diet for seizure control. In case 1, the child who died of complications related to torsade de pointes, with documented QT prolongation; post mortem examination revealed selenium-deficiency cardiomyopathy. In case 2, a child experienced QT prolongation while on the ketogenic diet and later died suddenly at home. Both children exhibited selenium deficiency. These two cases suggest that patients on the ketogenic diet require monitoring of the QT interval by electrocardiography, myocardial function by echocardiography, and selenium levels before and during the ketogenic diet.

Developmental and functional outcomes at school entry in children with congenital heart defects.

OBJECTIVE: To describe developmental and functional outcomes of children with congenital heart defects (CHDs) at school entry after open heart surgery. STUDY DESIGN: Infants with CHDs who underwent surgical repair in infancy were recruited and assessed prospectively for developmental progress. At 5 years of age (64.2 +/- 11.3 months), 94 subjects were evaluated in a blind fashion by using a variety of standardized measures. RESULTS: Mean IQ scores were in the low average range (90-94). Receptive language was in the average range (103.6 +/- 14.4). Behavioral difficulties were common (27.1%), with internalizing problems being more frequent. Functional limitations in socialization (93.0 +/- 17.1), daily living skills (94.6 +/- 16.4), communication (90.0 +/- 14.1), and adaptive behavior (92.1 +/- 15.8) were noted in 11% to 17% of children. With the Functional Independence Measure for Children, 20% to 22% of subjects were more dependent than their peers in self-care and social cognition, although few (4.5%) had mobility restrictions. Predictors of developmental and functional limitations included: abnormal postoperative neurologic examination, microcephaly, deep hypothermic circulatory arrest time, palliation, acyanotic heart lesion, age at surgery, and maternal education. CONCLUSIONS: After infant open-heart surgery, children with CHDs may exhibit a range of developmental difficulties at school entry that enhances risk for learning challenges and decreased social participation.

Simultaneous Guillain-Barré syndrome and acute disseminated encephalomyelitis in the pediatric population.

Few cases of simultaneous acute demyelination of the peripheral and central nervous systems are reported. Four patients diagnosed as having Guillain-Barré syndrome and acute disseminated encephalomyelitis during the same hospitalization are described herein. Two patients manifest an atypical form of Guillain-Barré syndrome, with magnetic resonance imaging of the head showing acute disseminated encephalomyelitis. A third patient has acute disseminated encephalomyelitis and develops Guillain-Barré syndrome during his hospitalization. A fourth patient demonstrates transverse myelitis that evolves into Guillain-Barré syndrome, with demyelination seen on brain magnetic resonance imaging. All patients are treated with intravenous immunoglobulins or corticosteroids. Three patients have a favorable outcome; 1 patient has a chronic inflammatory demyelinating polyradiculoneuropathy. Guillain-Barré syndrome and acute disseminated encephalomyelitis can occur simultaneously in the pediatric population. This may be explained by a shared epitope between peripheral and central nervous system myelin. Further research is necessary to better describe this entity and its prognosis.

Patterns of use of educational and rehabilitation services at school age for children with congenitally malformed hearts.

BACKGROUND: Infants with congenitally malformed hearts who require early open-heart surgery are at high risk for developmental, psychosocial, and academic difficulties. Our objective was to describe the pattern of use of educational supports and rehabilitation services in these children at early school age. METHODS: Parents of children who participated in a prospective study of developmental progress following open-surgery were contacted to participate in a telephone survey. The questionnaire included questions regarding current educational and rehabilitation resources their child was receiving, as well as the needs perceived by the parents for services, and obstacles to accessing services. RESULTS: The survey was completed by 60 families, the mean age of the children being 8.1 years, with standard deviation of 1.1 years. Of the children, 22% received educational supports, which primarily included supplemental tutoring. Rehabilitation services were received by 23%, speech therapy for 9 children, psychologic support for 6, occupational therapy for 3, and physical therapy for 1. Children receiving these services were significantly more likely to have had low developmental scores in the expected domains, when compared to those not receiving services. The majority of developmentally delayed children were not receiving adequate, if any, resource support. Medical and surgical history was not associated with greater likelihood of receipt of services. CONCLUSIONS: Children with congenitally malformed hearts who are now of school age are at risk for developmental challenges and academic difficulties, yet many do not receive services to optimize performance. Modification of current practice to include systematic, periodic screening, as well as the availability of a resource person for information and referral, may be warranted to meet the ongoing needs of these children and their families, and to optimize their health and well-being.