Early arteriopathy in Aicardi-Goutières syndrome 5. Case report and review of literature.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive disease that mimics congenital viral infection and mainly affects the brain, immune system, and skin. The dominant clinical symptom is the subacute onset of severe encephalopathy, which manifests as irritability, loss of ability, slowing of head growth, and poor nutrition. Arteriopathy in AGS is an uncommon manifestation usually associated with mutations in the SAMHD1 gene. We present a rare case of a 3-year-old male due to failure to thrive, global developmental delay, microcephaly, poor vision, upper and lower limbs spasticity, and gastroesophageal reflux disease (GERD), who harbored early stenotic lesions of the large and medium intracranial arteries with ischemic sequelae in the early postnatal life. Performed genetic testing confirmed homozygous gene mutation, SAMHD1 associated with AGS type 5. By reviewing the available literature, we were able to find only one patient whose arterial lesions were diagnosed after 6 months.

Telemedicine for Individuals with epilepsy: Recommendations from the International League Against Epilepsy Telemedicine Task Force.

Worldwide, People with Epilepsy (PWE) are confronted with several barriers to face-to-face consultations. These obstacles hamper appropriate clinical follow-up and also increase the treatment gap for Epilepsy. Telemedicine holds the potential to enhance management as follow-up visits for PWE are focused on more on clinical history and counselling rather than physical examination. Besides consultation, telemedicine can also be used for remote EEG diagnostics and tele-neuropsychology assessments. In this article, the Telemedicine Task Force of the International League Against Epilepsy (ILAE) outlines recommendations regarding optimal practice in utilizing in the management of individuals with epilepsy. We formulated recommendations for minimum technical requirements, preparing for the first tele-consultation and the specificities for follow-up consultations. Special considerations are necessary for specific populations, including paediatric patients, patients who are not conversant with tele-medicine and those with intellectual disability. Telemedicine for individuals with epilepsy should be vigorously promoted with the aim of improving the quality of care and ultimately reduce the wide clinician access related treatment gap across several regions of the globe.

Childhood Absence Epilepsy Associated With Concomitant Centrotemporal Spikes.

Objectives The coexistence of generalized epileptiform discharges of 3Hz spike-and-wave complexes, which are the hallmark of childhood absence epilepsy (CAE), and centrotemporal spikes, which are characteristic of benign epilepsy with centrotemporal spikes (BECTs) in the same or subsequent EEGs appears to be very rare. Only a few published reports have shown a possible concomitance of CAE and BECTs electrographic changes. The study aimed to analyze electrographic and clinical features of patients with CAE who had concomitant or subsequent EEG features of BECTs. Method During a five-year analysis period (2014-2018), 277 children with BECTs and 93 children with CAE were diagnosed and treated at the pediatric neurology unit of Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. Nine patients were identified to have overlapping EEG findings of both epileptic syndromes. We then analyzed the nine children's clinical features, outcomes, and EEG findings in detail. Results The clinical onset of all our patients aged 5-14 years (six boys, three girls) was characterized by the absence of seizures, either typical (seven children) or atypical (two children). Six out of nine patients presented with concomitant electrographic features of both syndromes, whereas three patients experienced the EEG pattern of two syndromes at different times. All nine children were treated with valproate as the first-line medication, with reasonable seizure control. However, three patients required a second add-on medication. Despite good seizure control, six of our patients had poor school performance and five children had comorbid conditions such as ADHD and learning disability. Conclusion The coexistence of CAE and BECTS is described in the literature albeit rare. This overlap is mostly in electrographic features with or without the clinical features seen in both syndromes.

Stroke in sickle cell disease in association with bilateral absence of the internal carotid arteries. Case report.

BACKGROUND: Congenital absence of the internal carotid artery (ICA) is a highly infrequent congenital incidence and occurs in less than 0.01% of the population; bilateral absence is exceedingly rare, diagnosed below 10% of the unilateral absence of the ICA. Sickle cell disease (SCD) is a serious disorder and carries a high risk of stroke. CASE PRESENTATION: We present a five-year-old child with SCD who experienced an ischemic stroke episode with epileptic seizures. Neuroimaging revealed the agenesis of both ICAs. The frequency, embryology, and collateral pathway of the vascular anomaly as the clinical presentation, of this rare hematologic disease, are discussed. CONCLUSIONS: Sickle cell disease (SCD) carries a high risk of stroke. Congenital absence of ICA occurs in less than 0.01% of the population; bilateral absence is diagnosed below 10% of the unilateral absence of the ICA.

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

Clinical and genetic analysis of a family with two rare reflex epilepsies.

PURPOSE: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. METHOD: Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. RESULTS: The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. CONCLUSION: This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.

Adverse effects of antiepileptic drugs and quality of life in pediatric epilepsy.

BACKGROUND: In pediatric epilepsy, health-related quality of life (HRQOL) may be affected across the physical, psychological, social, and school domains. Studies have shown that antiepileptic drugs (AEDs) could have a significant negative impact on HRQOL, but these findings are scarce and inconsistent. AIM: To evaluate the influence that the adverse effects of AEDs have on HRQOL in pediatric epilepsy. MATERIALS AND METHODS: A total of 75 children with epilepsy and at least one parent participated in this study. The Pediatric Quality of Life Inventory (PedsQL) was utilized to assess the HRQOL, while the Adverse Event Profile (AEP) was used to assess the presence and severity of the adverse effects of AEDs. RESULTS: Assessing the children's ratings, the AEP score significantly influenced the PedsQL based psychosocial functioning score (P < 0.02; partial ç2 = 0.07); and, assessing the parents' ratings, the AEP score significantly influenced both the PedsQL based physical functioning score (P < 0.02; partial ç2 = 0.07) as well as the PedsQL psychosocial functioning score (P < 0.001, partial ç2 = 0.30). CONCLUSION: The frequency and severity of AED-related adverse effects could significantly predict the lowered levels of HRQOL among children with epilepsy, in particular having a large impact on their psychosocial functioning.

CHD2 variants are a risk factor for photosensitivity in epilepsy.

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Convulsions associated with gastroenteritis in the spectrum of benign focal epilepsies in infancy: 30 cases including four cases with ictal EEG recording.

Benign convulsions associated with gastroenteritis are now recognized as a clinical entity, characterized by an acute cluster of afebrile seizures during an episode of mild diarrhoea with excellent prognosis. We observed 30 children who each experienced at least two seizures associated with mild gastroenteritis. The inclusion criteria were: afebrile seizures during gastroenteritis, dehydration at ≤ 5%, normal neurological findings, normal psychomotor development and no underlying pathology according to laboratory and neuroimaging studies. Mean age was 21 months (range: 6-38). Familial history for epilepsy was positive in 3/30 (10%) and for febrile convulsions in 11/30 (36.6%). Seizure onset was mainly on the third day of gastroenteritis. Seizures were described as generalised by parents in 16/30 patients (53.3%). We directly observed seizures in 14/30 patients (47.7%), and the semiology was partial with secondary generalisation. Focal onset was confirmed in two patients by EEG and in two patients by video-EEG recording. Twenty of 30 patients (66.6%) received antiepileptic drugs during the acute phase. Ten patients (33.3%) received no treatment. During follow-up (mean duration: 53 months), one patient had an isolated afebrile seizure and two others a febrile seizure. At the end of follow-up, antiepileptic treatment was withdrawn for all but two patients. None developed epilepsy. Although the pathogenesis of this clinical entity is unknown, we hypothesize that mild gastroenteritis may provoke a transient brain dysfunction which in turn provokes seizures in children with genetically determined susceptibility.

Health-Related Quality of Life Measure for Children with Epilepsy (CHEQOL-25): preliminary data for the Serbian version.

The objectives of this study were to translate into Serbian the Health-Related Quality of Life Measure for Children with Epilepsy (CHEQOL-25) and to provide preliminary data on its measurement properties. Translation, cultural adaptation, and pretesting were performed first, followed by evaluation of several reliability aspects of this version administered to 50 children with epilepsy and their parents. The mean scores of the CHEQOL-25 subscales ranged from 12.2 to 14.4 for children and from 12.4 to 15 for parents (possible range: 5-20). The internal consistency coefficients of the subscales ranged from 0.11 to 0.87. Between the children's and parents' reports, there was a moderate level of agreement (0.43-0.57). It was concluded that the Serbian version is a feasible measure, all subscales except one demonstrate sufficient reliability, and a parent form could be used as a proxy measure.

Frontal-onset absences in children: associated with worse outcome? A replication study.

We studied the clinical and electroencephalographic features in 30 children who were diagnosed with childhood absence epilepsy. According to their EEG pattern we divided the 30 children into two groups: group A: 11 children with classical absences whose ictal EEG showed primary generalized spikes and waves and group B: 19 children with frontal onset of the EEG epileptic abnormalities ('frontal group'). In the frontal group, more frequently complex absences were seen. Although the majority of children responded very well to valproate monotherapy, ethosuximide has to be added in 3 children of the frontal group to achieve seizure freedom. In the frontal group, also more learning and behavioural problems were encountered. This study largely confirms a previous study of Lagae et al. [Lagae L, Pauwels J, Monte B, Verhelle J, Vervisch J. Frontal absences in children. Eur J Pediatr Neurol 2001;5:243-251]. It seems that frontal onset absences constitute a specific subtype within the childhood absence epilepsies.

Malignant migrating partial seizures in Aicardi syndrome.

This article reports on a female infant with Aicardi syndrome presenting with malignant migrating partial seizures from her first day of life. Initially, unilateral tonic seizures were seen with contralateral ictal electroencephalogram findings. Typically, these tonic seizures were accompanied by head and eye deviation and were followed by a tonic seizure on the other side of the body. At 6 months of age she developed epileptic spasms. She showed no motor development, did not respond to eye contact, and was nasogastric tube-fed. The epilepsy syndrome in this child is refractory to antiepileptic treatment and there is no psychomotor development. This case expands the phenotype of this catastrophic epileptic encephalopathy and suggests that the corpus callosum is not necessary for the 'migration' of partial seizures in this syndrome.

Epileptic encephalopathy with bilateral continuous spike-waves during slow sleep in a child with vacuolating megalencephalic leukoencephalopathy.

This case report describes the clinical evolution of a symptomatic epileptic encephalopathy with bilateral continuous spike-waves during slow wave sleep (BCSWS) in a 3-year-old girl. Her epilepsy with focal motor seizures during sleep was later complicated by myoclonic, atonic and clonic seizures culminating in BCSWS. The clinical picture, clinical course and magnetic resonance imaging findings were characterstic of primary white matter disease, probably, vacuolated megalencephalic leukoencephalopathy with subcortical cysts (MLC). To the best of our knowledge, this is the first reported case of BSCWS in a patient with leukodystrophies or MLC. This case report indicates that epileptic encephalopathy with BSCWS may be a cause of neurological or neuropsychological deterioration in MLC.

Verbal memory impairment in children with focal epilepsy.

Findings of both material- and hemisphere-specific influence on memory performance in children with epilepsy are inconsistent. Verbal memory of 80 children with focal epilepsy, aged 7 to 16, was assessed and compared with verbal memory of 80 healthy schoolchildren. The Verbal Selective Reminding test was used to distinguish between patients with left-sided (N=38) and patients with right-sided (N=42) electroencephalographic focal abnormalities. In addition, groups with temporal (N=36) and extratemporal (N=44) focal epilepsy were compared. Effects of seizure-related variables were also assessed. Children with focal epilepsy scored significantly lower on tests when compared with the healthy group. Lateralization of the EEG focus was not found to significantly affect verbal memory performance. Only the CLTR component of the Verbal Selective Reminding test was susceptible to lateralization and localization effects. Differences between the group with left and the group with right temporal epilepsy (P<0.03) and between the group with temporal and the group with extratemporal epilepsy (P<0.01) reached statistical significance.