Drug-resistant generalized epilepsies: Revisiting the frontiers of idiopathic generalized epilepsies.

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities.

Tuberous sclerosis complex and epilepsy in infancy: prevention and early diagnosis.

Numerous studies showed that epilepsy represents a high burden in Tuberous Sclerosis Complex (TSC), affecting 63 to 78% of the patients. Epilepsy will be refractory to medication in over 60% of cases in early presentations, and accompanied by intellectual disabilities and/or autism spectrum disorders. The emerging experimental and clinical data suggest that the molecular and cellular changes triggered by seizures, particularly during the first weeks of life, can be limited by early action. Making any effort to avoid or delay epilepsy onset is a promising pathway to improve global outcome for TSC patients, although it is not possible to tidy up the specific roles of seizures, interictal abnormalities, and cortical abnormalities upon neurodevelopment. Early diagnosis of epilepsy can be made during a "symptomatic phase," shortly after the onset of seizures (focal seizures or spasms), revealing the TSC in a young infant. As soon as the diagnosis is made, a treatment with Vigabatrin is now recommended. The diagnosis of epilepsy can also be performed during a "presymptomatic phase", with the improvement of fetal and neonatal diagnosis of TSC. Recent studies demonstrated a significant delay of more than 3 months between the detection of EEG abnormalities and the first clinical seizures, which allows to consider a preventive treatment. Beside vigabatrin, mTOR inhibitors may have a place in this early management. The last recommendations about early detection and treatment of epilepsy in TSC will be detailed in this review. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[Is there a bridge between migraine and familial mesial temporal lobe epilepsy?]. / Migraines et épilepsies temporales mésiales familiales : quel est le lien ?

Numerous reviews have emphasized the links between certain types of epilepsy and migraine. Historically, Gowers was one of the first, in 1907, to have drawn attention to a possible relationship between migraine headache and epilepsy in a period when no additional examination was available. In the last two decades, progress in molecular biology, electrophysiology, and neuro-imaging has enabled a better approach to the fundamental elements underlying the interrelationship between these two nosological domains. During this same time, a new term "channelopathy" has appeared in the literature. This term groups together affections involving a dysfunction of ion channels. In this article, the links between the different types of migraine and familial mesial temporal lobe epilepsy are illustrated by two case reports. This association does not appear to occur at random but would undoubtedly depend on a common genetic substratum, leading to a direct comorbidity. These occasional recurring symptoms would lie within the framework of a more general concept of "Primary Brain Channelopathies".

[Refractory partial epilepsy: what are the neuropediatrician's criteria for drug resistance?]. / Les épilepsies partielles pharmaco-résistantes. Quels sont les critères de pharmaco-résistance pour le neuropédiatre?

Despite the emergence of new antiepileptic drugs, 10 to 20% of children with epilepsy, half of whom have localization-related epilepsy, remain refractory to drug treatment. Careful syndromic identification is essential before retaining the diagnosis of intractable childhood epilepsy in order to optimize treatment and avoid iatrogenic worsening. The use of appropriate associations of new antiepileptic drugs should lead to better control in some situations, but further studies are still necessary. A significant number of children with medically intractable localization-related epilepsy may benefit from surgical treatment. Because of the cognitive consequences of epilepsy in children, the question of the appropriate time for surgery is still debated; the current trend is for early surgery in children. For many authors, intractability can be assessed after 18 months of evolution, and retained when seizures persist at a frequency of one or more a month despite more than two correctly administered antiepileptic drugs. In case of epileptogenic encephalopathy, time to surgery may be shorter. Early predictive criteria of intractability have been identified by several cohort studies and include the presence of frequent seizures at disease onset, status epilepticus, with the prevalence of certain etiologies such as encephalitis or neuronal migration disorders. Conversely, some children may develop late intractability after an early benign course; the identification or early predictive criteria is still unclear in this situation.

Two cousins with partial trisomy 12q and monosomy 12p recombinants of a familial pericentric inversion of the chromosome 12.

Partial trisomy 12q and monosomy 12p lead to multiple malformation syndromes. Instead of trisomy 12q that has been reported as a clinically identifiable syndrome, monosomy 12p is characterized by a wide phenotypic spectrum. We report two cousins suffering from severe mental retardation, seizures, and dysmorphic features related to a trisomy 12q24.3-->qter and a monosomy 12p13-->pter resulting from a familial pericentric inversion of chromosome 12. In an attempt to improve the clinical delineation of these two syndromes, we compared our two patients with previous reports of these aneusomies. This review emphasizes the high frequency of familial translocations, including a breakpoint at 12q24 involved in trisomy 12q whereas monosomy 12p occurs most frequently de novo. Despite the poor specificity of the signs, this comparison allowed us to determine the clinical features present in more than 20% of patients with trisomy 12q or monosomy 12p. We particularly emphasize some consistent leading features of monosomy 12p, including microcephaly, dental, cardio-vascular, extremity, and sensorial abnormalities, initially not reported as recurrent in this syndrome.

[Focal cortical dysplasia possibly related to a probable prenatal ischemic injury]. / Dysplasie corticale focale liée à un probable accident ischémique anténatal.

Focal cortical dysplasias are a frequent etiology of partial seizure disorders refractory to medical treatment. We report the case of a patient with focal cortical dysplasia, confirmed by surgery, in association with ischemic cerebral lesions that possibly occurred during the intra-uterine development. This observation reinforces the hypothesis of a possible factor of causality between prenatal ischemia and anomalies of cortical development.

An unusual human mosaic for skin pigmentation.

Patterned pigmentary disturbances are seen in a large variety of human genetic disorders. Cytogenetic studies have provided evidence that such skin lesions often reflect chromosomal mosaicism. In addition to the well-known pattern of Blaschko's lines a classification of several distinct types was proposed by Happle. This report add the case of a boy with an unusual mosaic-like distribution of skin pigmentation and a further chromosomal anomaly which has not been described in pigmentary mosaicism previously. The proband was born after an uneventful pregnancy and delivery. Developmental milestones were delayed. A generalised hirsutism was noted with a facial dysmorphia: coarse facies. short philtrum, synophris, and large low set years. Hyperpigmentation followed a checkerboard pattern: alternating squares of pigmentary anomalies with a sharp midline separation. Cytogenetic findings Included a normal karyotype (peripheral blood) and a mosaicism 12q;14q translocation (70% of fibroblasts). The present case stresses the importance of careful chromosomal analysis of different tissues in patients with pigmentary anomalies.

Pallister-Hall syndrome with stenosis of the cricoid cartilage and microphallus without hypopituitarism.

The Pallister-Hall syndrome is characterised by a spectrum of anomalies including congenital hypothalamic "hamartoblastoma" hypopituitarism, imperforate anus, polydactyly and various visceral anomalies. Rare familial cases with an autosomal dominant inheritance pattern with variable expressivity have been reported. Cases of more mildly affected individuals with Pallister-Hall syndrome have been described, including cases of asymptomatic individuals. We report a case of Pallister-Hall syndrome with microphallus and without growth hormone deficiency that has been followed successfully for two years. The patient presented postaxial polydactyly of hands, dysplasic nails, imperforate anus, small penis, scrotum bifidum with very thin urethra, bifid epiglottis and a bilateral simian crease. There was vesico-ureteral-reflux, insertional hexadactyly of the left hand and two Y shaped metacarpal with six fingers at the right hand. Brain MR imaging revealed a large sellar and suprasellar mass. A perineal anorectoplasty and a vesicostomy were performed. Laryngeal dyspnea appeared when he was 13 months old. Bronchoscopy revealed anterior synechia of vocal cords with cricoidian stenosis. A tracheostomy was performed. Mental development was normal. No mutation of the zinc finger transcription factor gene, GLI 3 was detected.

EEG criteria predictive of complicated evolution in idiopathic rolandic epilepsy.

BACKGROUND: Although so-called "benign" epilepsy with centrotemporal spikes (BECTS) always has an excellent prognosis with regard to seizure remission, behavioral problems and cognitive dysfunctions may sometimes develop in its course. To search for clinical or EEG markers allowing early detection of patients prone to such complications, the authors conducted a prospective study in a cohort of unselected patients with BECTS. METHODS: In 35 children with BECTS, academic, familial, neurologic, neuropsychological, and wake and sleep EEG evaluations were repeated every 6 to 12 months from the beginning of the seizure disorder up to complete recovery. RESULTS: In 25 of 35 patients (72%), behavioral and intellectual functioning remained unimpaired. In 10 of 35 patients (28%), educational performance and familial maladjustment occurred. These sociofamilial problems were correlated with impulsivity, learning difficulties, attention disorders, and minor (7/35 cases, 20%) or serious (3/35 cases, 8%) auditory-verbal or visual-spatial deficits. Worsening phases started 2 to 36 months after onset and persisted for 9 to 39 months. Occurrence of atypical evolutions was significantly correlated with five qualitative and one quantitative interictal EEG pattern: intermittent slow-wave focus, multiple asynchronous spike-wave foci, long spike-wave clusters, generalized 3-c/s "absence-like" spike-wave discharges, conjunction of interictal paroxysms with negative or positive myoclonia, and abundance of interictal abnormalities during wakefulness and sleep. Clinical deterioration was not linked with seizure characteristics or treatment. CONCLUSION: Different combinations of at least three of six distinctive interictal EEG patterns and their long-lasting (> or =6-month) persistence seem to be the hallmarks of patients with BECTS at risk for neuropsychological impairments.

Congenital mitochondrial cytopathy and chronic progressive external ophthalmoplegia.

BACKGROUND: Chronic Progressive External Ophthalmoplegia (CPEO) encompasses different conditions having in common a slowly progressive external and general ophthalmoplegia. The discovery of CPEO is suggestive of mitochondrial cytopathy, but this is not necessarily so. CASE REPORT: We report here a case, presenting at age 9 months, characterized by bilateral blepharoptosis and partial third nerve oculomotor deficiency, with no nystagmus. Mitochondrial cytopathy was suspected on cranial MRI and confirmed by muscle biopsy. Enzyme studies revealed a defect on the complex I respiratory chain. This case is unique in that the symptoms completely resolved under a Ketogen diet.

New insights into the clinical management of partial epilepsies.

The diagnosis, treatment, and prognosis of seizure disorders depend on the correct identification of epileptic syndromes. Partial epilepsies are heterogeneous and can be divided into idiopathic, cryptogenic, and symptomatic epilepsies. The most common of the idiopathic localization-related epilepsies is benign epilepsy with rolandic or centrotemporal spikes (BECTS). Seizures remain rare and the use of antiepileptic drug (AED) treatment in all patients does not appear justified. Children who present with some of the electroclinical characteristics of BECTS may also display severe unusual neurologic, neuropsychological, or atypical symptoms. In some cases, carbamazepine has been implicated as a triggering factor. Primary reading epilepsy and idiopathic occipital lobe epilepsies with photosensitivity are examples of an overlap between idiopathic localization-related and generalized epilepsies and respond well to sodium valproate. Autosomal dominant nocturnal frontal lobe epilepsy and benign familial infantile convulsions are recently described syndromes, differing in several ways from classical idiopathic localization-related epileptic syndromes. In cryptogenic or symptomatic epilepsy, the topography of the epileptogenic zone might influence drug efficacy. An individualized approach to AED selection, tailored to each patient's needs, should be used. Resistance of seizures to antiepileptic therapy may be due to diagnostic and/or treatment error or may be the result of noncompliance. Increasing the dosage, discontinuation or replacement of a drug, or addition of a second drug is indicated in truly resistant cases. The use of more than two AEDs rarely optimizes seizure control, and in some cases reduction of treatment may improve seizure control while lessening side effects. EEG-video assessment of patients with refractory epilepsy is important. Indications for and timing of epilepsy surgery should be reconsidered. Surgical therapy should probably be used more often and earlier than it is at present.

Landau-Kleffner syndrome: sleep EEG characteristics at onset.

OBJECTIVES: Landau-Kleffner syndrome (LKS) and benign epilepsy with centro-temporal spikes (BECTS) are two forms of non-lesional age-related focal epilepsies. LKS is a severe disease, affecting language abilities, attention and behavior, and evolving to acquired global aphasia. As LKS is usually readily responsive to an adequate pharmacological management, an early diagnosis of children at risk for this syndrome is essential. BECTS is characterized by the absence of neurological or neuropsychological deficits throughout the course of epilepsy. However, children initially presenting some clinical and EEG features suggesting BECTS may develop severe cognitive impairments during the course of epilepsy. These cases raise the question of whether LKS and BECTS delineate fundamentally different conditions, or represent subclasses of a broad continuum. METHODS: We compared sleep EEG characteristics of 7 children with typical LKS to those of 6 children with classical BECTS. RESULTS: Morphology, topography, organization, and abundance of interictal abnormalities during sleep differentiated these two syndromes from epilepsy onset, before the occurrence of aphasic deficits in LKS. The specific sleep EEG patterns possibly predictive of LKS were (1) unilateral slow wave foci, (2) bilateral independent spike-and-wave discharges, and (3) major activation of spike-and-wave discharges during sleep, exceeding 40% (40-90%) of the first sleep cycle and 30% (30-80%) of the following cycles. CONCLUSIONS: These data support the hypothesis that during LKS evolution, language networks involved in the spread of abundant idiopathic interictal abnormalities (and mainly slow waves) may be progressively inhibited and become unable to carry out their normal physiological role.