Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Evaluation of first unprovoked seizures in children by general paediatricians in New Zealand.

AIM: To determine current practice of general paediatricians in New Zealand in the investigation and management of a first unprovoked seizure in childhood. METHODS: A self-administered questionnaire was emailed to 109 general paediatricians in New Zealand. The questionnaire presented the participant with three hypothetical case scenarios representing a generalised tonic clonic seizure, a complex partial seizure and an episode of non-specific collapse. The participant was asked to indicate what investigations and course of management was required. RESULTS: Forty-seven questionnaires were returned. Primary investigations included an electroencephalogram (EEG) in 47% of cases after a first generalised tonic clonic seizure increasing to 89% after a second. Ninety-one per cent of paediatricians were likely to request an EEG after a complex partial seizure. No paediatrician would request neuroimaging following a first generalised tonic clonic seizure. Neuroimaging was requested by 10% of paediatricians following a second generalised tonic clonic seizure and by 47% following a complex partial seizure. No paediatrician elected to initiate antiepileptic drugs after a first generalised tonic clonic seizure, but 49% would initiate treatment after a second generalised tonic clonic seizure. Eleven per cent of paediatricians would start treatment after a single complex partial seizure. CONCLUSION: Less than 50% of general paediatricians would request an EEG after a first unprovoked seizure. This is an unexpectedly low rate that may reflect accessibility. New Zealand paediatricians had an appropriately low rate of requesting neuroimaging. As currently recommended no general paediatricians began antiepileptic drugs in the scenario of a single uncomplicated seizure in the absence of other risk factors.

Recurrent intractable seizures in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor.

The purpose of this study was to identify the pathologic features that predict postoperative outcome in children with cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumors. We reviewed the records of children with dysembryoplastic neuroepithelial tumor who underwent epilepsy surgery and who had at least 1 year of surgical follow-up. We divided the dysembryoplastic neuroepithelial tumors into three pathology classes (simple, complex, and nonspecific), categorized adjunctive cortical dysplasia into four types, and compared histopathology with seizure outcomes. We identified 26 children with dysembryoplastic neuroepithelial tumors. Dysembryoplastic neuroepithelial tumors were complex in 19 patients (73%), simple in 6 (23%), and nonspecific in 1 (4%). Cortical dysplasia was adjacent to dysembryoplastic neuroepithelial tumors in 18 patients. Six patients had type IA cortical dysplasia, 5 had type IB, 3 had type IIA, and 1 had type IIB. The 3 remaining patients had repeated surgeries; of these, 2 patients had cortical dysplasias of type IA/IB and 1 was type IIA/IIB. Eight (39%) of 18 patients with dysembryoplastic neuroepithelial tumors and cortical dysplasia required further surgery for recurrent intractable seizures (P < .05), whereas none of 8 patients without cortical dysplasia required additional surgery. Of 13 patients with type I cortical dysplasia, only 4 had a poor seizure outcome, whereas all 5 patients with type II had a poor seizure outcome postoperatively (P < .05). Children with dysembryoplastic neuroepithelial tumor and cortical dysplasia often had recurrent intractable seizures postoperatively and required further epilepsy surgery. Cortical dysplasia adjacent to dysembryoplastic neuroepithelial tumor can play a role in the epileptogenicity of dysembryoplastic neuroepithelial tumor. Complete resection of a dysembryoplastic neuroepithelial tumor and its adjacent cortical dysplasia should be considered.

Startle-induced seizures associated with infantile hemiplegia: implication of the supplementary motor area.

This case illustrates an uncommon form of symptomatic startle-induced epilepsy associated with infantile hemiplegia. Seizure semiology, neuroimaging and neurophysiological findings support involvement of the supplementary motor area in the generation of this seizure type. We present the case of an 11-year-old girl with an uncommon form of startle-induced seizures, illustrated on video-EEG, against the background of left infantile hemiplegia associated with extensive right hemispheric porencephaly but preserved cognitive functioning. The epileptic focus appears to be in the dorsolateral frontal lobe, with seizure semiology involving the supplementary motor cortex.

Intelligence in childhood epilepsy syndromes.

UNLABELLED: Intellectual deficits play a significant role in the psychosocial comorbidity of children with epilepsy. Early educational intervention is critical. OBJECTIVE: This study aims to determine the intellectual ability of children with common childhood epilepsy syndromes-generalised idiopathic epilepsy (GIE), generalised symptomatic epilepsy (GSE), temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), central epilepsy (CE) and non-localised partial epilepsy (PE). METHODS: A prospective consecutive series of 169 children were recruited. Epilepsy syndrome was identified by clinical data, seizure semiology, interictal and ictal EEG in each child, using International League Against Epilepsy criteria. Each child had neuropsychology assessment using age-normed and validated instruments. After adjusting for important epilepsy variables, 95% confidence intervals were generated for mean full-scale intelligence quotient (FSIQ) using ANCOVA. RESULTS: Significant differences between epilepsy syndrome groups were found for age of onset (P<0.001), duration of active epilepsy (P=0.027), seizure frequency (P=0.037) and polytherapy (P=0.024). Analysing FSIQ, children with GIE, CE and TLE performed best, and did not differ statistically. Children with GSE had a statistically lower FSIQ than other syndrome groups except PE. FLE functioned significantly better than GSE, but did not differ statistically from other groups. CONCLUSIONS: In childhood epilepsy, delineation of the syndrome has important implications when considering intellectual potential. This information is invaluable in planning educational interventions and supporting the family.