Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

Childhood neurodegeneration associated with a specific UBTF variant: a new case report and review of the literature.

BACKGROUND: A new monogenic neurodegenerative disease affecting ribosomal metabolism has recently been identified in association with a monoallelic UBTF putative gain of function variant (NM_001076683.1:c.628G>A, hg19). Phenotype is consistent among these probands with progressive motor, cognitive, and behavioural regression in early to middle childhood. CASE PRESENTATION: We report on a child with this monoallelic UBTF variant who presented with progressive disease including regression, episodes of subacute deterioration during febrile illnesses and a remarkable EEG pattern with a transient pattern of semi-periodic slow waves. CONCLUSIONS: This case further supports the phenotype-genotype correlation of neurodegeneration associated with UBTF c.628G>A. Moreover, it brings new insights into the clinical features and EEG that could possibly serve as diagnostic markers of this otherwise nonspecific phenotype.

Midazolam as a first-line treatment for neonatal seizures: Retrospective study.

Midazolam is commonly used to treat refractory seizures in newborns and as a first-line anti-epileptic drug in children. Its use as first-line treatment of neonatal seizures has not been investigated so far. We retrospectively studied the tolerability of midazolam in 72 newborn infants who received i.v. or i.n. midazolam as first-line treatment for seizures. No major side-effect exclusively due to midazolam was reported. The i.n. route was used for 20 patients (27.8%). Effectiveness could not be formally evaluated due to the absence of systematic electroencephalogram recording while midazolam was administered. In conclusion, midazolam was well-tolerated as a first-line abortive emergency treatment of neonatal seizure. The i.n. route offers a useful alternative to i.v. phenobarbital or phenytoin in emergency settings.

[Pediatrics - New classification of seizures and epilepsies]. / Pédiatrie. Nouvelle classification des crises épileptiques et des épilepsies.

The International League Against Epilepsy published a new classification of epileptic seizures and epilepsies. It is more transparent and important notions like etiologies and comorbities have been added. The identification of seizures, epilepsies then epilepsy syndromes constitutes the three steps of this classification.

En 2017, la Ligue internationale contre l'épilepsie a publié une nouvelle classification des crises épileptiques et des épilepsies. Elle est devenue plus accessible et des notions comme les étiologies et les comorbidités ont été introduites.

Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.

The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.

Instruction manual for the ILAE 2017 operational classification of seizure types.

This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.

Lamotrigine can be beneficial in patients with Dravet syndrome.

Dravet syndrome, a severe infantile epilepsy syndrome, is typically resistant to anti-epileptic drugs (AED). Lamotrigine (LTG), an AED that is effective for both focal and generalized seizures, has been reported to aggravate seizures in Dravet syndrome. Therefore, LTG is usually avoided in Dravet syndrome. We describe two adults and a child with Dravet syndrome in whom LTG resulted in decreased seizure duration and frequency. This benefit was highlighted in each patient when LTG was withdrawn after 6 to 15 years, and resulted in an increased frequency of convulsive seizures together with longer seizure duration. A 25-year-old male required hospital admission for frequent seizures for the first time in 7 years, 6 weeks after ceasing LTG. Reintroduction of LTG improved seizure control, suggesting that in some patients with Dravet syndrome, LTG may be beneficial.

[Genetics of childhood epilepsies: for who? how? why?]. / Pédiatrie 2. Génétique des épilepsies de l'enfant: Pour qui ? Comment? Pourquoi?

Recent advances in genetics led to significant improvement in the field of childhood epilepsies diagnosis and physiopathology. Genetic testing is indicated by geneticist who is himself guided by the pediatric neurological approach. In rare circumstance, genetic etiology affects the clinical management. Cost remains the main limitation. Those new genetic tools are the first step toward a better understanding of seizure mechanism and therefore more efficient treatments.

Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase.

Encephalitis is a rare and potentially fatal manifestation of herpes simplex type 1 infection. Following genome-wide genetic analyses, we identified a previously uncharacterized and very rare heterozygous variant in the E3 ubiquitin ligase WWP2, in a 14-month-old girl with herpes simplex encephalitis. The p.R841H variant (NM_007014.4:c.2522G > A) impaired TLR3 mediated signaling in inducible pluripotent stem cells-derived neural precursor cells and neurons; cells bearing this mutation were also more susceptible to HSV-1 infection compared to control cells. The p.R841H variant increased TRIF ubiquitination in vitro. Antiviral immunity was rescued following the correction of p.R841H by CRISPR-Cas9 technology. Moreover, the introduction of p.R841H in wild type cells reduced such immunity, suggesting that this mutation is linked to the observed phenotypes.

Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring.

Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug-resistant epilepsy, including electric source and nuclear imaging. Left operculo-insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years.

Precision or narrative medicine? Child neurology needs both!

Precision medicine aims to understand the mechanisms of diseases and to find treatments adapted to each individual or group of patients, on the basis of biological characteristics and environment. It uses new tools based on digital technologies. Narrative medicine was theorized, in the 2000s, as a reaction to the increasing technicality and the notion of a lack of human relations in care: It focuses on recognizing the essential place of the patient's experience of illness and life history in the diagnosis and management of diseases as well as in the training of caregivers. These two opposite currents are rarely considered together. In fact, they have in common the basic principle that each patient is unique, and both are often more closely intertwined than we think, especially in the field of child neurology. Five case histories and discussions presented here aim to demonstrate that combining the precision approach with the narrative approach can improve the diagnosis, treatment, classification, and understanding of neurological conditions, as well as enhance the dialog with families and make teaching more meaningful. Not only rare diseases but common problems, such as paroxysmal events, pain, epilepsy, intellectual disability, and autism spectrum disorder, are addressed from both perspectives.

Central quadrantotomy for intractable childhood epilepsy: operative technique and functional neuroanatomy.

Refractory subhemispheric epilepsy has been traditionally treated by resection. The last few decades have seen the emergence of disconnective techniques, for both hemispheric and subhemispheric disease. The aim of this study was to describe the technique for a disconnective surgery for large epileptogenic lesions involving the central (perirolandic cortices), parietal, and occipital lobes. This junctional cortex within the hemisphere (in contrast to anterior and posterior quadrantotomies) presents unique challenges when contemplating a complete disconnection of the region. The surgical technique is achieved through six distinct steps: fronto-central, inferior frontoparietal, lateral temporo-occipital, medial frontal, basal temporo-occipital, and posterior parasagittal callosal disconnections. The functional neuroanatomy of each step is described, along with cadaveric dissections. The authors describe this technique and include a case description of a young girl who presented with childhood-onset intractable epilepsy associated with cognitive stagnation. The postoperative seizure outcome in this patient remains excellent at 2 years' follow-up, with gains in cognition and behavior. Excellent seizure outcomes can be achieved if the network encompassing the entire epileptogenic cortex is disconnected while ensuring preservation of fiber systems that link functionally eloquent uninvolved cortices adjacent to the central quadrant.

Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep.

PURPOSE: To present the long-term follow-up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike-waves during slow wave sleep (CSWS). METHODS: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. KEY FINDINGS: After a mean duration of follow-up of 15.6 years (range, 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long-term outcome correlated best with duration of CSWS. SIGNIFICANCE: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

[Therapeutic advances in refractory epilepsies in children]. / Avancées thérapeutiques dans les epilepsies réfractaires de l'enfant.

Epilepsy concerns several thousands of children in Switzerland, and is refractory to classic antiepileptic drugs in an important proportion of cases. This percentage has remained stable, despite a constant production of new antiepileptic molecules. To alleviate this problem, several alternative approaches have been developed these last years. In this article, we present three children who suffer from different forms of pharmacoresistant epilepsy, managed with immunomodulatory or neurosurgical treatments, and we summarize the current knowledge about these therapeutic options.