Search

International audience; Background: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]).Objective: We sought to better describe adult IEN and understand the aetiology.Methods: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls.Results: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL.Conclusions: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

International audience; Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

Summary: Purpose: The management of epilepsy during pregnancy entails a number of concerns. While seizures may affect adversely maternal and fetal outcome, antiepileptic drugs (AEDs) may increase the incidence of congenital abnormalities and possibly affect postnatal cognitive development in the offspring. Experimental animal studies can aid in assessing teratogenic features associated with individual AEDs and/or with seizures, and to identify the mechanisms involved. The purpose of this study was to investigate the consequences of prenatal exposure to (a) different AEDs and (b) maternal seizures on brain maturational processes in rats. Methods: Pregnant rats received from embryonic days 14 to 19 intraperitoneal injections of carbamazepine (20 mg/kg/day), vigabatrin (200 mgkg/day), and valproate (100 mg/kg/day) at doses not widely different from those used clinically. Pups exposed to AEDs in utero were analyzed postnatally. Animals born to “kindled” pregnant animals that had experienced one generalized convulsive seizure per day during the same gestational period were analyzed in parallel. Results: Prenatal exposure to vigabatrin and valproate, which act on GABA signaling, induced hippocampal and cortical dysplasias, which were likely to result from a neuronal migration defect and neuronal death. By contrast, offspring of rats exposed to carbamazepine (which at the dose used produced low plasma concentrations) or to generalized convulsive seizures showed no clear-cut evidence of dysplasias. Conclusions: We suggest that AEDs that increase the extracellular concentration of GABA might induce severe neuronal migration disorders. Drugs acting through other molecular targets would also perturb cortical maturation. The potential clinical relevance of these results should be a subject of future research.

Summary: Purpose: To evaluate the effect on visual function of a concomitant antiepileptic drug (AED) in patients treated with vigabatrin (VGB). Methods: Sixty-four consecutive patients with a history of partial seizures currently treated with VGB with either carbamazepine (CBZ) or valproate (VPA) were examined with automated kinetic perimetry, static perimetry, electrooculogram (EOG), and electroretinogram (ERG). An original device based on kinetic perimetry was developed to quantify the area of perception for each isopter. Results: Fifty-two patients were finally included. The results showed a significant difference in patients treated with VGB-VPA compared with patients treated with VGB-CBZ concerning the mean defect of static perimetry and the peripheral and midperipheral isopter (III 4e and III 1a Goldmann equivalent, respectively) in kinetic perimetry. EOG and ERG results did not differ significantly between the two groups. Conclusions: The visual impairment due to visual field constriction was more important in patients treated with VGB and VPA compared with patients treated with VGB and CBZ. The origin of this difference between the two associations could not be related to any particular retinal electrophysiologic abnormality.

International audience; BACKGROUND: Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect to neuroleptic drugs. METHODS: We report on 2 cases where NMS dramatically improved with carbamazepine. Incidental removal and reapplication of carbamazepine attests to its effectiveness for this condition. RESULTS: A 34-year-old woman treated for a major depressive disorder experienced NMS with a phenothiazine. Her condition dramatically improved in 8 hours after she was administered carbamazepine. Since carbamazepine was discontinued, NMS recurred in 10 hours and remitted anew within less than 24 hours after reintroduction. A 31-year-old woman experiencing a schizoaffective disorder displayed NMS with aphenothiazine and a butyrophenone. NMS completely resolved within 8 hours after she was administered carbamazepine. NMS recurred within 12 hours after carbamazepine discontinuation. CONCLUSIONS: These data thus account for a cause-effect relationship between carbamazepine administration and NMS relief, and argue against the neuroleptic withdrawal to be responsible by itself for NMS relief.