Background: Previous reports indicate that various drugs may induce linear IgA bullous dermatosis (LABD). The role of T cells and T-cell-derived cytokines in the pathomechanism of such skin lesions, however, has remained unclear. Objective: To describe a case of LABD induced by ceftriaxone and metronidazole in an 80-year-old female suffering from cholelithiasis with concomitant cholecystitis and provide evidence that drug-specific T cells and their cytokines may contribute to the development of LABD lesions. Methods: We performed flow cytometry analysis of peripheral blood T cells during LABD, epicutaneous testing (scratch-patch) and lymphocyte proliferation analysis (LTT) with the suspected drugs, routine histological and immunohistochemical examination of the acute skin lesions during LABD as well as of the positive epicutaneous test reactions and measurement of cytokines (IL-4, IL-5, IL-10, TNF-á, IFN-ã) in the supernatant of the LTT cultures. Results: An increased number mainly of activated CD8+ cells was detected in the peripheral blood during LABD. T cell sensitization to ceftriaxone and metronidazole was confirmed by epicutaneous testing and LTT, indicating that these methods may be useful in identifying the causative drugs. Enhanced cytokine levels, particularly of IL-5, were found in the supernatant of the LTT stimulated with ceftriaxone and metronidazole. Furthermore, in situ expression of IL-5 was confirmed in the patient’s skin lesions by immunohistochemistry. Conclusion: Our findings suggest that in addition to IgA antibodies drug-specific T cells and their subsequent release of cytokines may play an important role in the pathogenesis of drug-induced LABD.
Drug-resistant mesial temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as ‘gliosis only’ with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that ‘gliosis only’ represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. Based on their neuropathological exam patients with hippocampus sclerosis and ‘gliosis only’ were characterized and compared within the whole-cohort and within a subset of matched-pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. ‘Gliosis only’ revealed demographics, clinical and neuropsychological outcome fundamentally different from HS. ‘Gliosis only’ patients have a significantly later seizure onset (16.3 yr. vs. 12.2 yr., p = 0.005) and worse neuropsychological outcome after surgery compared to patients with HS. Epilepsy was less amendable by surgery in ‘gliosis only’ patients resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% vs 68%, p = 0.0001, OR = 2.8, CI 1.7-4.7). This finding remained significant after multivariate and matched pairs analysis. The ‘gliosis only’ group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in HS. RNA sequencing of ‘gliosis only’ patients deciphered a distinct transcriptional program that resembles an innate inflammatory response of reactive astrocytes. Our data indicates a new temporal lobe epilepsy syndrome for which we suggest the term ‘Innate inflammatory gliosis only’ (I2GO). Innate inflammatory ‘gliosis only’ is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, innate inflammatory ‘gliosis only’ patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients, surgical treatment of this subgroup should be considered with great precaution. Innate inflammatory ‘gliosis only’ requires innovative pharmacotreatment strategies.
Objective Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in‐depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes. Methods In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state‐of‐the‐art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls. Results Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low‐grade tumors), indicating (1) a secondary, putatively epilepsy‐independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy‐associated pathologies were not found in combination with the secondary pathology patterns of the study group. Interpretation Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision‐making. ANN NEUROL 2023;93:536–550
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