Alterations in GABAA Receptor Subunit Expression in the Amygdala and Entorhinal Cortex in Human Temporal Lobe Epilepsy.

The amygdala has long been implicated in the pathophysiology of human temporal lobe epilepsy (TLE). The different nuclei of this complex structure are interconnected and share reciprocal connections with the hippocampus and other brain structures, partly via the entorhinal cortex. Expression of GABAA receptor subunits α1, α2, α3, α5, ß2, ß2/3, and γ2 was evaluated by immunohistochemistry in amygdala specimens and the entorhinal cortex of 12 TLE patients and 12 autopsy controls. A substantial decrease in the expression of α1, α2, α3, and ß2/3 subunits was found in TLE cases, accompanied by an increase of γ2 subunit expression in many nuclei. In the entorhinal cortex, the expression of all GABAA receptor subunits was decreased except for the α1 subunit, which was increased on cellular somata. The overall reduction in α subunit expression may lead to decreased sensitivity to GABA and its ligands and compromise phasic inhibition, whereas upregulation of the γ2 subunit might influence clustering and kinetics of receptors and impair tonic inhibition. The description of these alterations in the human amygdala is important for the understanding of network changes in TLE as well as the development of subunit-specific therapeutic agents for the treatment of this disease.

The clinical relevance of distortion correction in presurgical fMRI at 7T.

Presurgical planning with fMRI benefits from increased reliability and the possibility to reduce measurement time introduced by using ultra-high field. Echo-planar imaging suffers, however, from geometric distortions which scale with field strength and potentially give rise to clinically significant displacement of functional activation. We evaluate the effectiveness of a dynamic distortion correction (DDC) method based on unmodified single-echo EPI in the context of simulated presurgical planning fMRI at 7T and compare it with static distortion correction (SDC). The extent of distortion in EPI and activation shifts are investigated in a group of eleven patients with a range of neuropathologies who performed a motor task. The consequences of neglecting to correct images for susceptibility-induced distortions are assessed in a clinical context. It was possible to generate time series of EPI-based field maps which were free of artifacts in the eloquent brain areas relevant to presurgical fMRI, despite the presence of signal dropouts caused by pathologies and post-operative sites. Distortions of up to 5.1mm were observed in the primary motor cortex in raw EPI. These were accurately corrected with DDC and slightly less accurately with SDC. The dynamic nature of distortions in UHF clinical fMRI was demonstrated via investigation of temporal variation in voxel shift maps, confirming the potential inadequacy of SDC based on a single reference field map, particularly in the vicinity of pathologies or in the presence of motion. In two patients, the distortion correction was potentially clinically significant in that it might have affected the localization or interpretation of activation and could thereby have influenced the treatment plan. Distortion correction is shown to be effective and clinically relevant in presurgical planning at 7T.

Field testing of ICHD-3 beta criteria of periictal headaches in patients with focal epilepsy - a prospective diary study.

Background To date we are lacking prospective data for field testing of ICHD-3 beta criteria for periictal headache (PIH). Methods Patients with focal epilepsy diagnosed by means of prolonged video-EEG monitoring completed a paper-pencil diary for three months and recorded seizures and headaches on a daily basis. According to ICHD-3 beta, we classified PIH, defined as headache present on a day with at least one seizure, as "7.6 headache related to epileptic seizure", "7.6.1 hemicrania epileptica" or "7.6.2 postictal headache". In addition, we compared the ICHD-3 beta diagnoses to the diagnoses according to ICHD-2. Results Thirty two patients completed the diary. Data analysis included 2,668 patient days, 300 seizures and 37 episodes of PIH. Two of these episodes (5.4%) were classified as headache related to seizure, three (8.1%) fulfilled both the criteria of headache related to seizure and hemicrania epileptica and four (10.8%) were postictal headaches. Twenty eight episodes (75.7%) did not fulfil any of the ICHD-3 beta criteria of seizure-related headaches, mostly because headache onset was before seizure onset. Applying ICHD-2 criteria allowed only one single episode of PIH to be classified as postictal headache. Discussion Our study is the first to present prospective field testing data of the ICHD-3 beta criteria for three types of seizure-related headaches. The majority of PIH episodes do not fulfil any of these criteria. One quarter can be classified according to ICHD-3 beta, whereas purely clinical diagnosis of PIH is markedly restricted in ICHD-2 because of mandatory electroencephalographic evidence.

GABAA receptor subunits in the human amygdala and hippocampus: Immunohistochemical distribution of 7 subunits.

GABAergic neurotransmission in the amygdala contributes to the regulation of emotional processes in anxiety, stress, reward, mnestic functions, addiction, and epilepsy. Species-specific differences in the distribution and composition of GABAA receptors may account for distinct effects and side-effects of GABAergic agents. However, data on the distribution and composition of GABAA receptors in the human amygdala are lacking. Here, the expression of GABAA receptor subunits α1, α2, α3, α5, ß2, ß2/3, and γ2 was studied in the human amygdala using immunohistochemistry. Hippocampi were evaluated as a reference structure. Neuronal counts and field fraction analyses were performed, and subcellular expression of GABAA receptor subunits was analyzed semiquantitatively. In the amygdala, field fraction analyses showed the highest α1 expression in the lateral nucleus (La), whereas α3 was prominent in intercalated nuclei (IC), and α5 and γ2 in the cortical nuclei, and amygdalo-hippocampal/parahippocampal-amygdala transition areas. In the hippocampus, α1 and α3 were accentuated in the dentate gyrus, CA1 region, and subiculum, whereas α5 expression was rather uniform. In both regions, α2 was homogenously distributed, and the two ß subunits and γ2 showed faint immunostaining. The intensity of subunit expression also varied in the neuropil, neuronal somata, and/or cellular processes in the subregions. GABAA receptors containing subunit α1, showing the strongest expression in the La, and α3, with the strongest expression in the IC and subiculum, could be targets for treating amygdala-related disorders. Differences in GABAA receptor subunit expression between the human and rodent amygdala should be taken into consideration when developing subunit-selective drugs.

Proteinuria and hemoglobin levels in patients with primary glomerular disease.

BACKGROUND: Anemia in association with nephrotic syndrome has been described in small patient series and case reports. Whether nephrotic patients develop anemia has not been formally investigated. METHODS: We undertook a retrospective cross-sectional study of patients with biopsy-proven primary glomerular disease, various degrees of proteinuria, and creatinine levels less than 2 mg/dL (< 177 micromol/L). In addition to proteinuria, values for hemoglobin (Hb), age, body mass index (BMI), serum albumin and protein, and estimated glomerular filtration rate (eGFR) were derived from patient charts. RESULTS: We studied 297 patients, 187 men and 110 women, aged between 16 and 81 years. Univariate analysis showed no correlation between Hb level and proteinuria in either sex. Stratification of women and men into quartiles according to proteinuria showed no differences in Hb levels among the 4 groups. Three of 52 non-nephrotic women (6%) were anemic (Hb < 12 g/dL [< 120 g/L]) compared with 11 of 58 nephrotic women (19%; P = 0.047). Multiple regression analysis of all patients showed Hb level to have a correlation with sex (P < 0.001), BMI (P < 0.001), and eGFR (P = 0.005); negative correlation with age (P = 0.028); and borderline negative correlation with proteinuria (P = 0.054). In women, BMI showed a positive correlation with Hb level (P = 0.030). Proteinuria did not reach statistical significance (P = 0.093). In men, BMI (P = 0.001) and eGFR (P = 0.013) were associated positively and age (P = 0.031) was associated negatively with Hb level. CONCLUSION: These results indicate that nephrotic syndrome is not associated with anemia in men, but with a tendency to decrease Hb levels in women.