Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

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

Therapeutic Drug Monitoring of Quinidine in Pediatric Patients with KCNT1 Genetic Variants

Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T member 1 (KCNT1) genetic variants. Here, we report the application of Therapeutic Drug Monitoring (TDM) in pediatric patients carrying KCNT1 genetic variants and orally treated with QND for developmental and epileptic encephalopathies (DEE). We measured plasma levels of QND and its metabolite hydroquinidine (H-QND) by using a validated method based on liquid chromatography coupled with mass spectrometry (LC-MS/MS). Three pediatric patients (median age 4.125 years, IQR 2.375-4.125) received increasing doses of QND. Cardiac toxicity was monitored at every dose change. Reduction in seizure frequency ranged from 50 to 90%. Our results show that QND is a promising drug for pediatric patients with DEE due to KCNT1 genetic variants. Although QND blood levels were significantly lower than the therapeutic range as an anti-arrhythmic drug, patients showed a significant improvement in seizure burden. These data underlie the utility of TDM for QND not only to monitor its toxic effects but also to evaluate possible drug-drug interactions

POLG1-Related Epilepsy. Review of Diagnostic and Therapeutic Findings

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

EPINETLAB:a software for seizure-onset zone identification from intracranial EEG signal in epilepsy

The pre-operative workup of patients with drug-resistant epilepsy requires in some candidates the identification from intracranial EEG (iEEG) of the seizure-onset zone (SOZ), defined as the area responsible of the generation of the seizure and therefore candidate for resection. High-frequency oscillations (HFOs) contained in the iEEG signal have been proposed as biomarker of the SOZ. Their visual identification is a very onerous process and an automated detection tool could be an extremely valuable aid for clinicians, reducing operator-dependent bias and computational time. In this manuscript we present the EPINETLAB software, developed as a collection of routines integrated in the EEGLAB framework that aim to provide clinicians with a structured analysis pipeline for HFOs detection and SOZ identification. The tool implements an analysis strategy developed by our group and underwent a preliminary clinical validation that identifies the HFOs area by extracting the statistical properties of HFOs signal and that provides useful information for a topographic characterization of the relationship between clinically defined SOZ and HFO area. Additional functionalities such as inspection of spectral properties of ictal iEEG data and import and analysis of source-space MEG data were also included. EPINETLAB was developed with user-friendliness in mind to support clinicians in the identification and quantitative assessment of HFOs in iEEG and source space MEG data and aid the evaluation of the SOZ for pre-surgical assessment

Refractory Status Epilepticus in Genetic Epilepsy-Is Vagus Nerve Stimulation an Option?

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

Language Delay in Patients with CLN2 Disease: Could It Support Earlier Diagnosis?

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric disorder associated with rapid neurodegeneration, and premature death in adolescence. An effective enzyme replacement therapy (cerliponase alfa) has been approved that can reduce this predictable neurological decline. The nonspecific early symptoms of CLN2 disease frequently delay diagnosis and appropriate management. Seizures are generally recognized as the first presenting symptom of CLN2 disease, but emerging data show that language delay may precede this. An improved understanding of language deficits in the earliest stage of CLN2 disease may support the early identification of patients. In this article, CLN2 disease experts examine how language development is affected by CLN2 disease in their clinical practices. The authors' experiences highlighted the timings of first words and first use of sentences, and language stagnation as key features of language deficits in CLN2 disease, and how deficits in language may be an earlier sign of the disease than seizures. Potential challenges in identifying early language deficits include assessing patients with other complex needs, and recognizing that a child's language abilities are not within normal parameters given the variability of language development in young children. CLN2 disease should be considered in children presenting with language delay and/or seizures to facilitate earlier diagnosis and access to treatment that can significantly reduce morbidity

ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

The International League Against Epilepsy (ILAE) Task Force on Nosology andDefinitions proposes a classification and definition of epilepsy syndromes in theneonate and infant with seizure onset up to 2 years of age. The incidence of epi-lepsy is high in this age group and epilepsy is frequently associated with significantcomorbidities and mortality. The licensing of syndrome specific antiseizure medi-cations following randomized controlled trials and the development of precision,gene- related therapies are two of the drivers defining the electroclinical pheno-types of syndromes with onset in infancy. The principal aim of this proposal, con-sistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsydiagnosis and emphasize the importance of classifying epilepsy in an individualboth by syndrome and etiology. For each syndrome, we report epidemiology, clini-cal course, seizure types, electroencephalography (EEG), neuroimaging, genetics,and differential diagnosis. Syndromes are separated into self- limited syndromes,where there is likely to be spontaneous remission and developmental and epilep-tic encephalopathies, diseases where there is developmental impairment related toboth the underlying etiology independent of epileptiform activity and the epilep-tic encephalopathy. The emerging class of etiology- specific epilepsy syndromes,where there is a specific etiology for the epilepsy that is associated with a clearlydefined, relatively uniform, and distinct clinical phenotype in most affected in-dividuals as well as consistent EEG, neuroimaging, and/or genetic correlates, ispresented. The number of etiology- defined syndromes will continue to increase,and these newly described syndromes will in time be incorporated into this clas-sification. The tables summarize mandatory features, cautionary alerts, and exclu-sionary features for the common syndromes. Guidance is given on the criteria forsyndrome diagnosis in resource- limited regions where laboratory confirmation,including EEG, MRI, and genetic testing, might not be available

Impact of the COVID-19 lockdown on patients and families with Dravet syndrome

We explored the impact of coronavirus virus 2019 (COVID-19) pandemic on patients with Dravet syndrome (DS) and their family. With European patient advocacy groups (PAGs), we developed an online survey in 10 languages to question health status, behavior, personal protection, and health services before and after lockdown. Approximately 538 European PAG members received electronic invitations. Survey ran from April 14, to May 17, 2020, with 219 answers; median age 9year 10months. Protection against infection was highly used prior to COVID-19, but 88% added facemask-use according to pandemic recommendations. Only one patient was tested positive for COVID-19. Most had stable epilepsy during lockdown, and few families (4%) needed emergency care during lockdown. However, behavior disorder worsened in over one-third of patients, regardless of epilepsy changes. Half of appointments scheduled prior to lockdown were postponed; 12 patients (11%) had appointments fulfilled; and 39 (36%) had remote consultations. Responders welcomed remote consultations. Half of responders were unsatisfied with psychological remote support as only few (21 families) received this support. None of the five of patient in clinical trials stopped investigational treatment. Prior adoption of protective measures against general infection might have contributed to avoiding COVID-19 infections. Protocols for the favored remote contact ought to now be prepared

International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions

The 2017 International League Against Epilepsy classification has defined a three- tiersystem with epilepsy syndrome identification at the third level. Although a syndromecannot be determined in all children with epilepsy, identification of a specific syn-drome provides guidance on management and prognosis. In this paper, we describethe childhood onset epilepsy syndromes, most of which have both mandatory seizuretype(s) and interictal electroencephalographic (EEG) features. Based on the 2017Classification of Seizures and Epilepsies, some syndrome names have been updatedusing terms directly describing the seizure semiology. Epilepsy syndromes beginningin childhood have been divided into three categories: (1) self- limited focal epilepsies,comprising four syndromes: self- limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, andphotosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syn-dromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsywith eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies,comprising five syndromes: epilepsy with myoclonic– atonic seizures, Lennox– Gastautsyndrome, developmental and/or epileptic encephalopathy with spike- and- wave acti-vation in sleep, hemiconvulsion– hemiplegia– epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s),EEG features, phenotypic variations, and findings from key investigations

Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: A critical period for early neurodevelopment

OBJECTIVE: To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS). METHODS: Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function®-Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p ≤ 0.05) and Cramér's V. RESULTS: Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05). SIGNIFICANCE: In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment