Introduction
SLC6A1
pathogenic variants have been associated with epilepsy and neurodevelopmental disorders. The clinical phenotype includes different seizure types, intellectual disability, and ...psychiatric symptoms affecting mood and behavior. Few data regarding neuropsychological features have been described, and details on cognitive profiles are often missing due to the lack of standardized tests.
Methods
We retrospectively reviewed the neuropsychological assessments of five subjects carrying heterozygous missense genetic variants in
SLC6A1
. We also collected data on epileptic features, EEGs, and brain MRIs. Additionally, we reviewed neuropsychological data from 204 previously reported patients with
SLC6A1
pathogenic variants.
Results
In our series, at the last evaluation (median 12.6 years), three patients had borderline intellectual functioning, one patient had mild cognitive impairment, and one patient presented with a moderate cognitive disability. Three out of five patients underwent at least two neuropsychological evaluations, which revealed a worsening of cognitive functions over time. We detected attention deficits in all patients. In addition, we observed anxiety, disruptive behavior disorder, emotional instability, and hetero aggressiveness. We also performed a literature review that highlighted that most of the patients with
SLC6A1
pathogenic variants have mild-to-moderate intellectual disability and that one-third of cases have autistic traits.
Discussion
Based on the literature review and the detailed description of our cases, we conclude that patients with
SLC6A1
-related epilepsy mostly present with mild-to-moderate intellectual disability, often associated with attention disorders. Such symptoms may worsen over time. Periodic standardized neuropsychological tests may be useful tools to follow development over time, and patient-specific rehabilitation programs could be tailored consistently.
Objective
Status epilepticus (SE) is the most common neurologic emergency in childhood. This study aimed to report on a large cohort of pediatric patients with SE, applying the International League ...Against Epilepsy (ILAE) Classification for SE to identify prognostic factors.
Methods
We included 173 children treated at “Bambino Gesù” Children's Hospital in Rome for SE exceeding 30 minutes (mean age 4.43 ± 4.93 years old, median 2.28, interquartile range IQR 0.41‐7.32; follow‐up for a mean of 4.9 ± 3.4 years, median 8.75, IQR 4,58‐12.63). A multivariate model was constructed to predict neurocognitive outcome, recurrence of SE, development of epilepsy, and mortality. Adjusted odds ratios ORs were calculated with 95% confidence interval (OR, 95% CIs).
Results
We observed a different prevalence of etiologies for the different semiologies (P < .05) and for each age group (P < .05), overlapping only in part with the recent ILAE classification. After SE, patients showed 69.9% epilepsy (drug‐resistant in half of them), 23.1% worsening of neurologic findings on examination, 28.9% cognitive deficit, and 28.3% recurrent SE. At multivariate analysis: superrefractory SE was correlated to an increased risk of developing cognitive (OR 6.00, 95% CI 2.09, 17.31) or neurologic sequelae (OR 4.9, 95% CI 1.75, 19.77). A similar finding was observed for patients with onset in the neonatal period for cognitive (OR 4.84, 95% CI 1.13, 17.3) and neurologic sequelae (OR 9.03, 95% CI 2.40, 34.04). Recurrence of SE was associated with unknown etiology (OR 6.15, 95% CI 1.43, 26.76), and myoclonic semiology (OR 6.1, 95% CI 1.23, 29.3). Patients with acute symptomatic etiology (OR 0.12, 95% CI 0.04, 0.40) had a lower risk for developing epilepsy.
Significance
Age at onset and duration of SE were critical independent variables associated with worse neurocognitive outcome. The risk of developing epilepsy was lower after acute symptomatic and febrile SE. Semiology and age at onset correlate with etiology of SE. For this reason, ILAE classification with respect to four axes seems an appropriate advancement.
Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases, characterized by progressive cerebral atrophy due to lysosomal storage disorder. Common clinical ...features include epileptic seizures, progressive cognitive and motor decline, and visual failure, which occur over different time courses according to subtypes. During the latest years, many advances have been done in the field of targeted treatments, and in the next future, gene therapies and enzyme replacement treatments may be available for several NCL variants. Considering that there is rapid disease progression in NCLs, an early diagnosis is crucial, and neurophysiological features might have a key role for this purpose. Across the different subtypes of NCLs, electroencephalogram (EEG) is characterized by a progressive deterioration of cerebral activity with slowing of background activity and disappearance of spindles during sleep. Some types of heterogeneous abnormalities, diffuse or focal, prevalent over temporal and occipital regions, are described in many NCL variants. Photoparoxysmal response to low-frequency intermittent photic stimulation (IPS) is a typical EEG finding, mostly described in CLN2, CLN5, and CLN6 diseases. Visual evoked potentials (VEPs) allow to monitor the visual functions, and the lack of response at electroretinogram (ERG) reflects retinal neurodegeneration. Taken together, EEG, VEPs, and ERG may represent essential tools toward an early diagnosis of NCLs.
To assess if ferroptosis, a new type of programmed cell death accompanied by iron accumulation, lipid peroxidation, and glutathione depletion, occurs in children with epilepsy, and in order to ...identify a panel of biomarkers useful for patient stratification and innovative-targeted therapies, we measured ferroptosis biomarkers in blood from 83 unrelated children with a clinical diagnosis of epilepsy and 44 age-matched controls. We found a marked dysregulation of three ferroptosis key markers: a consistent increase of 4-hydroxy-2-nonenal (4-HNE), the main by-product of lipid peroxidation, a significant decrease of glutathione (GSH) levels, and a partial inactivation of the enzyme glutathione peroxidase 4 (GPX4), the mediator of lipid peroxides detoxification. Furthermore, we found a significant increase of NAPDH oxidase 2 (NOX2) in the blood of children, supporting this enzyme as a primary source of reactive oxygen species (ROS) in epilepsy. Additionally, since the nuclear factor erythroid 2-related factor 2 (NRF2) induction protects the brain from epileptic seizure damage, we also evaluated the NRF2 expression in the blood of children. The antioxidant and anti-inflammatory transcription factor was activated in patients, although not enough to re-establish a correct redox homeostasis for counteracting ferroptosis. Ferroptosis-mediated oxidative damage has been proposed as an emergent mechanism underlying the pathogenesis of epilepsy. Overall, our study confirms a crucial role for ferroptosis in epilepsy, leading to the identification of a panel of biomarkers useful to find new therapeutic targets. Developing innovative drugs, which act by inhibiting the ferroptosis signaling axis, may represent a promising strategy for new anti-seizure medications.
Refractory and super-refractory status epilepticus (RSE, SRSE) are severe conditions that can have long-term neurological consequences with high morbidity and mortality rates. The usefulness of vagus ...nerve-stimulation (VNS) implantation during RSE has been documented by anecdotal cases and in systematic reviews; however, the use of VNS in RSE has not been widely adopted. We successfully implanted VNS in two patients with genetic epilepsy admitted to hospital for SRSE; detailed descriptions of the clinical findings and VNS parameters are provided. Our patients were implanted 25 and 58 days after status epilepticus (SE) onset, and a stable remission of SE was observed from the seventh and tenth day after VNS implantation, respectively, without change in anti-seizure medication. We used a fast ramp-up of stimulation without evident side effects. Our results support the consideration of VNS implantation as a safe and effective adjunctive treatment for SRSE.
Background: The clinical spectrum associated with POLG1 gene mutations ranges from non-syndromic epilepsy or mild isolated neurological signs to neurodegenerative disorders. Our aim was to review ...diagnostic findings, therapeutic approaches and outcomes of reported cases of epilepsy related to POLG1 mutation. Methods: The articles for review were identified through a systematic research on PubMed and EMBASE databases from January 2003 to April 2020, searching for the terms “Epilepsy AND POLG OR polymerase gamma,” OR “POLG1”. Results: Forty-eight articles were selected for review, which included 195 patients. Two main peaks of age at epilepsy onset were found: at ages 1 and 13 years. The most frequent seizure type was myoclonic. The occurrence of Status Epilepticus was reported in 46.4% of cases. Epileptiform and slow abnormalities were most frequently seen over occipital regions. Brain Magnetic Resonance Imaging (MRI) revealed increased T2 signal intensities in thalamic regions. Genetic analysis revealed a prevalence of A467T, W748S and G848S (74.2% of patients) mutations. Survival at 5 years was estimated at very low levels (30.2% of patients). Conclusion: In this review, we included cases with both pediatric and adult epilepsy onset. The analysis of data regarding prognosis showed that survival is related to age at onset of epilepsy.
Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, ...patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.
•Seizure frequency remained stable for most patients during the lockdown period.•Comorbidities such as behavioral and sleep disorder were more affected than epilepsy.•Due to lockdown, visits were ...canceled/postponed for 41.0%.•Patients/caregivers who had remote consultation were mostly satisfied.•Most of patients/caregivers are willing to embrace telemedicine for epilepsy care.
The recent COVID-19 pandemic has disrupted care systems around the world. We assessed how the COVID-19 pandemic affected children with epilepsy in Italy, where lockdown measures were applied from March 8 to May 4, 2020. We compiled an Italian-language online survey on changes to healthcare and views on telehealth. Invitations were sent to 6631 contacts of all patients diagnosed with epilepsy within the last 5 years at the BambinoGesù Children’s Hospital in Rome. Of the 3321 responses received, 55.6% of patients were seizure-free for at least 1 year before the COVID-19-related lockdown, 74.4% used anti-seizure medications (ASMs), and 59.7% had intellectual disability. Only 10 patients (0.4%) became infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Seizure frequency remained stable for most patients during the lockdown period (increased in 13.2%; decreased in 20.3%), and seizure duration, use of rescue medications, and adherence to treatment were unchanged. Comorbidities were more affected (behavioral problems worsened in 35.8%; sleep disorder worsened in 17.0%). Visits were canceled/postponed for 41.0%, but 25.1% had remote consultation during the lockdown period (93.9% were satisfied). Most responders (67.2%) considered continued remote consultations advantageous. Our responses support that patients/caregivers are willing to embrace telemedicine for some scenarios.
Mutations in the MED13 gene are reported in the literature in association with clinically variable, neurodevelopmental disorders, which are characterized by mild-to-severe intellectual disability, ...autism spectrum disorder, attention deficit/hyperactivity disorder, epilepsy, ocular or skeletal abnormalities, congenital cardiac defects, and facial dysmorphisms. Here, we report a patient with an epileptic phenotype carrying a novel missense mutation characterized by developmental and epileptic encephalopathy with infantile spasms.
Through trio-based WES, we identified a novel de novo heterozygous missense variant c.2501A>G in the MED13 gene. We reviewed all medical charts of the present patient and reviewed all previously reported cases with pathogenic variants of MED13.
This study involves a 24-month-old boy with epilepsy onset at the age of 3 months with drug-resistant focal seizures followed by infantile spasms at the age of 10 months. He had a severe, developmental delay along with microcephaly and dysmorphic features. From a literature review, it emerged that epilepsy is described in only one out of nineteen of previously reported patients with a phenotype of generalized, drug-resistant epilepsy with myoclonic-atonic seizures. Microcephaly, developmental delay, hypotonia, corpus callosum abnormalities, deafness, and retinal atrophy were common features in the previously described cases.
This case expands the genetic landscape of infantile spasms as well as the phenotype of MED13-related disorders adding the electroclinical features of early-onset developmental and epileptic encephalopathy with infantile spasms to the previously described, generalized epilepsy with myoclonic-atonic seizures.
Seizure threshold 2 (SZT2) gene mutations have been associated with developmental and epileptic encephalopathies (DEEs). Following a literature review, we collected 22 patients and identified the ...main clinical features related to SZT2 variants that are epilepsy with onset within the first years of life, intellectual disability (ID), macrocephaly with dysmorphic facial features, corpus callosum (CC) shape abnormalities, and cortical migration disorders. Moreover, we identified the c.7825T>G homozygous missense variant in SZT2 in two female siblings presenting with focal seizures, mild–moderate ID, behavioral disturbances, and facial dysmorphisms. Interictal Electroencephalogram (EEG) and ictal EEG were both informative and revealed, respectively, temporal bilateral asynchronous slow and epileptiform abnormalities and a focal onset in both of them. Neuroimaging study revealed a thick and abnormally shaped CC.
Seizure threshold 2 has been identified as a component of the KICSTOR complex, a newly recognized protein complex involved in the mammalian target of rapamycin (mTOR) pathway. mTOR signaling dysregulation represents common pathogenetic mechanisms that can explain the presence of both epileptogenesis and ID. Even if few cases had been reported, a new clinical phenotype is emerging, and recent hypothesis of hyperactivation of mTORC1 signaling might also open to targeted treatments, challenging an early diagnosis as of paramount importance.
•SZT2 variants cause a wide phenotypic spectrum from mild ID without epilepsy to DEE.•Epilepsy starts mostly during first year of life with focal to bilateral seizures.•Brain MRI may present with corpus callosum abnormalities and cortical malformations.•Macrocephaly and cortical malformations might be due to mTORC1 hyperactivation.•Diagnosis of SZT2 mutations might give chances for targeted treatment with rapamycin.
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