Neuropsychological assessment in pediatric epilepsy surgery: A French procedure consensus.

Neuropsychological assessment is a mandatory part of the pre- and post-operative evaluation in pediatric epilepsy surgery. The neuropsychology task force of the ILAE - French Chapter aims to define a neuropsychological procedure consensus based on literature review and adapted for French practice. They performed a systematic review of the literature published between 1950 and 2023 on cognitive evaluation of individuals undergoing presurgical work-up and post-surgery follow-up and focused on the pediatric population aged 6-16. They classified publications listed in the PubMed database according to their level of scientific evidence. The systematic literature review revealed no study with high statistical power and only four studies using neuropsychological scales in their French version. Afterwards, the experts defined a neuropsychological consensus strategy in pediatric epilepsy surgery according to the psychometric determinants of cognitive tests, specificity of epilepsy, surgery context, French culture and literature reports. A common French neuropsychological procedure dedicated to pediatric epilepsy surgery is now available. This procedure could serve as a guide for the pre- and post-surgical work-up in French centers with pediatric epilepsy surgery programs. The main goal is to anticipate the functional risks of surgery, to support the postoperative outcome beyond the seizure-related one, while taking into consideration the plasticity and vulnerability of the immature brain and allowing the possibility of collaborative studies.

Depression could modulate neuropsychological status in epilepsy.

While cognition and depression have often been studied in patients with epilepsy, only a few studies have so far attempted to link these two domains, and more specifically to investigate the specific impact of depression on cognition in epilepsy. In this review, we performed an extensive search of the literature database to provide a better understanding of this subject. Using several inclusion criteria (adult population, quantitative depression/neuropsychological assessment, statistical analyses of the impact of depression on cognitive scores, patients with epilepsy (PWE) and no other neurological disease, and studies including at least 20 patients), we identified 20 articles (out of 712 search results) that investigated both depression and cognition in PWE. Their results were summarized using a narrative and descriptive approach. This review highlights a variable impact of depression on cognition in PWE, depending on the laterality of the seizure onset zone, the type of epilepsy and the surgical context. We emphasize the need for a systematic depression assessment in these patients, especially since depressed PWE will benefit from prompt and appropriate care to help them avoid cognitive decline, particularly in a surgical context.

Long-term cognitive outcomes in patient with epilepsy.

In contrast to short-term cognitive outcomes, long-term cognitive outcomes (over 5 years) has been scarcely assessed so far. Yet, predicting long-term outcomes at any time point of the epilepsy, from initial diagnosis, to medically intractability is very important for therapeutic decision-making, patient information, and orientation. Assessing long-term cognitive outcomes in patients with epilepsy would ideally require longitudinal studies and a comparison with a healthy controls group. This issue has been addressed extensively, but with controversial results. However, there is a general consensus about the fact that cognitive outcome is not the same in all groups of patients with epilepsy. Possible prognostic factors include age at onset, duration of epilepsy, syndrome and etiology, seizure outcome and therapeutics. The multiplicity of factors makes it very difficult to assess their relative weight in individuals. Although long-term cognitive outcome studies are scarce, this issue has been specifically studied in newly diagnosed epilepsies and in focal drug-resistant epilepsies. In the first clinical setting, i.e. newly diagnosed epilepsy, it appears that cognitive deficits are already present at epilepsy onset in a significant proportion of patients but seem to remain stable over time. In focal drug-resistant epilepsies, cognitive deficits (mainly verbal memory) were generally shown to remain stable provided that seizures were controlled either by medication or by surgery. Beyond the possible correlation between seizure and cognitive outcome, no causal link however has been demonstrated between these two important outcomes.

French neuropsychological procedure consensus in epilepsy surgery.

INTRODUCTION: Neuropsychological assessment is an integral component of the surgical procedure in patients with epilepsy. As no French consensus for neuropsychological assessment was available, the main goal of this work was to define French neuropsychological procedure consensus in regard to literature review. METHOD: A panel of expert in neuropsychology was created within the framework of the French League Against Epilepsy. A systematic search of publications from 1950 to 2017 listed in PubMed database was conducted leading to a classification of articles according to their level of scientific evidence. French neuropsychological procedure consensus was then carried out with an expert panel of expert. RESULTS: Low scientific evidence of neuropsychological data was reported. A panel of expert proposed a comprehensive neuropsychological assessment procedure including the exploration of intellectual efficiency, long-term memory, short-term and working memory, attention, executive functions, processing speed and motor skills, language, visual processing, praxis, psychobehavioral, and social cognition. DISCUSSION: A common procedure for assessing cognitive and psychobehavioral function is now available in patients with epilepsy undergoing surgical evaluation have been established, they may help to improve the quality of care and the patient experience. This work highlights the need of furthers investigations and the necessity to develop specific tools with normative data.

Attention disorders in adults with epilepsy. Determinants and therapeutic strategies.

Cognitive consequences in epilepsy are often described in the following domains: verbal memory, language, executive functions, and attention. Attention is involved in all cognitive activities, and attention disorders (AD) are reported in patients with various neurological diseases. This paper proposes to define the concept of AD and its assessment, to consider their determinants in epilepsy and potential therapies (drug or not). ADs are reported in new onset epilepsy, generalized epilepsy of presumed genetic origin, and in focal epilepsy. In focal epilepsy, alertness and divided attention impairment are observed and seem to improve after successful curative surgery. Additional studies are needed to assess the prevalence and nature of AD related to status epilepticus. In the field of therapeutic strategies, anti-epileptic drugs show an impact on AD. Effects of antidepressive drug therapy are not reported, as well as psychotherapy. Cognitive rehabilitation on AD is a promising therapeutic intervention but specific studies are needed to assess its efficacy.

Induction and inactivation of a cytochrome P450 confering herbicide resistance in wheat seedlings.

Cytochrome P450-dependent enzymes from wheat catalyze the oxidation of endogenous compounds (lauric and oleic acids) and of several herbicides (diclofop, chlortoluron, bentazon). Treatment of wheat seedlings with the safener, naphthalic anhydride and with phenobarbital increases dramatically several P450-dependent enzyme activities including diclofop and lauric acid hydroxylation. The parallel induction of lauric acid (omega-1)-hydroxylase and diclofop hydroxylase activities suggests that both compounds proceeds from the same or very similar forms of P450. To test whether either one or multiple P450 forms are involved in these oxidations, we have designed selective irreversible inhibitors of lauric acid (omega-1)-hydroxylase. Results of in vivo and in vitro experiments with acetylenic analogs of lauric acid (10- and 11-dodecynoic acids) strongly suggest that a single P450 catalyzes both laurate and diclofop hydroxylation. Treatment of wheat seedlings with these acetylenes results in a strong inhibition of the in vivo metabolism of diclofop although oxidation of chlortoluron and bentazon are not affected. Our results suggest that at least three distinct P450 forms are involved in the detoxification process of the three herbicides. Interestingly, we also demonstrate that herbicides themselves are potent inducers of the amount of total P450 and laurate/diclofop hydroxylase activies. This increased capacity of wheat to detoxify the herbicide through the induction of P450 enzymes seems to be for a large extend the mechanism which confers a tolerance on various herbicides.

Neutral magnesium-dependent sphingomyelinase from liver plasma membrane: purification and inhibition by ubiquinol.

Plasma membranes isolated from pig liver contained almost no acid sphingomyelinase but significant neutral magnesium-dependent sphingomyelinase that was activated by phosphatidylserine. We report here the purification to apparent homogeneity of neutral sphingomyelinase of about 87 kDa from liver plasma membranes. The purified enzyme strictly required magnesium and had a neutral optimal pH. In contrast with neutral sphingomyelinase purified from other sources (such as brain), the enzyme purified from from liver plasma membrane was not inhibited by GSH and, strikingly, it was not activated by phosphatidylserine. Liver sphingomyelinase was inhibited by several lipophilic antioxidants in a dose-dependent way. Ubiquinol-10 was more effective than alpha-tocopherol, alpha-tocopherylquinone, alpha-tocopherylquinone, and ubiquinone-10, and inhibition was noncompetitive. Differential inhibition of neutral sphingomyelinase by antioxidants did not correlate with different levels of protection against lipid peroxidation. The purified sphingomyelinase was not inhibited significantly by ubiquinone-10 and ubiquinol- 10, but ubiquinol-0 and ubiquinone-0 inhibited by 30 and 60% respectively. Our results demonstrate a direct inhibitory effect of ubiquinol on the plasma membrane n-SMase and support the participation of this molecule in the regulation of ceramide-mediated signaling.

Optimized expression and catalytic properties of a wheat obtusifoliol 14alpha-demethylase (CYP51) expressed in yeast. Complementation of erg11Delta yeast mutants by plant CYP51.

CYP51s form the only family of P450 proteins conserved in evolution from prokaryotes to fungi, plants and mammals. In all eukaryotes, CYP51s catalyse 14alpha-demethylation of sterols. We have recently isolated two CYP51 cDNAs from sorghum [Bak, S., Kahn, R.A., Olsen, C. E. & Halkier, B.A. (1997) Plant J. 11, 191-201] and wheat [Cabello-Hurtado, F., Zimmerlin, A., Rahier, A., Taton, M., DeRose, R., Nedelkina, S., Batard, Y., Durst, F., Pallett, K.E. & Werck-Reichhart, D. (1997) Biophys. Biochem. Res. Commun. 230, 381-385]. Wheat and sorghum CYP51 proteins show a high identity (92%) compared with their identity with their fungal and mammalian orthologues (32-39%). Data obtained with plant microsomes have previously suggested that differences in primary sequences reflect differences in sterol pathways and CYP51 substrate specificities between animals, fungi and plants. To investigate more thoroughly the properties of the plant CYP51, the wheat enzyme was expressed in yeast strains overexpressing different P450 reductases as a fusion with either yeast or plant (sorghum) membrane targeting sequences. The endogenous sterol demethylase gene (ERG11) was then disrupted. A sorghum-wheat fusion protein expressed with the Arabidopsis thaliana reductase ATR1 showed the highest level of expression and activity. The expression induced a marked proliferation of microsomal membranes so as to obtain 70 nmol P450.(L culture)-1, with CYP51 representing 1.5% of microsomal protein. Without disruption of the ERG11 gene, the expression level was fivefold reduced. CYP51 from wheat complemented the ERG11 disruption, as the modified yeasts did not need supplementation with exogenous ergosterol and grew normally under aerobic conditions. The fusion plant enzyme catalysed 14alpha-demethylation of obtusifoliol very actively (Km,app = 197 microm, kcat = 1.2 min-1) and with very strict substrate specificity. No metabolism of lanosterol and eburicol, the substrates of the fungal and mammalian CYP51s, nor metabolism of herbicides and fatty acids was detected in the recombinant yeast microsomes. Surprisingly lanosterol (Ks = 2.2 microM) and eburicol (Ks = 2.5 microm) were found to bind the active site of the plant enzyme with affinities higher than that for obtusifoliol (Ks = 289 microM), giving typical type-I spectra. The amplitudes of these spectra, however, suggested that lanosterol and eburicol were less favourably positioned to be metabolized than obtusifoliol. The recombinant enzyme was also used to test the relative binding constants of two azole compounds, LAB170250F and gamma-ketotriazole, which were previously reported to be potent inhibitors of the plant enzyme. The Ks of plant CYP51 for LAB170250F (0.29 microM) and gamma-ketotriazole (0.40 microM) calculated from the type-II sp2 nitrogen-binding spectra were in better agreement with their reported effects as plant CYP51 inhibitors than values previously determined with plant microsomes. This optimized expression system thus provides an excellent tool for detailed enzymological and mechanistic studies, and for improving the selectivity of inhibitory molecules.