Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex.

Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether 'limbic encephalitis with GAD antibodies' is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern. We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration. In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis; three cases developed hippocampal sclerosis within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure-free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8+ cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early/active cases (but not in late/inactive stages) revealed 'T cell immunity' and 'Regulation of immune processes' as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation. Surgically treated patients with GAD-TLE go through an early active inflammatory, 'encephalitic' stage (≤6 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. 'Limbic encephalitis' with GAD antibodies should be subsumed under GAD-TLE. The early tissue damage explains why immunotherapy does not usually lead to freedom from seizures.

The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals.

PURPOSE: Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. METHODS: We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). RESULTS: We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. CONCLUSION: Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

[QTc-interval prolongation in therapy with atypical antipsychotics--results of an open, non-randomized survey]. / QTc-Zeitverlängerung unter Therapie mit atypischen Neuroleptika--Ergebnisse einer klinikinternen Anwendungsbeobachtung.

The introduction of Ziprasidone stimulated discussion about frequency and importance of QTc-interval prolongations with antipsychotic therapy. In an open non-randomized study we collected data about QTc-interval, electrolytes, vital parameters and associated clinical symptoms in patients treated with atypical antipsychotics. 33 patients were scanned and some moderate QTc-interval prolongations but no clinical events were seen. Due to scarcity of such events existing data should be completed by large scale clinical studies and by registration of severe QTc-interval prolongations and torsades de pointes in central drug monitoring systems.

[Violence by Psychiatric In-Patients of the BZK Gabersee - First Results of a Standardized Documentation] / Aggressionen psychiatrischer Patienten - Erste Ergebnisse einer standardisierten Dokumentation des BZK Gabersee.

After a cluster of severe assaults against our staff we performed a standardized documentation concerning aggressive behaviour of in-patients at the BZK Gabersee, a major District Hospital with a typical spectrum of psychiatric patients. From July 1996 to March 2001 23 037 patients were admitted and 1618 cases of aggressive behaviour were documented. About 75 % of the patients were males, more than 50 % were treated involuntarily. The aggressions were most frequently directed against the nursing staff, severe injuries occured very rarely. We tried to analyse triggers and the individual motivations of aggressive behaviour. Countermeasures were often aggressive as well (reinforced medication, restraint e. g.). The results are discussed in the context of the literature, approaches to cope with and to reduce aggressions are mentioned briefly.

[Aggression of psychiatric patients--first results of a standardized documentation at the Gabersee district hospital]. / Aggressionen psychiatrischer Patienten--Erste Ergebnisse einer standardisierten Dokumentation des BZK Gabersee.

After a cluster of severe assaults against our staff we performed a standardized documentation concerning aggressive behaviour of in-patients at the BZK Gabersee, a major District Hospital with a typical spectrum of psychiatric patients. From July 1996 to March 2001 23037 patients were admitted and 1618 cases of aggressive behaviour were documented. About 75% of the patients were males, more than 50% were treated involuntarily. The aggressions were most frequently directed against the nursing staff, severe injuries occurred very rarely. We tried to analyse triggers and the individual motivations of aggressive behaviour. Countermeasures were often aggressive as well (reinforced medication, restraint e.g.). The results are discussed in the context of the literature, approaches to cope with and to reduce aggressions are mentioned briefly.