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Objective Evaluating the efficacy of an opioid antagonist, naloxone (NLX), to reduce the severity of post‐ictal hypoxemia and immobility after focal to bilateral tonic–clonic seizures (FBTCS). Methods ENALEPSY is a double‐blind placebo (PCB)‐controlled trial conducted in patients with focal epilepsy undergoing long‐term video‐EEG monitoring (LTM). Patients with a FBTCS during LTM were randomized 1:1 to receive intravenous NLX or PCB within the 2 min following the end of FBTCS. After database lock, a discrepancy between the allocated arm and the received treatment was detected, resulting in a 4:1 NLX:PCB ratio. To further explore the efficacy of NLX, we used historical control (HC) data collected in patients included in the REPO2MSE study whose characteristics matched those of patients randomized in ENALEPSY. The efficacy of NLX was then assessed versus PCB and versus HC. The primary endpoint was the delay between the end of the seizure and recovery of SpO2 ≥ 90%. Secondary efficacy outcomes included desaturation nadir and duration of the post‐ictal immobility. Results 33 patients contributed to the NLX group, 7 to the PCB group, and 43 to the HC group. The proportion of FBTCS type 1 or 3 was 84% in NLX, 100% in PCB, and 84% in HC. NLX did not improve the delay of recovery of SpO2 ≥ 90% or the desaturation nadir. By contrast, the duration of the post‐ictal immobility differed across groups. The time to mobility recovery within the first 5 min post‐ictal was very similar in the PCB (200.3 ± 215.8 s) and HC (194.4 ± 192.0 s) groups, and significantly shorter in the NLX group (128.9 ± 151.1 s) when compared to HC (Hazard Ratio, 1.84; 95% CI, 1.11–3.05; p = 0.021). Significance NLX did not prevent post‐ictal respiratory dysfunction but might reduce the duration of post‐ictal immobility. Confirmation of this effect and its impact on SUDEP risk will require additional studies. Plain Language Summary Release of endogenous opioids might participate in the severity of post‐ictal hypoxemia and immobility after focal to bilateral tonic–clonic seizures (FBTCS). We conducted a multicenter double‐blind randomized placebo‐controlled trial evaluating the efficacy of an opioid antagonist, naloxone (NLX), administered within 2 min following the end of FBTCS. The efficacy of NLX was further explored with a comparison with historical control. NLX did not improve the delay of recovery or the severity of post‐ictal hypoxemia. Post‐ictal immobility was significantly shorter in the NLX group when compared to historical control. The impact of these results on SUDEP prevention will require additional studies.

BackgroundPatients who present with only simple or complex partial seizures have a poorly documented prognosis. Treatment may be advocated to prevent future secondary generalised seizures, reduce the frequency of further simple or complex partial seizures or a combination of both.MethodsA full statistical analysis on 1334 patients was carried out. The outcomes measured were post-randomisation times to first seizure of any type and first tonic–clonic seizure. Methodology was adopted that accounted for individuals' underlying pre-randomisation seizure counts and allowed for the possibility that there may be a proportion of the sample that will not experience post-randomisation seizure recurrence.Results103 subjects randomised to the MESS (Multicentre Study of Early Epilepsy and Single Seizures) study had only partial seizures at randomisation. Only 17 of these had a tonic–clonic seizure during follow-up. The presence of an abnormal EEG at randomisation influenced this risk: an estimated 23% of those with EEG abnormality were at risk of tonic–clonic seizures during follow-up compared with 16% of those with a normal EEG. The group did, however, continue to have partial seizures during follow-up, and modelling showed that the impact of treatment on these seizures was significantly less than the effects of treatment on the frequency of tonic–clonic seizures in those patients with such pre-randomisation seizures.ConclusionPatients presenting with a history of only partial seizures are at low risk of subsequent tonic–clonic seizures in the period of time to which therapeutic decisions are relevant. The effects of the antiepileptic drugs used in the MESS study are greater for tonic–clonic seizures than they are for partial seizures.

Novel biomarkers of the risk of sudden unexpected death in epilepsy (SUDEP) are needed to better inform people with epilepsy of their individual risk and identify those at a high risk. The aim of this study was to identify such biomarkers, particularly with the exploration of seizures characteristics that have not been previously investigated, including peri-ictal peripheral oxygen saturation (SpO2) and site of seizure onset. We conducted a nested case–control study of SUDEP within a dedicated nationwide prospective cohort. Eligible participants were adults with drug-resistant focal epilepsy undergoing in-hospital seizure monitoring at 16 epilepsy monitoring units in France. Clinical data, results from presurgical investigations, and raw recordings from video EEG, electrocardiogram (ECG), and SpO2 were collected until the end of the recruitment period. The French National Directory of Natural Persons Identification was queried annually to identify deaths. SUDEP cases were adjudicated on the basis of medical records and interviews documenting the circumstances of death. Each SUDEP case was matched to four controls on the basis of study centre and date of inclusion. SUDEP risk factors were identified using LASSO-penalised conditional logistic regression. From May 18, 2010, to Aug 23, 2015, we enrolled a total of 1074 participants and followed their vital status until the end of 2018, yielding a total of 6828 patient-years of follow-up. 42 participants died during follow-up, including 18 cases of definite or probable SUDEP, resulting in a SUDEP rate of 2·64/1000 patient-years (95% CI 1·36–3·92). Four risk factors were significantly associated with the risk of SUDEP: an extratemporal epileptogenic zone (OR 37·8, 95% CI 3·21–446·2, p=0·0039), a BMI of 30 or higher (26·0, 2·0–339·6, p=0·013), male sex (12·6, 1·5–106·8, p=0·0201), and predominantly nocturnal seizures (6·0, 1·2–28·7, p=0·026). In contrast, the presence of peri-ictal SpO2 of less than 80% during focal seizures, the frequency of focal-to-bilateral tonic–clonic seizures, heart rate variability, age at epilepsy onset, number of antiseizure medications, and history of depression were not significantly associated with SUDEP. Extratemporal epilepsies involving the perisylvian region or frontal lobe appear to be associated with an increased risk of SUDEP. This finding warrants confirmation in larger cohorts and underscores the need to improve the diagnosis and surgical management of extratemporal epilepsies, which might contribute to improved SUDEP risk stratification and prevention. French Ministry of Health (Programme Hospitalier de Recherche Clinique National 2009).

Purpose Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. Methods We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). Results Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1–2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. Conclusions This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Hypothalamic hamartoma is a less common condition characterized by the several types of epileptic seizures including the gelastic type. It is reported that gelastic seizures are resistant to medical treatment with anticonvulsants, while stereotactic thermocoagulation or Gamma Knife radiosurgery are effective for seizure control. Here, we report an individual case where direct surgical resection disconnecting hypothalamic hamartoma from mammillothalamic tract resulted in complete disappearance of gelastic seizures without deterioration of cognitive function. A 6-year-old boy developed gelastic seizures at the age of 2 and suffered from precocious puberty. Anticonvulsants including carbamazepine and zonisamide failed to control seizures. The patient underwent direct division of the mammillothalmic tract by removal of hypothalamic hamartoma partially via anterior interhemispheric approach. It was observed that gelastic seizures disappeared completely after the surgical treatment without any endocrine and cognitive dysfunction for a follow-up period of 14 years. The mammillothalamic tract which connects anterior nucleus of thalamus and mammillary bodies plays a key role in gelastic seizures related to hypothalamic hamartoma. In this case, we disconnected the hamartoma specifically from the mammillary bodies and not from the rest of hypothalamus. Effectively, it enabled permanent control of seizures. This result shows that fibers connecting other hypothalamic structures and the dorsomedial nucleus of thalamus are not involved in gelastic seizure propagation from the hypothalamic hamartoma. When surgical treatment of hypothalamic hamartomas is performed it has high morbidity associated with hypothalamic disorders. Therefore, disconnection between hypothalamic hamartoma and mammillary bodies presents a possibility of reducing hypothalamic damage. Surgical disconnection between hamartoma and mammillothalamic tract carries minimal hypothalamic injury risk and our results suggest that it has the potential of seizure control for intractable gelastic seizures with less complications.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind, dose ranging, placebo controlled, crossover study of adjuvant GBP. Each treatment phase lasted three months, during which the dose of GBP or matched placebo was increased stepwise at intervals of four weeks (1200 mg/day, 1800 mg/day, and 2400 mg/day in three daily doses). Psychomotor and memory testing was carried out at the end of each four week period, at which time the patient also completed subjective measures of cognition, fatigue, worry, temper, and dysphoria. A visual analogue scale was used to assess drowsiness and a questionnaire was employed to gauge the severity of side effects. RESULTS: In the 21 patients completing the study, GBP produced a significant reduction in median monthly seizure frequency from 7 to 4.3 (P = 0.02), the decrease being most pronounced for secondarily generalised seizures (from 1.0 to 0.3, P = 0.01). Forty three per cent of patients reported a reduction in seizure frequency of at least 50% throughout all GBP doses. Mean (SD) plasma concentrations of GBP at 1200, 1800, and 2400 mg/day were 4.7 (2.6), 6.8 (3.8), and 8.6 (3.3) mg/l respectively. The drug had no effect on composite psychomotor and memory scores; nor was there alteration in any self assessment subscore. The mean drowsiness (P = 0.03) score was higher during treatment with 2400 mg GBP daily compared with matched placebo. Composite psychomotor (r = -0.47, P < 0.01), tiredness (r = 0.42, P < 0.01), and side effect (r = 0.61, P < 0.001) scores correlated significantly with seizure frequency but not with GBP dose. CONCLUSION: GBP is a well tolerated and effective antiepileptic drug which had no measurable effect on cognition but did produce sedation at the highest dose. This study also supports the suggestion that seizures can cause cognitive impairment.

Introduction Biallelic variants in QARS1 , a house-keeping gene involved in protein synthesis, cause a rare encephalopathy classically characterized by severe developmental delay, drug-resistant neonatal-onset epilepsy, microcephaly, and brain atrophy. We aim to raise awareness on mild QARS1 -related phenotypes describing a 6-year-old patient. Case description Epilepsy onset occurred at 3.5 years with a sleep-related focal autonomic seizure, accompanied by interictal occipital spikes at EEG. In the following months, daytime focal impaired awareness seizures appeared. Due to developmental delay and short stature, trio-based whole-exome sequencing was performed, unraveling two compound heterozygous QARS1 variants: the likely pathogenic c.1304A>G (p.Y435C) and the c.799C>T (p.R267W), extremely rare and predicted deleterious by in silico analysis. At 5 years, the patient had a para-infectious encephalopathy with acute psychomotor slowing, delta-theta activity at EEG, new-onset bilateral subcortical white matter T2-hyperintensities with diffusion restriction at brain MRI, and optimal response to intravenous methylprednisolone administration. At 12-month follow-up, the patient had been seizure-free for a year with levetiracetam monotherapy. Discussion Mild QARS1 -related encephalopathies may present with a childhood-onset focal epilepsy accompanied by developmental delay and short stature as red flags of monogenic etiology. The episode of steroid-responsive acute para-infectious encephalopathy, previously reported in another patient harboring the p.Y435C variant, suggests that milder cases might be more susceptible to encephalopathy caused by intercurrent illnesses (e.g., infection). As recommended for other aminoacyl-tRNA synthetase-related diseases, it is important to provide this cohort with an early genetic diagnosis in order to encourage precision medicine and personalized treatment.

Atonic seizures are typically observed in younger children with Lennox–Gastaut syndrome and have been rarely described in adults. Herein we present a case of the adolescent-onset drug-resistant focal epilepsy in a 31-year-old woman with focal atonic seizures originating in the left posterior temporoparietal area and manifesting without aura with abrupt impairment of consciousness and slow falling down. According to the video-EEG monitoring, the seizure began with the medium amplitude spikes principally at T5 area evolving onto the left centroparietal area, which was immediately followed by the diffuse suppression of the background EEG activity. The underlying mechanism might be related to high-frequency electrical stimulation of the negative motor areas within the inferior frontal gyrus or anterior to the supplementary sensorimotor area. •Focal atonic seizures may be noted in patients with adolescent-onset epilepsy.•Focal atonic seizures may originate in the posterior temporoparietal area.•They can manifest without aura with abrupt decline of consciousness and slow falls.•The underlying mechanism may be related to stimulation of the negative motor areas.•Correct diagnosis of focal atonic seizures is crucial for appropriate treatment.

Objective Amygdala enlargement has been the subject of controversial studies regarding its significance in terms of pathogenicity both in epilepsy and in psychiatric comorbidities such as anxiety, depression, and post‐traumatic stress disorder. However, no causal link has been established in either direction, and the role of distinct amygdala nuclei remains unknown. We investigated volumetric changes of the amygdala and its nine main nuclei and their associations with psychiatric comorbidities in patients with drug‐resistant focal epilepsy. Methods Eighty‐seven adult patients with drug‐resistant focal epilepsy, available 7 T MRI, and completed standardized psychiatric assessments were included. Whole amygdala and nuclei volumes were quantified and compared to healthy controls. Correlations between the amygdala or nuclei volumes and psychiatric scores were analyzed, as well as the prevalence and severity of each comorbidity depending on the presence of enlargement. Results Amygdala enlargement was present in 41% of patients, with bilateral enlargement observed in 30% of these cases, while atrophy was noted in 2%. Bilateral enlargement correlated with higher posttraumatic stress disorder and depression scores. Central nucleus enlargement was associated with a greater prevalence of depression and more severe anxiety. Bilateral enlargement of distinct nuclei in the basolateral group was linked to more severe depression or posttraumatic stress disorder. Interpretation These findings suggest that bilateral amygdala enlargement, particularly in specific nuclei, may serve as a morphological marker of psychiatric comorbidities in epilepsy. Further research is needed to explore the specific roles of amygdala nuclei in psycho‐epileptogenesis.

Patients with epilepsy are at risk of sudden unexpected death. Neurogenic cardiac arrhythmias have been postulated as a cause. Electrocardiograms (ECG) can be monitored by use of an implantable loop recorder for up to 18 months. We aimed to determine the frequency of cardiac arrhythmias in patients with refractory focal seizures over an extended period. 20 patients received an implantable loop recorder at one hospital in the UK. Devices were programmed to record automatically if bradycardia (<40 beats per min) or tachycardia (>140 beats per min) were detected. Additionally, in the event of a seizure, patients and relatives could initiate ECG recording with an external activator device. Data were analysed at regular intervals and correlated with seizure diaries. More than 220 000 patient-hours were monitored over 24 months, during which ECGs were captured on implantable loop recorders in 377 seizures. One patient withdrew from the study. In 16 patients, median heart rate during habitual seizures exceeded 100 beats per min. Ictal bradycardia (<40 beats per min) was rare, occurring in eight (2·1%) recorded events, in seven patients. Four patients (21%) had bradycardia or periods of asystole with subsequent permanent pacemaker insertion. Three of these four (16% of total) had potentially fatal asystole. Clinical characteristics of patients with peri-ictal cardiac abnormalities are closely similar to those at greatest risk of sudden unexpected death in epilepsy. Asystole might underlie many of these deaths, which would have important implications for the investigation of similar patients and affect present cardiac-pacing policies.