Epilepsy with migrating focal seizures

To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine. We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies. The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency. The majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients

How to distinguish seizures from non-epileptic manifestations

The first and most important step in establishing diagnosis of epilepsy consists of careful history taking from patients and witnesses. The clinical evaluation of the event will lead the indication for further diagnostic tests including e.g. EEG and MRI. Hence, identifying the paroxysmal event as epileptic or non-epileptic is the very first step in the diagnostic process. Paroxysmal events pose a clinical challenge, as these are unpredictable and do not usually occur in the doctor's office. History taking, hunting for witness reports and home-video recordings are the main tools to conclude whether a paroxysmal event is a seizure or not. In this review, we describe the most common differential diagnoses of epileptic seizures, including syncope, psychogenic non-epileptic seizures, as well as a variety of paroxysmal conditions and behaviours of all age groups. Misdiagnosis of non-epileptic events as epilepsy may not only defer the correct diagnosis and treatment but also poses additional risk by prescribing antiepileptic drugs unnecessarily. Moreover, missing the diagnosis of epilepsy implies risk of additional seizures and therefore possibly injuries, sudden death in people with epilepsy, or status epilepticus. Studies have shown that patient and witness accounts are unreliable in a high percentage of cases. Therefore, the core competency of doctors and medical professionals assessing paroxysmal events is knowledge of the clinical features that help define the different aetiologies, thus empowering them to establish the most accurate appraisal of an event. [Published with video sequences]

Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis?

Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis

Analysis of exotic squirrel trade and detection of human infections with variegated squirrel bornavirus 1, Germany, 2005 to 2018

Following the discovery in 2015 of the variegated squirrel bornavirus 1 (VSBV-1) in fatal encephalitis cases among exotic squirrel breeders and a zoo animal caretaker in Germany, a case definition was developed. It was employed during trace-back animal trade investigations and sero-epidemiological studies among breeders and zoo animal caretakers of holdings with VSBV-1 infected squirrels. During the investigation, two possible human cases who had died of encephalitis were identified retrospectively among the squirrel breeders. Moreover, one probable human case was detected among the breeders who had a positive memory T-cell response to VSBV-1 antigen and antibodies against VSBV-1. The low rate of seropositivity found among living persons in risk groups that handle exotic squirrels privately or at zoos may reflect rareness of exposure to VSBV-1 during animal contact, a high lethality of infection or a combination of these factors. As a precaution against human exposure, testing of exotic squirrels for VSBV-1 infection and/or avoiding direct contact with exotic squirrels in zoos and private holdings is strongly advised.Peer Reviewe

West Nile Virus Epidemic in Germany Triggered by Epizootic Emergence, 2019

One year after the first autochthonous transmission of West Nile virus (WNV) to birds and horses in Germany, an epizootic emergence of WNV was again observed in 2019. The number of infected birds and horses was considerably higher compared to 2018 (12 birds, two horses), resulting in the observation of the first WNV epidemy in Germany: 76 cases in birds, 36 in horses and five confirmed mosquito-borne, autochthonous human cases. We demonstrated that Germany experienced several WNV introduction events and that strains of a distinct group (Eastern German WNV clade), which was introduced to Germany as a single introduction event, dominated mosquito, birds, horse and human-related virus variants in 2018 and 2019. Virus strains in this clade are characterized by a specific-Lys2114Arg mutation, which might lead to an increase in viral fitness. Extraordinary high temperatures in 2018/2019 allowed a low extrinsic incubation period (EIP), which drove the epizootic emergence and, in the end, most likely triggered the 2019 epidemic. Spatiotemporal EIP values correlated with the geographical WNV incidence. This study highlights the risk of a further spread in Germany in the next years with additional human WNV infections. Thus, surveillance of birds is essential to provide an early epidemic warning and thus, initiate targeted control measures.Peer Reviewe

Functional cortico-subcortical reorganization after complete hemispheric disconnection for intractable epilepsy

Hemispherotomy is a treatment for drug-resistant epilepsy with the whole hemisphere involved in seizure onset. As recovery mechanisms are still debated, we characterize functional reorganization with multimodal MRI in two children operated on the right hemisphere (RH). We found that interhemispheric functional connectivity was abolished in both patients. The healthy left hemispheres (LH) displayed focal hyperperfusion in motor and limbic areas, and preserved network-level organization. The disconnected RHs were hypoperfused despite sustained network-level organization. Functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. The classification probability of the RH corresponding to a minimally conscious state was smaller than for the LH. We conclude that after hemispherotomy, neurological rehabilitation is sustained by cortical disinhibition and reinforcement of connectivity driven by subcortical structures in the remaining hemisphere. Our results highlight the effect of vascularization on functional connectivity and raise inquiries about the conscious state of the isolated hemisphere

Epilepsy in young Tsc1+/− mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex

International audienceObjective - To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). Methods - Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. Results - Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. Significance - Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy

Abnormal Spontaneous Blood Oxygenation Level Dependent Fluctuations in Children with Focal Cortical Dysplasias:Initial findings in surgically confirmed cases

Background  Focal cortical dysplasias (FCD) are a frequent cause of drug-resistant epilepsy in children but are often undetected on structural magnetic resonance imaging (MRI). We aimed to measure and validate the variation of resting state functional MRI (rs-fMRI) blood oxygenation level dependent (BOLD) metrics in surgically proven FCDs in children, to assess the potential yield for detecting and understanding these lesions. Methods  We prospectively included pediatric patients with surgically proven FCD with inconclusive structural MRI and healthy controls, who underwent a ten-minute rs-fMRI acquired at 3T. Rs-fMRI data was pre-processed and maps of values of regional homogeneity (ReHo), degree centrality (DC), amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) were calculated. The variations of BOLD metrics within the to-be-resected areas were analyzed visually, and quantitatively using lateralization indices. BOLD metrics variations were also analyzed in fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolic areas. Results  We included 7 patients (range: 3-15 years) and 6 aged-matched controls (range: 6-17 years). ReHo lateralization indices were positive in the to-be-resected areas in 4/7 patients, and in 6/7 patients in the additional PET hypometabolic areas. These indices were significantly higher compared to controls in 3/7 and 4/7 patients, respectively. Visual analysis revealed a good spatial correlation between high ReHo areas and MRI structural abnormalities (when present) or PET hypometabolic areas. No consistent variation was seen using DC, ALFF, or fALFF. Conclusion  Resting-state fMRI metrics, noticeably increase in ReHo, may have potential to help detect MRI-negative FCDs in combination with other morphological and functional techniques, used in clinical practice and epilepsy-surgery screening.</p

Complete hemispherotomy leads to lateralized functional organization and lower level of consciousness in the isolated hemisphere

International audienceObjectiveTo quantify whole-brain functional organization after complete hemispherotomy, characterizing unexplored plasticity pathways and the conscious level of the dissected hemispheres.MethodsEvaluation with multimodal magnetic resonance imaging in two pediatric patients undergoing right hemispherotomy including complete callosotomy with a perithalamic section. Regional cerebral blood flow and fMRI network connectivity assessed the functional integrity of both hemispheres after surgery. The level of consciousness was tested by means of a support vector machine classifier which compared the intrinsic organization of the dissected hemispheres with those of patients suffering from disorders of consciousness.ResultsAfter hemispherotomy, both patients showed typical daily functionality. We found no interhemispheric transfer of functional connectivity in either patient as predicted by the operation. The healthy left hemispheres displayed focal blood hyperperfusion in motor and limbic areas, with preserved network-level organization. Unexpectedly, the disconnected right hemispheres showed sustained network organization despite low regional cerebral blood flow. Subcortically, functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. One patient further showed unusual ipsilateral right cerebello-cortical connectivity, which was explained by the mediation of the vascular system. The healthy left hemisphere had higher probability to be classified as in a minimally conscious state compared to the isolated right hemisphere.SignificanceComplete hemispherotomy leads to a lateralized whole-brain organization, with the remaining hemisphere claiming most of the brain's energetic reserves supported by subcortical structures. Our results further underline the contribution of nonneuronal vascular signals on contralateral connectivity, shedding light on the nature of network organization in the isolated tissue. The disconnected hemisphere is characterized by a level of consciousness which is necessary but insufficient for conscious processing, paving the way for more specific inquiries about its role in awareness in the absence of behavioral output.Key PointComplete hemispherotomies are rare operations permitting the evaluation of functional processing in both hemispheres as compared to other surgical proceduresAfter hemispherotomy, no interhemispheric transfer was identified in two pediatric patients evaluated with multimodal MRICortical connectivity was lateralized, with preserved network organization in the defected right hemisphere despite hypoperfusionThalamo-cortical and cerebello-cortical connectivity was preserved in the healthy hemispheres; intercerebellar connectivity was unaffectedThe defected right hemisphere resembled less the conscious capacities of patients in minimally conscious stat

Occupation-Associated Fatal Limbic Encephalitis Caused by Variegated Squirrel Bornavirus 1, Germany, 2013

Limbic encephalitis is commonly regarded as an autoimmune-mediated disease. However, after the recent detection of zoonotic variegated squirrel bornavirus 1 in a Prevost’s squirrel (Callosciurus prevostii) in a zoo in northern Germany, we retrospectively investigated a fatal case in an autoantibody-seronegative animal caretaker who had worked at that zoo. The virus had been discovered in 2015 as the cause of a cluster of cases of fatal encephalitis among breeders of variegated squirrels (Sciurus variegatoides) in eastern Germany. Molecular assays and immunohistochemistry detected a limbic distribution of the virus in brain tissue of the animal caretaker. Phylogenetic analyses demonstrated a spillover infection from the Prevost’s squirrel. Antibodies against bornaviruses were detected in the patient’s cerebrospinal fluid by immunofluorescence and newly developed ELISAs and immunoblot. The putative antigenic epitope was identified on the viral nucleoprotein. Other zoo workers were not infected; however, avoidance of direct contact with exotic squirrels and screening of squirrels are recommended