Antiepileptic and anesthetic drugs in the intensive care unit. Their impact on non-convulsive status epilepticus mortality / Drogas antiepilépticas y anestésicas en la unidad de terapia intensiva. Su impacto en la mortalidad en el estado de mal epiléptico no convulsivo

Abstract Background: Status epilepticus (SE) is a neurological emergency. Non-convulsive status epilepticus (NCSE) can only be diagnosed by electroencephalogram (EEG) because the motor clinical symptoms are usually subtle or absent, with high mortality. The best treatment is still unknown. Objectives: Our aim was to assess anticonvulsive and anesthetic drugs in NCSE and their correlation with Epidemiology-based Mortality Score in Status Epilepticus (EMSE), Status Epilepticus Severity Score (STESS) and mortality. Methods: Retrospective, observational, descriptive, cross-sectional study. Ninety patients in intensive care unit over 18 years-old (57 females [63.3%] and 33 males [36.6%], mean age 63.5 years [SD ± 19]) with NCSE, at the Buenos Aires British Hospital. Data was collected between January 2018 and June 2021. An adjusted mul tivariate statistical analysis was performed. Ninety-five (95%) CI, p<0.05 as statistically significant. EMSE and STESS were used in this study. Results: Total mortality rate was 37.8% (34/90), and in patients ≥ 65 years-old (54/90) it was 40.7% (22/54). Patients with 0-2 STESS (11/90) were discharged, while those with STESS ≥ 3 (79/90) had a 43% death rate (34/79). Patients with EMSE < 34 (27/90) had 7.4% (2/27) death rate, while those with EMSE ≥ 34 (63/90) had 50.8% (32/63). No significant differences were found in survival with regard to the number of antiepileptic drugs administered. Pa tients treated with anesthetics presented a 2.6-fold death risk increase (95% CI 1.001-6.83). Discussion: It could be assumed that mortality rate increases 2.6-fold when patients are treated with anes thetic drugs, regardless of the number of antiepileptic drugs previously administered.

Resumen Introducción: El estado de mal epiléptico (SE) es una emergencia neurológica. El SE no convulsivo (SENC) se diagnostica únicamente por electroencefalograma de bido a la ausencia o sutileza de sintomatología clínica motora, con una mortalidad elevada. No se conoce aún el mejor tratamiento. Objetivos: Evaluar drogas anticonvulsivas y anestési cas en el SENC y su correlación con Epidemiology-based Mortality Score in Status Epilepticus (EMSE), Status Epilep ticus Severity Score (STESS) y el índice de mortalidad. Métodos: Estudio retrospectivo, observacional, de scriptivo, de corte transversal. Noventa pacientes ≥ 18 años (57 mujeres [63.3%] y 33 hombres [36.6%], media de edad 63.5 años [DS ± 19]) con diagnóstico de SENC, en el Hospital Británico. Estudio realizado entre enero 2018 y junio 2021. Análisis estadístico multivariado ajustado. IC 95% p< 0.05 como estadísticamente significativo. Se utilizaron escalas de EMSE y STESS. Resultados: La mortalidad total fue de 37.8% (34/90). Los pacientes ≥ 65 años (54/90) presentaron una mayor tasa de muerte 40.7% (22/54), todos aquellos con STESS de 0-2 (11/90) egresaron, mientras que entre los que presentaron ≥ 3 (79/90) el 43% (34/79) falleció. De los pacientes con EMSE < 34 (27/90) dos fallecieron (7.4%) y de aquellos con EMSE ≥ 34 (63/90) falleció el 50.8% (32/63). No hallamos diferencias significativas entre cantidad de drogas antiepilépticas utiliza das y supervivencia. Pacientes con anestésicos tuvieron un aumento del riesgo de muerte 2.6 veces (IC 95% 1.001-6.83). Discusión: De acuerdo a esto la mortalidad con drogas anestésicas aumenta, independientemente de la cantidad de drogas anticonvulsivas utilizadas previamente.

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment.

The efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120mg/kg) and valproic acid (400mg/kg) could not prevent PTZ-induced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p=0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p<0.05), which were also more frequent than in the naïve group (p<0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY- and ΔFosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na(+) and Ca(2+) Channels Permeability.

Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na(+) and Ca(2+) channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca(2+) induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca(2+) induced by high K(+), or on the selective increase in Na(+) induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca(2+) induced by 4-AP, which was dependent on the out-in Na(+) gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca(2+) induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na(+) or Ca(2+) channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na(+) or Ca(2+) channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na(+) and/or Ca(2+) channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.

Severe Anti-epileptic Drug-induced Gingival Overgrowth in a Physically Disabled Patient.

Anti-epileptic drugs are considered to be the main drugs associated with gingival overgrowth. The co-administration of phenytoin and other anti-epileptic drugs, which increases the risk of phenytoin-induced gingival overgrowth, has been previously reported. However, no report has been done considering the new generation of anti-epileptic drug topiramate and its association with gingival overgrowth. High levels of dental plaque and calculus have also been reported as being a critical risk factor in the development and severity of drug-induced gingival overgrowth. Thus, this case report highlights the occurrence of severe gingival overgrowth and generalized periodontitis in a physically disabled patient with epilepsy who had been taking phenytoin and topiramate drugs for 10 years. It also emphasizes the importance for both medical and dental professionals to reduce the severity and impact of drug-induced gingival overgrowth.

MDR-1 and MRP2 Gene Polymorphisms in Mexican Epileptic Pediatric Patients with Complex Partial Seizures.

Although the Pgp efflux transport protein is overexpressed in resected tissue of patients with epilepsy, the presence of polymorphisms in MDR1/ABCB1 and MRP2/ABCC2 in patients with antiepileptic-drugs resistant epilepsy (ADR) is controversial. The aim of this study was to perform an exploratory study to identify nucleotide changes and search new and reported mutations in patients with ADR and patients with good response (CTR) to antiepileptic drugs (AEDs) in a rigorously selected population. We analyzed 22 samples In Material and Methods, from drug-resistant patients with epilepsy and 7 samples from patients with good response to AEDs. Genomic DNA was obtained from leukocytes. Eleven exons in both genes were genotyped. The concentration of drugs in saliva and plasma was determined. The concentration of valproic acid in saliva was lower in ADR than in CRT. In ABCB1, five reported SNPs and five unreported nucleotide changes were identified; rs2229109 (GA) and rs2032582 (AT and AG) were found only in the ADR. Of six SNPs associated with the ABCC2 that were found in the study population, rs3740066 (TT) and 66744T > A (TG) were found only in the ADR. The strongest risk factor in the ABCB1 gene was identified as the TA genotype of rs2032582, whereas for the ABCC2 gene the strongest risk factor was the T allele of rs3740066. The screening of SNPs in ACBC1 and ABCC2 indicates that the Mexican patients with epilepsy in this study display frequently reported ABCC1 polymorphisms; however, in the study subjects with a higher risk factor for drug resistance, new nucleotide changes were found in the ABCC2 gene. Thus, the population of Mexican patients with AED-resistant epilepsy (ADR) used in this study exhibits genetic variability with respect to those reported in other study populations; however, it is necessary to explore this polymorphism in a larger population of patients with ADR.

Late side-effects of valproate and lamotrigine

Lamotrigine (LTG) is a generally well-tolerated antiepileptic drug with broad-spectrum efficacy in several forms of partial and generalized epilepsy. Adverse effects of lamotrigine are usually associated with introduction and titration. This risk increases in children and in the co-medication with valproate. Herein, we report four patients with late adverse-effects, under the co-medication valproate and LTG, not related to drug introduction or titration. This study demonstrates that late side-effects without apparent etiology in children, adolescents and adults in chronic use of LTG, especially when associated to VPA, led to a diagnostic investigation, sometimes invasive. It must be emphasized that, due to the excellent seizure control, the authors opted for drug decrease instead of drug withdrawal, as previously done. Studies on late adverse effects are scarce, but physicians must be aware of these risks.

Lamotrigina (LTG) é uma droga antiepiléptica bem tolerada com eficácia em diferentes formas de epilepsia, parcial e generalizada. Os efeitos adversos da lamotrigina estão freqüentemente associados com a sua introdução e a sua titulação. Este risco encontra-se aumentado em crianças e quando a LTG é usada em associação com o valproato. Nós relatamos quatro pacientes que apresentaram efeitos adversos tardios com a co-administração de LTG e valproato, não relacionados à introdução ou o escalonamento das drogas antiepilépticas. Este estudo demonstra que efeitos adversos tardios sem etiologia aparente nas crianças, adolescentes e adultos em uso crônico de LTG, especialmente quando associados ao valproato, levou à investigação diagnóstica, por vezes invasiva. Os autores enfatizam que, devido ao bom controle de crises, os autores optaram pela redução da dose ao invés da suspensão da medicação, como previamente realizado. Embora os estudos sobre efeitos adversos tardios das drogas antiepilépticas sejam escassos, os clínicos devem estar cientes deste risco.