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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.

Juvenile myoclonic epilepsy (JME) is both a frequent and a very characteristic epileptic syndrome with female preponderance. Treatment of JME in women of childbearing potential must consider multiple factors such as desire for pregnancy, use of contraception, seizure control and previously used antiepileptic drugs (AEDs). Approximately 85% of cases are well controlled with valproate, which remains the reference AED in JME but is nowadays considered unsafe for the expecting mother and her fetus. The prescription of valproate is now severely restricted in women of childbearing potential but may still be considered, at the lowest possible dose and when pregnancies can be reliably planned, with temporary alternatives to valproate prescribed before fertilization. Alternatives have emerged, especially lamotrigine and levetiracetam, but also topiramate, zonisamide, and recently perampanel, but none of these AEDs can be considered fully safe in the context of pregnancy. In special settings, benzodiazepines and barbiturates may be useful. In some cases, combination therapy, especially lamotrigine and levetiracetam, may be useful or even required. However, lamotrigine may have the potential to aggravate JME, with promyoclonic effects. Carbamazepine, oxcarbazepine and phenytoin must be avoided. Valproate, levetiracetam, zonisamide, topiramate if the daily dose is ≤ 200 mg and perampanel if the daily dose is ≤ 10 mg do not affect combined hormonal contraception. Lamotrigine ≥ 300 mg/day has been shown to decrease levonorgestrel levels by 20% but does not compromise combined hormonal contraception. Patients with JME taking oral contraceptive should be counselled on the fact that the estrogenic component can reduce concentrations of lamotrigine by over 50%, putting patients at risk of increased seizures. Pregnancy is a therapeutic challenge, and the risk/benefit ratio for the mother and fetus must be considered when choosing the appropriate drug. Lamotrigine (< 325 mg daily in the European Registry of Antiepileptic Drugs in Pregnancy) and levetiracetam seem to be comparatively safer in pregnancy than other AEDs, especially topiramate and valproate. Plasma concentration of lamotrigine and levetiracetam decreases significantly during pregnancy, and dosage adjustments may be necessary. With persisting generalized tonic–clonic seizures, the combination of lamotrigine and levetiracetam offer the chance of seizure control and lesser risks of major congenital malformations. The risk of malformation increases when valproate or topiramate are included in the drug combination. In one study, the relative risk of autism and autism spectrum disorders (ASD) in children born to women with epilepsy (WWE) treated with valproate were, respectively, 5.2 for autism and 2.9 for ASD versus 2.12 for autism and 1.6 for ASD in WWE not treated with valproate. More studies are needed to assess the risk of autism with AEDs other than valproate. The current knowledge is that the risk appears to be double that in the general population. In patients with JME, valproate remains an essential and life-changing agent. The consequences of a lifetime of poorly controlled epilepsy need to be balanced against the teratogenic risks of valproate during limited times in a woman’s life. The management of JME in WWE should include lifestyle interventions, with avoidance of sleep deprivation, and planned pregnancy.

Normal EEG variants, especially the epileptiform variants, can be challenging to interpret because they often have sharp contours and may be confused with “epileptic” interictal activities. However, they can be recognized by the fact that “ most spikes or sharp wave discharges of clinical import are followed by a slow wave or a series of slow deflections ” (Maulsby, 1971). If there is no wave after the spike, electroencephalographers should be suspicious of artifacts and normal EEG variants. Most normal EEG variants display a single rhythm with the same frequency within the pattern and the morphology remains stable throughout the entire EEG recording with repetition of the same pattern. In case of doubt or difficulties with a standard EEG, it is recommended to undergo an EEG that includes sleep stages with or without sleep deprivation. Finally, epileptiform is an ambiguous term corresponding to an electroencephalographic trait. Epileptiform does not imply a pathological condition, including epilepsy. The clinical context remains the most paramount in the diagnosis of epilepsy. In this article, we propose a set of rules and guidelines to identify normal EEG variants in EEG tracings and normal variation of the background activity. It is not easy to accurately assign a specific/precise name to all EEG activity, but with an orderly approach to EEG that involves using a set of criteria, nonepileptic activity can be identified .

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18–50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6–9·2) per 1000 patient-years, with a risk of 1·2 (0·6–2·1) per 10 000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time. Commission of European Affairs of the International League Against Epilepsy.

Historically, periodic EEG patterns were described as any pattern with stereotyped paroxysmal complexes occurring at regular intervals, i.e., the period ( T ). T is the sum of the duration of the waveform (t1) and, eventually, the duration of the interval between two consecutive waves (t2). The American Clinical Neurophysiology Society introduced the concept of a clearly discernible inter-discharge interval between consecutive waveforms (i.e., t2). As this definition was not applied to what have previously been termed triphasic waves and in some cases of lateralized periodic discharges, we propose reconsideration of terminology that includes historical use of definitions. This will allow the development and usage of the concept for periodic EEG patterns as any runs of stereotyped paroxysmal waveforms separated by nearly identical intervals and prolonged repetitive complexes on the EEG . Prolonged expression means EEG is recorded for a sufficient period of time to prove that the pattern is repetitive, thus resulting in a monomorphic/monotonous pattern. More important than the inter-discharge interval (t2), periodic EEG patterns occur at time regular intervals (T). As a result, periodic EEG activity should be considered along a continuum and not the opposite of rhythmic EEG activity where no interval activity exists between consecutive waveforms.

Anna-Elina Lehesjoki and colleagues report exome sequencing of 84 cases of progressive myoclonus epilepsy (PME) and targeted resequencing of an additional 28 cases. They identify de novo mutations in KCNC1 in 13 cases and mutations in genes not previously associated with PME, including PRNP , SACS and TBC1D24 , in additional cases. Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes K V 3.1, a subunit of the K V 3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes ( NEU1 , NHLRC1 , AFG3L2 , EPM2A , CLN6 and SERPINI1 ). Identification of mutations in PRNP , SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

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).

ABSTRACTFocal epilepsies are often associated with blood-brain barrier disruption. In 4 entorhinal cortex tissue samples and 13 hippocampal samples from patients with pharmacoresistent temporal lobe epilepsy, we observed immunoglobulin G (IgG) leakage in the parenchyma and IgG-positive neurons that had evidence of neurodegeneration, such as shrinkage and eosinophilia. These findings were not present in samples from 12 nonepileptic control subjects. To complement these findings, we used a rat in vivo model that mimics the development of limbic epilepsy with blood-brain barrier disruption. During epileptogenesis, IgG leakage and neuronal IgG uptake increased concomitantly with the occurrence of seizures. Immunoglobulin G accumulation in neurons was selective, particularly for interneurons and pyramidal neurons. Immunohistochemistry and electron microscopy showed that IgG uptake in the rat neurons was associated with eosinophilia, shrinkage, and ultrastructural degenerative changes. Moreover, IgG-positive neurons lost their NeuN immunohistochemical staining. Together, these observations suggest that IgG leakage is related to neuronal impairment and may be a pathogenic mechanism in epileptogenesis and chronic epilepsy.

A useful tool to analyze physiological EEG awake and sleep activities in children and adults.