Children with seizures and radiological diagnosis of focal cortical dysplasia: can drug-resistant epilepsy be predicted earlier?

OBJECTIVE: Focal cortical dysplasia (FCD) is a malformation of cortical development and is associated with drug-resistant epilepsy. Standard indication for epilepsy surgery is drug resistance (as defined by the ILAE). Given the high incidence of drug resistance in these children, this delay may not be warranted. The aim of the study was to determine the proportion of patients with a presumed FCD who develop drug resistance, and evaluate post-operative outcomes. METHODS: This study incorporated a survey within a regional paediatric epilepsy network and a retrospective database review of a paediatric epilepsy centre serving the network to identify children with epilepsy and a presumed FCD on MRI. RESULTS: The survey revealed that 86% of the patients with epilepsy and presumed FCD on MRI within the network were referred to our centre. Of 139 paediatric patients included in the study, 131 (94.2%) had drug-resistant epilepsy. One hundred and ten (83.9%) patients were referred to epilepsy surgery, of whom 97 underwent surgery. Of 92 with one-year postoperative follow-up, 59.8% had an Engel Class 1 (seizure-free) outcome. Concordance of location between MRI and ictal EEG was strongly associated with Engel Class 1 outcome (p<0.001), as was older age at seizure onset (p=0.03). Time from diagnosis to surgery, number of medications, type of surgery and histology were not associated with improved outcome. SIGNIFICANCE: Our data suggest that most children presenting with seizures and a radiological diagnosis of FCD will develop drug-resistant epilepsy and are candidates for epilepsy surgery. The main outcome predictors are the correlation between MRI and ictal EEG localization and age at onset. This suggests that patients with FCD and epilepsy may be considered for surgery before traditional criteria of drug resistance are met. This change in practice has the potential to improve quality of life and cognitive function, and reduce burden on epilepsy services.

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.

BACKGROUND: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. METHODS: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data. FINDINGS: Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9-5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1-17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). INTERPRETATION: This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes. FUNDING: UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.

Precision therapy in the genetic epilepsies of childhood.

Despite recent advances in both the understanding and treatment of the epilepsies, the rate of refractory epilepsy has remained static for many years. However, given our greater understanding of the aetiology and genetic basis of many paediatric and adult epilepsies, there is now scope to expand treatment. In this review, we discuss the current and potential use of precision medicine in the genetic epilepsies of childhood. We will discuss how optimal control and a reduction in the rate of refractory seizures using targeted therapy could be developed and assessed. We propose a six-tier approach to defining precision therapeutics in epilepsy and discuss how this can be incorporated into a clinical trial design. The lower tiers (1-2) represent therapies in common usage that we know work for certain epilepsy syndromes but do not precisely target the underlying problem. They work to reduce seizures but do not directly or effectively attenuate the developmental phenotype. The higher tiers (5-6) are currently purely speculative and look to a future with highly disease-specific therapies based on correction of underlying genomic and proteomic issues. In order to achieve this, scientists will have to embark on a 'whole-omic' approach to understand the underlying pathophysiology in order to design a precision therapy. What this paper adds Epilepsy treatment is classified into six tiers depending on how precisely the mechanism of action addresses the aetiology. Tier 1 treatment is based on the historical response of certain epilepsy phenotypes to specific medication. Tier 6 concerns therapy targeting genes and networks that rescue the whole phenotype. Clinical trial infrastructure and population-based disease registries are necessary so that patients can participate in trials for novel precision therapies.

Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps.

There is a major unmet need for biomarkers of epilepsy. Biofluids such as blood offer a potential source of molecular biomarkers. MicroRNAs (miRNAs) fulfill several key requirements for a blood-based molecular biomarker being enriched in the brain and dysregulated in epileptic brain tissue, and manipulation of miRNAs can have seizure-suppressive and disease-modifying effects in preclinical models. Biofluid miRNAs also possess qualities that are favorable for translation, including stability and easy and cheap assay techniques. Herein we review findings from both clinical and animal models. Studies have featured a mix of unbiased profiling and hypothesis-driven efforts. Blood levels of several brain-enriched miRNAs are altered in patients with epilepsy and in patients with drug-resistant compared to drug-responsive seizures, with encouraging receiver-operating characteristic (ROC) curve analyses, both in terms of sensitivity and specificity. Both focal and generalized epilepsies are associated with altered blood miRNA profiles, and associations with clinical parameters including seizure burden have been reported. Results remain preliminary, however. There is a need for continued discovery and validation efforts that include multicenter studies and attention to study design, sample collection methodology, and quality control. Studies focused on epileptogenesis as well as associations with covariables such as sex, etiology, and timing of sampling remain limited. We identify 10 knowledge gaps and propose experiments to close these. If adequately addressed, biofluid miRNAs may be an important future source of diagnostic biomarkers that could also support forthcoming trials of antiepileptogenesis or disease-modifying therapies.

Prevalence of left ventricular hypertrabeculation/noncompaction among children with sickle cell disease.

OBJECTIVES: Incidence of sickle cell disease (SCD) in Ireland has dramatically increased. Disease survival has also steadily improved however cardiovascular manifestations remain important causes of morbidity. These include reports of left ventricular hypertrabeculation (LVHT)/noncompaction. We sought to investigate the prevalence of LVHT among a large cohort of children with SCD. METHODS: We retrospectively reviewed the records of all patients with a diagnosis of SCD who had undergone surveillance echocardiography at Our Lady's Children's Hospital Crumlin (OLCHC) from 1998 to 2015. Demographics, hemoglobin phenotype and treatment information was recorded. LV systolic function, evidence of LVHT, and possible pulmonary arterial hypertension was assessed. RESULTS: Two hundred thirty-six patients had echocardiograms available for interpretation. One hundred twenty-one (51.3%) were female; mean age was 11.3 years (± 4.1 years). Twenty-six patients (11%) had features of LVHT on echocardiography. Eleven patients (4.7%) had borderline features of LVHT. Mean LVEDD across the whole cohort was 4.2 ± 0.69 cm, LVEDD z-score of 1.44 ± 1.9, and mean LVSF was 37.3% ±15.7%. There were no significant differences in terms of age, LVEDD, LVEDD z-score, or LVSF between patients with and those without LVHT. CONCLUSIONS: The prevalence of LVHT/noncompaction in children with SCD is lower than the adult population and LV systolic function is well preserved throughout our patient group. The mechanism behind the development of LVHT in this population remains speculative. Further work is required in this field. Sickle cell patients require longitudinal evaluation to ascertain changes in left ventricular function and the presence of LVHT/noncompaction.