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.

Pathways to epilepsy surgery in children with tuberous sclerosis complex-associated epilepsy.

BACKGROUND: Previous studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex. METHODS: We identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected. RESULTS: Forty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery. CONCLUSION: Despite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

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".

Bilateral focal polymicrogyria in Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a heterogeneous group of generalized connective tissue disorders that has been described in association with epilepsy and cerebral cortical dysplasia, mostly gray matter heterotopias, in 3 reports. However, to our knowledge, association of EDS with another type of cortical cerebral dysplasia, bilateral focal polymicrogyria, has never previously been described. SETTING: Two research-oriented hospitals. PATIENTS: We describe 2 patients with EDS and bilateral polymicrogyria. The first, a 29-year-old black man, presented with EDS of unspecified type, seizures, and bilateral frontocentral and frontoposterior polymicrogyria with hypoplasia of the inferior part of the cerebellar vermis. The second, a 20-year-old woman, had type III EDS, seizures and congenital bilateral perisylvian syndrome with polymicrogyria. CONCLUSIONS: The association of bilateral focal polymicrogyria and EDS in these 2 patients suggests that extracellular matrix proteins implicated in the pathogenesis of EDS, such as collagen and tenascin, may play an important role in cerebral cortical formation and organization. In a clinical setting, the association of EDS with these cortical structural lesions has implications for diagnosis and management.

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.

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.

Isotope tracer-techniques in rolandic epilepsy and its variants.

For ethical and practical reasons there are few studies on brain metabolism in rolandic epilepsy and it's variants. Most studies are performed in Landau-Kleffner syndrome or epilepsy with continuous spikes and waves during slow wave sleep (CSWS) which are considered to be included within the spectrum of rolandic epilepsy. The results of studies using isotope tracer-techniques in rolandic epilepsy and its variants are summarized.

Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: a video-EEG-controlled, open study.

PURPOSE: This prospective, open, video-EEG-controlled study examined the efficacy of lamotrigine (LTG) as add-on and monotherapy in idiopathic generalized epilepsy (IGE). METHODS: 47 patients received LTG either because of insufficient seizure control (n = 35) or serious side effects of prior antiepileptic drugs (AED). Long-term video-EEG recordings were performed before and after the introduction of LTG. The mean follow-up time was 25.5 months. RESULTS: Of 12 patients with refractory childhood absence epilepsy, 9 became seizure free; in one child with absences with eyelid myoclonia, absence frequency was reduced > 50%; in 2 children with absences with a mild atonic component, seizure reduction was only transient. Of 12 patients with juvenile absence epilepsy, 10 became seizure-free and, in 2, a > 50% reduction was obtained. In 15 patients with juvenile myoclonic epilepsy, complete seizure control was achieved in 7 patients, in 6 patients myoclonia persisted. In one patient generalized tonic-clonic seizures also persisted and another patient developed a rash, LTG was therefore stopped. Of 5 patients with grand-mal on awakening, 3 became seizure-free, and a reduction of > 50% was obtained in one patient; LTG was stopped in one patient because of poor compliance. Three patients with pure photosensitive epilepsy became seizure-free. At the end of the study, 11 patients were seizure-free on LTG monotherapy, and in most other patients concomitant AED dosage could be substantially reduced. CONCLUSIONS: Lamotrigine was effective and well tolerated in patients with various IGE syndromes, although differences were observed between individual syndromes and seizure types.

Twelve cases with hemihypertrophy: etiology and follow up.

Twelve patients with hemihypertrophy are described. All but one are sporadic cases. The parents were unrelated. Family and pregnancy histories are otherwise unremarkable in all cases. Diagnosis was always performed at birth or in the weeks following birth. There were 5 boys and 7 girls including one mother and her daughter. Hemihypertrophy was localized to the upper limb in one case and to the lower limb in one case. One patient had some features of Mc Cune Albright syndrome. Hemihypertrophy was associated with Silver-Russel syndrome in two patients. In all other cases hemihypertrophy was idiopathic. Mental and motor development were normal in all cases, as was puberty. During growth the body asymmetry was unchanged. Orthopedic problems complicated growth in some cases. The most obvious of these problems was scoliosis. Limb lengthening was necessary in 2 cases. One of our patients developed an abdominal tumor. One of our patients had two normal children. Hemihypertrophy is usually not inherited. However, the mother of one of our patients also had hemihypertrophy.

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.

[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.

[Benign familial neonatal convulsions: a model of idiopathic epilepsy]. / Les convulsions néonatales familiales bénignes: un modèle d'étude des épilepsies idiopathiques.

Benign neonatal familial convulsions have been recognized as a distinctive epileptic syndrome since 1964. This rare epileptic syndrome was classified in the category of idiopathic generalized epilepsies. Recently, mutations of potassium channel genes (KCNQ2, KCNQ3) were identified as responsible for this autosomic dominant epileptic syndrome. Generalized tonico-clonic seizures start at the second or third day after birth in children with no prenatal or perinatal pathological history. Interictal EEG is normal. This epilepsy is age-dependent: less than ten percent of children present seizures later in life. Despite their rarity, BNFC represent a useful model to understand the pathophysiology of idiopathic age dependant epilepsies.

[Diurnal and nocturnal paroxysmal dyskinesia in young children: a new entity?]. / Dyskinésie paroxystique diurne et nocturne du jeune enfant: une nouvelle entité?

Paroxysmal dyskinesias are intermittent attacks of involuntary hyperkinetics abnormal movements. Among paroxysmal dyskinesias were individualized three entities: paroxysmal kinesigenic choreoathetosis, paroxysmal choreoathetosis of Mount and Reback, hypnogenic paroxysmal dystonia. New classifications are based upon the circumstances of occurrence, the duration of attacks and their etiology. We report here two observations of idiopathic non familial paroxysmal dyskinesias in three-year-old children. Both were seen first in consultation for falls and nocturnal motor agitation. The attacks were paroxysmal jerky "puppet-like" movements lasting from 20 seconds to 15 minutes. They could occur during non REM sleep, during the day, at rest, after a sudden movement, or during prolonged exercise. Carbamazepine was inefficient. These cases were not classifiable according to the classical criteria and could constitute a new entity. Moreover, some sleep-EEG showed abnormal patterns (frontal rapid rhythms, central spikes in one case) and led us to discuss the pathophysiology of this episodic movements disorder, and its relation with frontal partial epilepsy.

[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.

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.

[Superior sagittal sinus thrombosis and nephrotic syndrome: favorable outcome with low molecular weight heparin]. / Thrombose du sinus longitudinal et syndrome néphrotique: évolution favorable sous héparine de faible poids moléculaire.

BACKGROUND: Nephrotic syndrome is known to be associated with thrombosis but rarely of cerebral vessels. CASE REPORT: A 3-year old child with steroid-dependent nephrotic syndrome was hospitalized for drowziness followed by a left hemiparesis. The CTscan showed a superior sagittal sinus thrombosis. The child completely recovered after treatment by low molecular weight heparin (LMWH). CONCLUSION: LMWH could be used for preventing and/or treating thrombosis associated with nephrotic syndrome. Nevertheless, controlled studies are necessary for assessing its efficacy and absence of risk in children.