Chiari 1 malformation in a child with febrile seizures, parasomnias, and sleep apnea syndrome

Introduction: The type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to disturbances in cerebrospinal fluid circulation and to direct compression of nervous tissue. Case report: We describe a 4-year-old Caucasian female child with febrile seizures, headache, parasomnias, and a delay of speech. The child underwent a magnetic resonance imaging to investigate these neurological signs, disclosing a Chiari malformation type 1. The polysomnography showed a mild-moderate sleep-disordered breathing, increased number of central sleep apneas, and generalized spike waves at sleep onset. Conclusions: Seizures have been seldom described in CM1 patients. The main reasons for performing MRI in this case were frequent seizures, a delay of speech, and headache, leading to an unexpected diagnosis of CM1. Polysomnography detected a discrete SDB

Chiari 1 Malformation in a Child with Febrile Seizures, Parasomnias, and Sleep Apnea Syndrome

Introduction. The type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to disturbances in cerebrospinal fluid circulation and to direct compression of nervous tissue. Case report. We describe a 4-year-old Caucasian female child with febrile seizures, headache, parasomnias, and a delay of speech. The child underwent a magnetic resonance imaging to investigate these neurological signs, disclosing a Chiari malformation type 1. The polysomnography showed a mild-moderate sleep-disordered breathing, increased number of central sleep apneas, and generalized spike waves at sleep onset. Conclusions. Seizures have been seldom described in CM1 patients. The main reasons for performing MRI in this case were frequent seizures, a delay of speech, and headache, leading to an unexpected diagnosis of CM1. Polysomnography detected a discrete SDB

Migrating focal seizures and myoclonic status in ARV1-related encephalopathy

Objective: To report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters. Methods: Clinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology. Results: Since their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum. Conclusions: This report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS

A registry for Dravet syndrome: The Italian experience

Objectives: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. / Methods: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. / Results: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0–9) while at last follow-up was 11 years (IQR 5–18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). / Significance: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes

Nuove strategie per diagnosticare e delineare la storia naturale nelle encefalopatie dello sviluppo ed epilettiche: modelli applicati alla Sindrome di Dravet.

Le encefalopatie dello sviluppo ed epilettiche (ESE) sono condizioni caratterizzate da ritardo dello sviluppo e fasi di plateau/regressione cognitiva indotte dall’attività epilettica. Il trattamento mira al controllo delle crisi ed ad una presa in carico riabilitativa appropriata. La diagnosi precoce e la definizione della storia naturale rappresentano fattori cruciali per mettere in atto trattamenti mirati ed individuare prontamente/prevenire le specifiche comorbidità. La Sindrome di Dravet (SD) è tra le più note ESE. L’esordio è nel primo anno di vita con crisi convulsive, cui seguono la comparsa di una epilessia farmacoresistente ed un deficit cognitivo. La diagnosi viene mediamente posta dopo i 2 anni. Questo ritardo è spesso dovuto alla difficoltà nel differenziare all’esordio la SD dalle convulsioni febbrili (CF), condizioni simili nella loro presentazione iniziale. La SD è una condizione di relativa recente descrizione. Solo negli ultimi anni stanno venendo alla luce le caratteristiche cliniche degli adulti affetti da Sindrome di Dravet, delle comorbidità associate, ed una miglior definizione dell’outcome a lungo termine. In questo progetto di ricerca, abbiamo esplorato l’utilizzo di nuove strategie per diagnosticare e delineare la storia naturale della SD, attraverso diversi approcci: i) Applicando il Natural Language Processing (NLP), una tecnologie che consiste nella processazione di informazioni scritte, ai referti medici digitali. I dati sono stati raccolti da un database ospedaliero. Attraverso l’Unified Medical Language System Meta-thesaurus, i concetti clinici sono stati riconosciuti e decodificati nei referti medici. Abbiamo selezionato due coorti: pazienti con SD e pazienti con CF. Attraverso una phenome-wide analisi, abbiamo analizzato la frequenza dei concetti presenti nei referti prodotti prima dei 2 anni, nelle due popolazioni. Abbiamo riscontrato una maggior rappresentazione di concetti legati alle caratteristiche tipiche della SD nei referti dei pazienti con SD, rispetto a quella con CF. In un secondo studio abbiamo applicato la stessa tecnica con l’obiettivo di ricostruire la storia naturale, confrontando i concetti presenti in tutti i referti dei pazienti con SD, con quelli di due popolazioni di controllo. I concetti risultati più presenti nei pazienti con SD, permettevano, attraverso l’analisi dell’età della loro comparsa, di ricostruire le caratteristiche fenotipiche longitudinali della SD. In conclusione, questi due studi dimostrano che i referti clinici di soggetti con SD contengono termini clinici che possono essere estrapolati “automaticamente” attraverso il NLP al fine di permettere una diagnosi precoce e la profilazione della storia naturale. ii) Attraverso la somministrazione di questionari ai caregiver, con il fine di esplorare quali aspetti relativi al benessere del proprio figlio, impattassero maggiormente sul pazienti, nelle diverse età. Gli ambiti relativi alla vita quotidiana hanno ottenuto punteggi più alti rispetto a quelli legati alle crisi epilettiche. La durata delle crisi e la necessità di un ricovero ospedaliero, assumono un impatto meno significativo con l’aumentare dell’età. iii) Attraverso l’analisi del profilo adattivo (PA) di adolescenti ed adulti con DS e l’esplorazione di eventuali correlazioni con la storia clinica. Abbiamo individuato due sottopopolazioni: una con PA 'peggiore' e una ‘migliore’, corrispondenti rispettivamente a individui che avevano presentato o meno crisi miocloniche o attività di tipo generalizzato all’ EEG. Questi studi delineano ulteriormente la storia naturale della DS. Gli approcci utilizzati potrebbero essere trasposti ad altre ESE, meno conosciute clinicamente, per accelerare il tempo della diagnosi e delinearne la storia naturale.Developmental and epileptic encephalopathies (DEEs) are a group of diseases characterized by developmental impairment and phases of plateauing/regression induced by epileptic activity. Treatment aims to reduce seizures and establish appropriate rehabilitation interventions. With the rising emerging potential for precision medicine, early diagnosis and acknowledgement of the natural history are crucial to put in place targeted treatments and promptly detect/prevent specific comorbidities. Dravet syndrome (DS) is a well-known type of DEE. Symptom onset is in the first year of life with convulsive seizures in otherwise typically developing infants. During childhood, drug-resistant epilepsy occurs together with developmental slowing, leading to cognitive impairment. Even if physician awareness of DS has improved in last decades, time to diagnosis is still over 2 year. Diagnosis is often delayed as it is difficult to differentiate at onset from Febrile Seizures (FS). These two conditions present substantial clinical differences, but might be overlapping at onset. The first description of DS is relatively recent. A few studies reporting clinical features of adults are emerging only the recent past. For these reasons, natural history and long-term outcome of DS are only partially known to date. In this research project we explored novel strategies for early diagnosing and understanding the natural history of DS, through different approaches. i) By using Natural Language Processing (NLP), a technology consisting in processing written information, in unstructured digital medical records. Data were collected from a document-based hospital data warehouse. Using Unified Medical Language System Meta-thesaurus, phenotype concepts could be recognized in medical reports. In a first study, we selected individuals with DS and individuals with Febrile Seizures (FS). A phenome-wide analysis was performed evaluating the statistical associations between the phenotypes of DS and FS, based on concepts found in the reports produced before 2 years. We found significative higher representation of concepts related to seizures’ phenotypes distinguishing DS from FS in the first phases. In a second study, we used the same technique to retrace the known natural history of DS, by comparing all reports of individual of DS Cohort with two control groups. This study showed that clinical concepts from reports of children with DS and their appearance during the clinical course (median age of appearance), follows the same outline as what is known in DS. We conclude that narrative medical reports of individuals with DS, contain specific clinical concept which can be automatically detected by software exploiting NLP, allowing an early diagnosis and the retracing of the natural history. ii) By addressing surveys to caregivers, to explore the domains that really matters for patients and their family at different ages. We found that items related to daily life had the highest compared to items about seizures. Increase of individuals’ age was associated with a less important impact of seizure duration and of the need of hospital referral. iii) By outlining the adaptive-behavior profile (ABP) of adolescents and adults with DS and exploring correlations with clinical history. We found two subpopulations: one with a ‘lower’ ABP and one with a ‘higher’ ABP, corresponding respectively to individuals in whom myoclonic seizures or generalized spike-and-wave activity were present or absent on EEG. These studies further delineate the natural history of DS and can help tailor patient-centered outcome measures in future clinical trials. These approaches could be transposed to other less known DEEs, to decrease time of diagnosis and outline the natural history

Chiari 1 Malformation in a Child with Febrile Seizures, Parasomnias, and Sleep Apnea Syndrome

Introduction. The type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to disturbances in cerebrospinal fluid circulation and to direct compression of nervous tissue. Case report. We describe a 4-year-old Caucasian female child with febrile seizures, headache, parasomnias, and a delay of speech. The child underwent a magnetic resonance imaging to investigate these neurological signs, disclosing a Chiari malformation type 1. The polysomnography showed a mild-moderate sleep-disordered breathing, increased number of central sleep apneas, and generalized spike waves at sleep onset. Conclusions. Seizures have been seldom described in CM1 patients. The main reasons for performing MRI in this case were frequent seizures, a delay of speech, and headache, leading to an unexpected diagnosis of CM1. Polysomnography detected a discrete SDB

Reversible tremor in an infant with vitamin E deficiency and cystic fibrosis

Infants with a history of persistent coughing, unwellness, and a tremor should raise suspicions of having cystic fibrosis—even if all newborn screening tests are negative

Non-convulsive febrile status epilepticus mimicking a postictal state after a febrile seizure: an ictal electroclinical and evolutive study

Objective. Febrile status epilepticus evolves from a febrile seizure (FS) in 5% of cases. Its prompt recognition is challenging, especially when motor manifestations are absent or subtle. We describe the ictal electroclinical features of non convulsive febrile status epilepticus (NCFSE) following an apparently concluded FS, initially misinterpreted as postictal obtundation and in some way mimicking the described "non-epileptic twilight state". Methods. We present an electroclinical study of 18 children, collected in our unit, who presented with NCFSE after an apparently resolved FS, longitudinally followed for one year to seven years and nine months (mean: four years and three months). The age at first NCFSE ranged between one year and two months and five years and eight months (mean: two years and six months). Patients were examined after spontaneous or rectal diazepam-induced resolution of a FS, while showing persisting impairment of awareness. Results. A lack of responsiveness to painful stimulation, abnormal posturing and aphasia were present in all cases, variably associated with perioral cyanosis, hypersalivation, automatisms, gaze deviation and other lateralizing signs; eyes were open. The EEG recording started 20 to 140 minutes after the apparent resolution of the FS and was invariably characterized by delta or theta-delta pseudorhythmic activity, mainly involving the fronto-temporal regions, with hemispheric predominance in two thirds of the cases. The electroclinical condition, lasting 25 to 210 minutes, quickly recovered after intravenous diazepam. Follow-up revealed normal neurodevelopment and EEG in almost all patients (learning disability emerged in three). In five subjects, NCSE relapsed (twice in two). None presented afebrile seizures. Significance. Our series highlights the electroclinical features of focal NCFSE. Distinctive elements are a lack of reactivity, cyanosis, lateralizing clinical and EEG signs, and resolution clearly tied to intravenous benzodiazepine administration

Refractory tonic-myoclonic status epilepticus with catamenial recurrence in epilepsy with myoclonic atonic seizures: A case report

In epilepsy with myoclonic-atonic seizures (EMA), status epilepticus (SE) may occur during the onset phase, uncommonly in post-puberal patients. We report a post-puberal patient with EMA who presented SE with insidious onset and catamenial recurrence.She had a stormy epilepsy onset at 4 years, with tonic seizures, atypical absences, and myoclonic-atonic seizures, in the absence of SE. After the onset phase, sporadic nocturnal tonic seizures persisted and a mild intellectual disability appeared. At the age of 7, after gonadotropin-releasing hormone analog administration due to central precocious puberty, she presented with SE characterized by recurrent atypical absences, tonic seizures, and awareness impairment, which was successfully treated in 4 days. At 11 years, one week before menstruation, the patient presented with analogous SE that lasted 8 days.One week before the subsequent menstruation, she presented again with SE, initially characterized by atypical absences alternating with phases of awareness and motor impairment related to fast low-voltage EEG activity in the central regions; later, tonic and myoclonic seizures occurring even in the awake state increased, and the “atonic-akinetic status” related to fast EEG activity worsened. After conventional antiepileptic drugs had failed to control the seizures, a progestin was added, with subsequent gradual complete recovery

SYNGAP1-related developmental and epileptic encephalopathy: The impact on daily life

SYNGAP1-developmental and epileptic encephalopathy (SYNGAP1-DEE) has been recently featured as a distinct genetic disease characterized by global psychomotor delay mainly involving language, moder-ate-to-severe cognitive impairment, autism spectrum disorder, and a generalized epilepsy with sponta-neous and reflex seizures. The severity and variability of function impairment and the impact on patients' and caregivers' daily life are still poorly acknowledged. The SYNGAP1 Italian Family Association developed a survey, shared online with caregivers, exploring several issues, including: epilepsy outcome, comorbidities, daily-living skills, hospitalizations, rehabilita-tion treatments, economic burden, and COVID-19 pandemic impact. Caregivers of 13 children and adolescents participated in the survey. They most often show a fine and gross-motor impairment and a drug-resistant epilepsy with possibility to experience pluridaily absence seizures that may lead to periods of psychomotor regressions. Eating and sleep problems are reported in the majority. Most parents are concerned about language impairment, behavioral issues and lack of autonomy in daily-living activities. Specific neuropsychological evaluations for autism should be early considered in order to identify intervention strategies involving alternative communication strategies, which can positively affect behavior and quality of life. Rehabilitation treatment should aim to the acquisition and consolidation of personal autonomy. (c) 2021 Elsevier Inc. All rights reserved