A Simple Score for Predicting Paroxysmal Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source in a Tunisian Cohort Study.

BACKGROUND: The annualized recurrent stroke rate in patients with Embolic Stroke of Undetermined Source (ESUS) under antiplatelet therapy is around 4.5%. Only a fraction of these patients will develop atrial fibrillation (FA), to which a stroke can be attributed retrospectively. The challenge is to identify patients at risk of occult AF during follow-up. OBJECTIVE: This work aims to determine clinical factors and electrocardiographic and ultrasound parameters that can predict occult AF in patients with ESUS and build a simple predictive score applicable worldwide. METHODS: This is a single-center, registry-based retrospective study conducted at the stroke unit of Sahloul University Hospital, Sousse, Tunisia, between January 2016 and December 2020. Consecutive patients meeting ESUS criteria were monitored for a minimum of one year, with a standardized follow-up consisting of outpatient visits, including ECG every three months and a new 24-hour Holter monitoring in case of palpitations. We performed multivariate stepwise regression to identify predictors of new paroxysmal AF among initial clinical, electrocardiographic (ECG and 24-hour Holter monitoring) and echocardiographic parameters. The coefficient of each independent covariate of the fitted multivariable model was used to generate an integerbased point-scoring system. RESULTS: Three hundred patients met the criteria for ESUS. Among them, 42 (14%) patients showed at least one episode of paroxysmal AF during a median follow-up of two years. In univariate analysis, age, gender, coronary artery disease, history of ischemic stroke, higher NIHSS at admission and lower NIHSS at discharge, abnormal P-wave axis, prolonged P-wave duration, premature atrial contractions (PAC) frequency of more than 500/24 hours, and left atrial (LA) mean area of more than 20 cm2 were associated with the risk of occurrence of paroxysmal AF. We proposed an AF predictive score based on (1.771 x NIHSS score at admission) + (10.015 x P-wave dispersion; coded 1 if yes and 0 if no) + (9.841x PAC class; coded 1 if ≥500 and 0 if no) + (9.828x LA class surface; coded 1 if ≥20 and 0 if no) + (0.548xNIHSS score at discharge) + 0.004. A score of ≥33 had a sensitivity of 76% and a specificity of 93%. CONCLUSION: In this cohort of patients with ESUS, NIHSS at both admission and discharge, Pwave dispersion, PAC≥500/24h on a 24-hour Holter monitoring, and LA surface area≥20 cm2 provide a simple AF predictive score with very reasonable sensitivity and specificity and is applicable almost worldwide. An external validation of this score is ongoing.

Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study.

BACKGROUND: The aim of this study was to evaluate whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null alleles may contribute to carbamazepine-induced hepatotoxicity. METHODS: A cross-sectional prospective study was conducted to identify the frequency distribution of GSTM1 and GSTT1 alleles in 129 Tunisian epileptic patients treated with carbamazepine. Null alleles were determined using a Polymerase Chain Reaction. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by standard methods. RESULTS: Our results showed that the frequencies of GSTM1 (-) null allele and GSTT1 null (-) allele were 74.4 and 17.8% respectively. The ALT and AST levels were elevated in 46 (35.7%) and 33 (25.6%) cases. The mean values of ALT and AST were approximately 1.32 and 3.61 times higher than the upper limit of normal levels, respectively. The values of ALT and AST were significantly higher in GSTM1 (-) allele than in GSTM1 (+) (p = 10-3.and 0.004, respectively). The level of ALT was significantly higher in combination of GSTM1 (-)/T1(-) than in combined GSTM1(-)/T1(+) and combined GSTM1(+)/T1(+) (p = 0.2 and 0.03, respectively), and that of AST was significantly higher in combination of GSTM1(-)/T1(-) and in combination of GSTM1(+)/T1(-) than in combination of GSTM1(+)/T1(+) (p = 10-3 and 10-3, respectively). CONCLUSIONS: Our findings suggest that the GSTM1 (-) allele may be considered as a key factor for the development of carbamazepine-induced hepatotoxicity. Results related to GSTT (-) allele and elevation in AST levels should be considered with caution as AST may be elevated in other pathophysiological conditions.

The relationship between pharmacokinetic parameters of carbamazepine and therapeutic response in epileptic patients.

INTRODUCTION: The prescribed dose and carbamazepine plasma concentration to achieve the optimal therapeutic efficacy are highly variable from one patient to the other. Our study aimed to determine whether biological parameters may be used as plasma markers that can individually adjust the carbamazepine dose necessary to optimize therapeutic efficacy. MATERIAL AND METHODS: Ninety-four epileptic patients under carbamazepine monotherapy and who have never used combination therapy were recruited from the consecutive admissions at the Department of Neurology "CHU Sahloul" of Sousse Central Hospital in Tunisia from February 2010 to April 2011. The patients were monitored for epilepsy for three years on average. Carbamazepine and 10,11-epoxide-carbamazepine concentrations were analyzed through high-performance liquid chromatography. Simultaneously, therapeutic efficacy was assessed through the annual number of seizures in each patient. RESULTS: Our results showed the absence of any significant correlations between specific dose (mg/kg/day), carbamazepine plasma concentrations and therapeutic efficacy (r = 0.0025, p = 0.30; r = 0.1584, p = 0.38 respectively), whereas both plasma 10,11-epoxide-carbamazepine concentration and 10,11-epoxide-carbamazepine to plasma carbamazepine ratio were closely correlated with therapeutic efficacy (r = 0.34, p = 0.03; r = 0.45, p = 0.008 respectively). The optimum therapeutic response was observed among patients who simultaneously had a plasma concentration of 0.8 µg/ml of metabolite and 5.5 µg/ml of carbamazepine. CONCLUSIONS: The results suggest that plasma levels of both carbamazepine and of 10,11-epoxide-carbamazepine must be set to achieve an optimum therapeutic response.

Effects of EPHX1 and CYP3A4*22 genetic polymorphisms on carbamazepine metabolism and drug response among Tunisian epileptic patients.

The aim of this study was to evaluate the impact of polymorphisms in the EPHX1 (c.416A > G, c.337T > C) and CYP3A4*22 genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants of EPHX1 c.416A > G and c.337T > C are significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. The CYP3A4*22 variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism.