NAPB and developmental and epileptic encephalopathy: Description of the electroclinical profile associated with a novel pathogenic variant.

Developmental and epileptic encephalopathies (DEE) are a group of neurodevelopmental disorders characterized by epileptic seizures associated with developmental delay or regression. DEE are genetically heterogeneous, and the proteins involved play roles in multiple pathways such as synaptic transmission, metabolism, neuronal development or maturation, transcriptional regulation, and intracellular trafficking. We performed whole exome sequencing on a consanguineous family with three children presenting an early onset (<6 months) with clusters of seizures characterized by oculomotor and vegetative manifestations, with an occipital origin. Before 1 year of age, interictal electroencephalographic recordings were well organized and neurodevelopment was unremarkable. Then, a severe regression occurred. We identified a novel homozygous protein-truncating variant in the NAPB (N-ethylmaleimide-sensitive fusion [NSF] attachment protein beta) gene that encodes the ßSNAP protein, a key regulator of NSF-adenosine triphosphatase. This enzyme is essential for synaptic transmission by disassembling and recycling proteins of the SNARE complex. Here, we describe the electroclinical profile of each patient during the disease course. Our findings strengthen the association between biallelic variants in NAPB and DEE and refine the associated phenotype. We suggest including this gene in the targeted epilepsy gene panels used for routine diagnosis of unexplained epilepsy.

Screening for epilepsy-specific anxiety symptoms: French validation of the EASI.

OBJECTIVES: (1) To translate and validate the Epilepsy Anxiety Survey Instrument (EASI) in French people with epilepsy (PWE); (2) to further investigate the screening properties of each dimension of the EASI in terms of Diagnostic and Statistical Manual of Mental Disorders (DSM) anxiety disorders and of epilepsy-specific anxiety disorders, namely, anticipatory anxiety of seizures (AAS) and epileptic social phobia. METHODS: Following back-translation, the French EASI was tested in PWE > 18 years using the Mini-International Neuropsychiatric Interview (MINI) as gold standard for DSM anxiety disorders. We added 3 original questions to explore epilepsy-specific anxiety symptoms. The Generalized Anxiety Disorders-7 (GAD-7), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), and Adverse Events Profile were performed for external validity. Receiver operator characteristics (ROC) were analyzed. RESULTS: One hundred and forty nine native French speakers with epilepsy were included. Concerning DSM disorders, around 25% had GAD, 18% Agoraphobia, and <10% Social Phobia or Panic Disorder. Concerning possible epilepsy-specific anxiety disorder, 35% had AAS and 38% had epileptic social phobia. Bi-dimensional structure of the EASI was confirmed. Internal and external validity was satisfactory. ROC analysis showed AUC of 0.83 for detection of GAD and AUC 0.79 for other DSM anxiety disorders. ROC analysis of the 8-item French brEASI showed good performance for detection of GAD (AUC 0.83) and other DSM anxiety disorders (AUC 0.76) but not for epilepsy-specific anxiety symptoms (AUC 0.63). Conversely, dimension 2 of the French EASI (=10 items) allowed good detection of epilepsy-specific anxiety symptoms (AUC 0.78); cutoff > 4, sensitivity 82.4, specificity 66.7. CONCLUSION: Epilepsy-specific anxiety symptoms were prevalent, in around 60%. The French version of the EASI showed robust performance. The French 8-item brEASI allows screening for all DSM anxiety disorders with superior performance than the GAD-7, but is less suited to screening for epilepsy-specific anxiety. We propose the "Epilepsy-Specific Anxiety" (ESA) 10-item screening instrument, based on dimension 2 of the EASI, as a complementary clinical and research tool.

Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature.

Epilepsies associated with hypothalamic hamartomas (HHs) are frequently drug resistant with severe psychiatric and cognitive comorbidities. We performed a prospective trial to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKS). Between October 1999 and October 2007, a total of 57 patients were investigated, included and treated by GKS in Timone University Hospital. Preoperative workup and 3-year postoperative evaluation consisted of seizure diary, neuropsychological, psychiatric, endocrinologic, visual field, and visual acuity examinations. Follow-up of >3 years was available for 48 patients. Topologic type was type I in 11 patients, type II in 15, type III in 17, type IV in one, type V in one, type VI in one, and mixed type in 2. The median marginal dose was 17 Gy (min 14 and max 25 Gy). The median target volume was 398 mm3 (28-1,600 mm3 ). Due to partial results, 28 patients (58.3%) required a second treatment. The median follow-up was 71 months (36-153 months). At last follow-up, the rate of Engel class I outcome was 39.6%, Engel class II was 29.2% (I+II 68.8%), and Engel class III was 20%. Global psychiatric comorbidity was considered cured in 28%, improved in 56%, stable in 8%, and continued to worsen in 8%. No permanent neurologic side effect was reported (in particular, no memory deficit). Nondisabling transient poikilothermia was observed in three patients (6.2%). A transient increase of seizure frequency was reported in 8 patients (16.6%) with a median duration of 30 days (9-90 days). Microsurgery was proposed because of insufficient efficacy of GKS in seven patients (14.5%) with a postoperative Engel class I-II in 28.6%. This prospective trial demonstrates very good long-term safety and efficacy of GKS for 2 patients. Beyond seizure reduction, the improvement of psychiatric and cognitive comorbidities along with better school performance and social functioning, being better socially integrated, having friends having a social life, working, participating to group activities turn out to be major benefits of GKS in this group of patients with frequently catastrophic epilepsy.

Clinical, neuropsychological, and metabolic characteristics of transient epileptic amnesia syndrome.

OBJECTIVE: Transient epileptic amnesia (TEA) is a recently individualized syndrome occurring in adult patients that includes epileptic seizures with amnestic features and interictal memory disturbances. METHODS: We investigated the clinical, neuropsychological, and 18F-FDG positron emission tomography (18F-FDG-PET) features of 30 consecutive cases of TEA in our center. RESULTS: The mean age of onset of amnestic seizures was 59 years. Pure acute amnesia was the only epileptic manifestation in 17% of cases. Interictal electroencephalography (EEG) abnormalities were present in 57% on awake recording and in most patients in whom sleep EEG was performed (96%). Nine of 30 patients showed anterograde memory deficit and six of 30 exhibited mild executive functioning impairment. On the autobiographical memory interview (AMI), patients showed a significant deficit for the recent period of the episodic subscale. Outcome under treatment was favorable in the majority of cases. A significant improvement was noted on recollection of autobiographical memory. 18F-FDG-PET (22 cases) showed positive correlations between left mesial temporal metabolism levels and anterograde and retrograde memory scores. SIGNIFICANCE: TEA is an emerging epileptic syndrome that likely remains misidentified and misdiagnosed. Neurometabolic data support a dysfunction of a hippocampal-neocortical network sustaining episodic memory.

Efficacy and tolerance of cannabidiol in the treatment of epilepsy in patients with Rett syndrome.

We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/mL oral solution). In our cohort, 26 patients had associated epilepsy (26/46 [56%]), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow-up was 15 mg/kg/day. The median treatment duration was 13 months (range: 1-32 months). CBD reduced the incidence of seizures in seven out of 10 patients (70%) with one seizure-free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug-resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.

Increased Gray Matter Density in the Right Mesencephalic Tegmentum Is Associated With Better Engel Classes I and II After Radiosurgery for Hypothalamic Hamartomas.

BACKGROUND: Hypothalamic hamartomas (HHs) are disabling congenital lesions, responsible for gelastic seizures frequently associated with catastrophic epilepsies, epileptogenic encephalopathy, and cognitive and psychiatric severe comorbidities. Stereotactic radiosurgery (SRS) is a well-established minimally invasive therapeutic approach. OBJECTIVE: To assess whether pretherapeutic gray matter density (GMD) correlates with seizure outcome. METHODS: We used voxel-based morphometry at whole-brain level, as depicted on pretherapeutic standard structural magnetic resonance neuroimaging. We examined 24 patients (10 male patients, 14 female patients; mean age, 12.7 yr; median, 9; range, 5.9-50) treated in Marseille University Hospital, France, between May 2001 and August 2018. RESULTS: Most relevant anatomic area predicting postoperative Engel classes I and II vs III and IV after SRS for HHs was mesencephalic tegmentum. Higher pretherapeutic GMD in this area was associated with better outcomes for seizure cessation. The only other statistically significant clusters were right cerebellar lobule VIIIb and VIIIa. Lower pretherapeutic GMD in both clusters correlated with better Engel class outcomes. GMD decreased with age in the left mediodorsal thalamus. CONCLUSION: Seizure cessation after SRS for HHs was associated with higher GMD in mesencephalic tegmental area, acknowledged to be involved in the neural control of explosive vocal behavior in animals. This area is connected by the mamillotegmental bundle to the lateral tuberal nucleus area of the hypothalamus, where HHs are known to rise. In the future, the detection of more gray matter in this "laugh" tegmental area based on pretherapeutic routine structural neuroimaging might help in patient selection for minimally invasive radiosurgery for HH.

Epileptic hypothalamic hamartomas impact of topography on clinical presentation and radiosurgical outcome.

INTRODUCTION: Evidence exists for the role of the hypothalamic hamartoma's topography as a determinant for the clinical presentation. How the hamartoma relation to the hypothalamic structures can make clinical presentations, severity and surgery outcomes different from patient to patient is largely unknown. Our aim was to analyze the effect of fine anatomical topography on clinical spectrum and radiosurgery outcome. METHODS: Forty-eight epileptic patients with hypothalamic hamartoma were treated by Gamma Knife Surgery and were reviewed for fine topography and morphology using magnetic resonance neuroimaging. We evaluated different topographic patterns; contact to prominent structures (the mammillary body, tuber cinereum and pituitary stalk), the degree of involvement within sagittally-oriented regions, (mammillary, tuberal, and supra optic) coronally-oriented zones (periventricular, medial, and lateral), lesion dimensions (length, width, and height),and volumes (total, intra-hypothalamic, and extra-hypothalamic volumes). This data were statistically analysed for correlation with all clinical variables and epilepsy surgery outcome. We reviewed all the classification protocols in the literature. RESULTS: Focal onset impaired awareness seizures started at an earlier age of onset with larger hypothalamic hamartoma volume and dimensions. Lateral extension within the hypothalamus was associated with more severe epilepsy, higher seizure frequency, more severe psychiatric comorbidity, hetero-aggression, hyperkinesia, and school difficulties. Presence of precocious puberty was positively correlated to anterior-posterior extension; tuberal region involvement, hypothalamic hamartoma volume, and type III-VI. Larger hypothalamic hamartoma presented precocious puberty at an earlier age of onset. After Gamma Knife Surgery, epilepsy outcome was better and rapid when lesion is smaller. Post-radiosurgical transient increased seizures were present when the mammillary region was more involved. CONCLUSION: Clinical presentation of epileptic hypothalamic hamartoma is significantly affected by fine topography patterns and invaded hypothalamic areas. Gamma Knife Radiosurgery effect is better and rapid in smaller hamartoma (Type I-III) and seizure outcome was not affected by the invaded hypothalamic areas.

Intellectual outcome from 1 to 5 years after epilepsy surgery in 81 children and adolescents: A longitudinal study.

OBJECTIVE: This longitudinal study aimed to measure the time course of intellectual changes after pediatric focal resective epilepsy surgery and to identify their predictors. METHODS: We analyzed a cohort of 81 school-aged children with focal epilepsy and intractable seizures who underwent neurosurgery (focal resection) from 2000 to 2018 in La Timone Hospital (Marseille). Neuropsychological assessments were carried out before and then 1, 2, 3, and 5 years after epilepsy surgery. RESULTS: Eighty-one patients with a median age at surgery of 13.74 years [4.25] were enrolled. Overall, 45 of the 81 (55%) recruited patients were improved after the surgery on at least one of the five domains of the Wechsler Intelligence Scale. Temporal lobe localization and postoperative seizure freedom were the main prognostic factors impacting intellectual outcome (improvement and decline) after epilepsy surgery. Younger patients at surgery were less likely to have a postoperative IQ decline. Intellectual improvement after epilepsy surgery could be delayed for up to 5 years after surgery and concerned all intellectual domains except the Verbal Comprehension Index (VCI). Intellectual decline after epilepsy surgery occurred mainly during the first two years after the surgery and was reflected in full-scale intelligence quotient (FSIQ) and Working Memory Index (WMI). CONCLUSIONS: Our study points out that children and adolescents with TLE who achieved freedom from seizure after epilepsy surgery are the leading candidates for achieving postoperative intellectual improvement. This enhancement in intellectual function shows a long time course, whereas intellectual decline is evidenced earlier.

Ictal paresis associated to PLEDS in two children: a video-EEG study.

Ictal paresis (IP) is a rare negative motor phenomenon presenting challenging differential diagnostic problems with transient ischemic attacks, post-ictal paralysis, migraine and psychogenic paralysis. Video-EEG undoubtedly represents the essential mean for a proper diagnosis. Periodic lateralised epileptiform discharges (PLEDs) are a distinctive EEG pattern, consisting of periodic spike or sharp wave discharges, often associated with seizures. It is under debate if PLEDs should be considered only a peri-ictal or also an ictal EEG pattern. We describe two children with severe focal epilepsies, who presented IP recorded during video-EEG monitoring, associated to PLEDs. Clinical observation along with interictal and ictal scalp-EEG findings, suggested a fronto-temporal seizure onset in the first, and a temporo-insular onset in the second. We confirm that PLEDs may be an ictal pattern associated with negative motor phenomena.

Reading abilities and cognitive functions of children with epilepsy: influence of epileptic syndrome.

Children with epilepsy are at risk of developing learning disorders. To explore the influence of the epileptic syndrome on reading abilities, we have compared the neuropsychological profile of 12 children with benign idiopathic epilepsy with rolandic spikes, 10 with temporal lobe epilepsy and 12 with idiopathic generalized epilepsy. Children underwent a selection of standardised tests designed to assess: oral language, reading, short-term memory, attention and behavioural adjustment. Analysis of variance was adjusted according to age of onset of the epileptic syndrome, duration of the syndrome, and performance IQ for each group. Children with temporal lobe epilepsy (TLE) had significantly lower scores for reading speed and comprehension, but epileptic variables (the age of onset of epilepsy, duration and activity of epilepsy) had influenced academic performances. In the TLE group there was a clear effect of the topography of the epileptic foci (left-side TLE vs. right-side TLE) on reading profile. Furthermore, the effect of epileptic syndromes was found in phonological, semantic and verbal working memory deficits in the TLE group. To a lesser extent children with idiopathic generalized epilepsy (IGE) also exhibit cognitive deficit. The results of the present study lend support to epilepsy-specific patterns of neuropsychological dysfunction in children that should be considered to improve remediation of academic underachievement in these populations.

Senile myoclonic epilepsy in Down syndrome: a video and EEG presentation of two cases.

Myoclonic epilepsy is being increasingly recognized as a late-onset complication in middle-aged or elderly patients with Down syndrome, in association with cognitive decline. We show video and EEG recordings of two patients, both aged 56 years, diagnosed with this condition. At onset, myoclonic epilepsy in elderly DS patients may resemble, in its clinical expression, the classical juvenile myoclonic epilepsy with the characteristic occurrence of jerks on awakening. It is clearly associated with an Alzheimer-type dementia, and may also occur in non-DS patients with Alzheimer's disease: hence the possible denomination of "senile myoclonic epilepsy". [Published with video sequences].

Responders to vagus nerve stimulation (VNS) in refractory epilepsy have reduced interictal cortical synchronicity on scalp EEG.

EEG desynchronization has been proposed to be an important mechanism for antiepileptic effect of vagus nerve stimulation (VNS) but has never been clearly documented in human. The aim of this study was to evaluate impact of VNS on the synchronicity of interictal EEG rhythms. We estimated synchronization between scalp EEG signals using phase lag index (PLI) in 19 patients with chronic VNS therapy. We estimated changes in synchronization between ON and OFF phases and between responder (R) and non-responder (NR) patients. We found that R have a lower global level of synchronization (EEG broadband) than NR (p<0.0001) In addition, ON periods were characterized by lower values in comparison with OFF periods (p<0.001). R had significantly lower global synchronization levels in delta and alpha frequency bands (p<0.0001). Patients responding to VNS have thus a lower level of broadband EEG synchronization than non-responders. Estimating changes of synchronization level is thus a promising tool for predicting response to VNS.

Cortical involvement in focal epilepsies with epileptic spasms.

The pathophysiological mechanisms of epileptic spasms are still poorly understood. The role of subcortical structures has been suggested on the basis of non-localized EEG features and from experimental data. The description of asymmetric spasms associated with lateralized EEG patterns has challenged this view and raises the possibility of a cortical origin. This study investigated the cortical organization of partial seizures associated with epileptic spasms in children undergoing intracerebral EEG recordings for presurgical evaluation. Eleven children with drug resistant epileptic spasms and for whom depth electrode recordings were performed were retrospectively studied. In all children several features suggested a focal origin. Cortical involvement was studied using the "Epileptogenicity Index" (EI). A focal origin was finally demonstrated in 10/11 patients. Seven patients demonstrated pre-ictal changes in the seizure onset zone area. EI analysis showed maximal values in the temporal (n=5), parietal (n=1) or frontal (n=5) cortices. EEG changes were also observed in the premotor cortex during spasms in patients with frontal or parietal seizures and in 3/5 patients with temporal lobe seizures. Good surgical outcome (class I or II) was obtained in 7/10 patients. Seizures associated with epileptic spasms may originate from various cortical regions. Premotor/motor cortices are probably involved in determining ictal clinical changes.

Absence epilepsy with onset before age three years: a heterogeneous and often severe condition.

PURPOSE: The classification of epilepsies and epileptic syndromes recognizes three syndromes with typical absences [TA, i.e., childhood and juvenile absence epilepsies (CAE and JAE), and epilepsy with myoclonic absences (EMA), none of which is characterized by onset in early childhood]. Although several other forms of absence epilepsies have been described recently, none concerns infants and very young children, and little is known about the nosology and prognosis of early-onset absences. METHODS: We retrospectively selected all cases with onset of absences as the only or major seizure type before age 3 years and >/=2 years of follow-up among cases newly referred between 1986 and 2002. Neuropsychological assessments (generally IQ measure), behavior patterns, and schooling situations were reviewed for each child. RESULTS: We found 10 patients (7 F, 3 M). No child had sensory or motor deficits: neuroimaging was performed in nine and was normal in eight, with aspecific findings in one. Only two could be characterized as CAE and EMA, respectively, both with seizure control and a good cognitive outcome. Among the remaining eight cases, four had a fairly homogeneous presentation with predominantly brief absences and clearly asymmetric interictal EEGs. All eight had neuropsychological and/or behavioral difficulties. Three had full seizure control, and five, persisting absences, with a follow-up ranging between 2 years 8 months to 9 years 4 months; only one child was older than 12 years. CONCLUSIONS: Great heterogeneity exists among absence epilepsies of early onset, which are rare conditions. Only a few patients can be categorized into well-known syndromes. The overall prognosis is poor. Early onset of absences is uncommon, and multicenter studies should help clarify the nosology and prognosis.