Abstract Refractory status epilepticus (SE) is a current daily therapeutic challenge. Electroconvulsive therapy (ECT), which is frequently used to treat psychiatric disorders, is known to raise the ...seizure threshold. As such, ECT could be of major interest in refractory SE. In this paper, we provide a brief overview of ECT in refractory SE. Although no placebo-controlled or open-label study has been published on the efficacy or safety of ECT in refractory SE, eight case reports have been identified. SE cessation was obtained in 80% of cases, and complete recovery was achieved in 27% of patients. Despite the heterogeneity of the ECT parameters used in these articles, we identified some common features that may be recommended for the use of ECT in refractory SE. ECT might be a viable therapeutic strategy for the most resistant and severe cases of SE, particularly after the failure of two inductions of anesthetic coma. This potential indication highlights the urgent need for clinical trials that assess the usefulness of ECT in refractory SE.
Summary
Objective
The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a ...complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum.
Methods
We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho‐S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants.
Results
We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1‐related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP).
Significance
GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.
Kainate receptors (KARs) are abundantly expressed in the central nervous system at a period of intense synaptogenesis and
might participate in the maturation of neural networks. We have described the ...postnatal development of mossy fibre excitatory
synaptic transmission in CA3 pyramidal cells and we have explored the potential role of KARs in synaptic maturation. In CA3
pyramidal cells, mossy fibre stimulation evokes EPSCs as early as postnatal day 3 (P3). At this early stage, mossy fibre (MF)-EPSCs
are fully blocked by GYKI 53655, an AMPA receptor (AMPAR) antagonist. A postsynaptic KAR component can only be detected from
P6. Thus, AMPAR-EPSCs precede KAR-EPSCs during postnatal maturation at this synapse. All MF-EPSCs display a KAR component
after P10. A key issue of the present work is that between P6 and P9, the presence of a postsynaptic KAR component tightly
coincides with AMPAR-mediated EPSCs of large amplitude, and with the onset of low frequency facilitation (from 0.1 Hz to 1
Hz), a presynaptic form of short-term synaptic plasticity. In addition, mice lacking functional KARs throughout postnatal
development display MF-EPSCs of significantly smaller amplitude at stages of maturation where synaptic KARs are normally present,
due to both pre- and postsynaptic impairment of synaptic transmission. These data suggest a role for KARs in the maturation
of mossy fibre synapses.
The pip, as the most common grapevine archaeological remain, is extensively used to document past viticulture dynamics. This paper uses state of the art morphological analyses to analyse the largest ...reference collection of modern pips to date, representative of the present-day diversity of the domesticated grapevine from Western Eurasia. We tested for a costructure between the form of the modern pips and the: destination use (table/wine), geographical origins, and populational labels obtained through two molecular approaches. Significant structuring is demonstrated for each of these cofactors and for the first time it is possible to infer properties of varieties without going through the parallel with modern varieties. These results provide a unique tool that can be applied to archaeological pips in order to reconstruct the spatio-temporal dynamics of grape diversity on a large scale and to better understand viticulture history. The models obtained were then used to infer the affiliations with archaeobotanical remains recovered in Mas de Vignoles XIV (Nîmes, France). The results show a twofold shift between the Late Iron Age and the Middle Ages, from table to wine grape varieties and from eastern to western origins which correlates with previous palaeogenomic results.
Abstract Adult-onset epilepsy is commonly thought to be secondary to a brain lesion. However, the etiology of adult-onset epilepsy remains unknown in approximately 25% of patients, despite progress ...in medical and diagnostic tools. In the present study, we investigated whether late-onset partial cryptogenic epilepsies could be subgrouped based on seizure semiology and clinical characteristics. A total of 41 patients with late-onset cryptogenic epilepsy were included, and the corresponding clinical and electrophysiological data were analyzed. The following three clinical subgroups were identified: 1) a group that fulfilled the diagnostic criteria of transient epileptic amnesia (TEA); 2) a group with late-onset cryptogenic epilepsies with a temporal seizure semiology; and 3) a cryptogenic extratemporal group, which was consistent with the categorization of cryptogenic epilepsies, i.e., epilepsies involving unknown lesions. The temporal group showed homogeneous clinical characteristics, especially a rapid evolution and a greater tendency toward generalization and pharmacoresistance compared with the other two groups. Transient epileptic amnesia was associated with a higher frequency of sleep disorders than either of the other groups. Our findings argue for the clinical identification of a subgroup of late-onset temporal epilepsy that might constitute an idiopathic form. The association between TEA and sleep disorders would suggest a possible pathophysiological role of sleep apnea syndromes in TEA.
Summary
Objective
Despite its well‐known effectiveness, the cost‐effectiveness of epilepsy surgery has never been demonstrated in France. We compared cost‐effectiveness between resective surgery and ...medical therapy in a controlled cohort of adult patients with partial intractable epilepsy.
Methods
A prospective cohort of adult patients with surgically remediable and medically intractable partial epilepsy was followed over 5 years in the 15 French centers. Effectiveness was defined as 1 year without a seizure, based on the International League Against Epilepsy (ILAE) classification. Clinical outcomes and direct costs were compared between surgical and medical groups. Long‐term direct costs and effectiveness were extrapolated over the patients’ lifetimes with a Monte‐Carlo simulation using a Markov model, and an incremental cost‐effectiveness ratio (ICER) was computed. Indirect costs were also evaluated.
Results
Among the 289 enrolled surgery candidates, 207 were operable—119 in the surgical group and 88 in the medical group—65 were not operable and not analyzed here, 7 were finally not eligible, and 10 were not followed. The proportion of patients completely seizure‐free during the last 12 months (ILAE class 1) was 69.0% in the operated group and 12.3% in the medical group during the second year (p < 0.001), and it was respectively 76.8% and 21% during the fifth year (p < 0.001). Direct costs became significantly lower in the surgical group the third year after surgery, as a result of less antiepileptic drug use. The value of the discounted ICER was 10,406 (95% confidence interval CI 10,182–10,634) at 2 years and 2,630 (CI 95% 2,549–2,713) at 5 years. Surgery became cost‐effective between 9 and 10 years after surgery, and even earlier if indirect costs were taken into account as well.
Significance
Our study suggests that in addition to being safe and effective, resective surgery of epilepsy is cost‐effective in the medium term. It should therefore be considered earlier in the development of epilepsy.
Scouting techniques combining rapid counting methods must be developed to help growers with immediate decision making in integrated pest management programs. We evaluated a method for estimating ...densities of western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), one of the most damaging insect pests of greenhouse cucumber, Cucumis sativus L., and rose, Rosa hybrida crops in southeastern France. This method is based on abundance classes of thrips observed on sampling units of flowers and foliage during a period of <1 min. Classes were calibrated using actual counts, and precision was improved by introducing additional predictive variables into multivariate nonparametric regression models. Regression models using infestation variables with and without climatic variables significantly increased calibration precision and made possible the accurate description of population dynamics. Rapid visual scouting methods could be combined for surveys of different pests and diseases. When calibrated, they provide growers or technicians with accurate tools guiding crop protection decisions.
Abstract Periventricular nodular heterotopia, the most common form of cortical malformation in adulthood, is characterized by nodules of neurons ectopically placed along the lateral ventricles. ...Classically, ectopic nodules are bilateral and symmetric defining bilateral periventricular nodular heterotopia (BPNH). BPNH can lead to epilepsy and intellectual disability of variable severity. The X-linked dominant form of BPNH, related to mutations in FLNA encoding filamin A, is the major cause of BPNH, causing prenatal and neonatal lethality in males that explain the excess of affected women. However, few living males have been described with this condition. In addition, mutations in FLNA have been also exceptionally associated with unilateral nodular heterotopia. We describe here three new patients, all carrying a novel missense mutation in FLNA . Two of the patients were adult males with BPNH; both had normal cognitive development and one did not manifest any seizure until he died at age 57. The last patient was a female adult with epilepsy and focal nodules essentially located along the right ventricle. We compare the clinical and imaging data of our patients with those of previously described similar cases. The type and location of FLNA mutations leading to such atypical presentations are discussed.
Background
Syncope in Wolff‐Parkinson‐White syndrome (WPW) is without relationship with WPW or reveals a poorly tolerated arrhythmia. Electrophysiologic study (EPS) is recommended. The purpose of the ...study was to evaluate the influence of the patient's age on the causes and prognosis of syncope.
Methods
A total of 98 patients, mean age 35 ± 18 years, with WPW were admitted for syncope. Note that 29 were aged between 9 and 19 years (mean 15 ± 3) (children and teenagers/group I), 45 between 20 and 49 years (mean 34 ± 8) (adults/group II), and 24 between 50 and 70 years (mean 60 ± 8) (elderly/group III). EPS consisted of atrial pacing and programmed atrial stimulation in control state and after isoproterenol.
Results
Potentially malignant form (rapid conduction in accessory pathway >240 beats/min in control state or >300 beats/min after isoproterenol and atrial fibrillation AF induction) was more frequent in group I (34%) than in groups II (7%) (P < 0.002) and III (0%) (P < 0.001). Orthodromic atrioventricular reentrant tachycardia (AVRT) and AF were induced as frequently in groups I (59, 34%), II (47, 15.5%), and III (54, 17%). AVRT was induced in all but one patient with malignant form. EPS was as frequently negative in groups I (27.5%), II (44%), and III (37.5%). Natural follow‐up (mean 8 ± 6 years) indicated a favorable prognosis, only related to AVRT induction. Induced AF was without significance.
Conclusions
Data in syncope and WPW syndrome depended on age: electrophysiological malignant form was frequent in children/teenagers, rare in adults, and absent in elderly. AVRT, the main cause of syncope, was as frequent in all ranges of age. AF's induction alone had no significance. Final prognosis was favorable.
Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule ...cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE.
We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE.
Here, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs.
Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023.
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