E. Pauli

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1-CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.

Summary To elucidate, in a pilot‐study, whether noninvasive transcutaneous vagus nerve stimulation (t‐VNS) is a safe and tolerable alternative treatment option in pharmacoresistant epilepsy. t‐VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients’ seizure diaries. For a more reliable assessment of seizure frequency, we carried out prolonged outpatient video–electroencephalography (EEG) monitoring. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t‐VNS. The noninvasive t‐VNS stimulation is a safe and well‐tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy.

PURPOSE: Cortical dysplasia (FCD) is a frequent cause of epilepsy in childhood. Two major pathological variants are distinguished, FCD type I and II. The aim of the study was to characterize differences between FCD type I and II with respect to imaging and EEG findings, clinical and neuropsychological presentations, and surgical outcome. METHODS: Forty children with refractory epilepsy and histopathologically confirmed FCD were retrospectively analyzed. FCD type I was identified in 24 and FCD type II in 16 patients. RESULTS: Characteristic MRI abnormalities in FCD type I included subtle white matter signal changes and regional reduction of the white matter volume. Typical MRI findings in FCD type II were increased cortical thickness, transmantle sign, gray-white matter junction blurring, fluid-attenuated inversion recovery (FLAIR) and proton density (PD) gray matter signal changes as well as T1w, and PD white matter signal changes. Continuous EEG slowing was significantly more common in patients with FCD type I. Children with FCD type I presented with lower levels of intelligence and were suffering more often from maladaptive behavior and behavioral disorders. Surgical outcome was significantly worse in the FCD type I group (seizure freedom was achieved in 21% FCD type I patients and in 75% FCD type II subjects, p < 0.001). CONCLUSIONS: Clinically important differences were found in children with distinct histopathological subtypes of FCD. Due to prominent neuropsychological deficits and worse seizure outcome, treatment strategies in FCD type I are more challenging than previously reported and these children should be recognized and specifically addressed within the incoherent group of patients with malformative brain disorders.

To clarify the anatomical organization of human memory remains a major challenge in clinical neuroscience. Experimental data suggest dentate gyrus granule cells play a major role in memory acquisition, i.e. pattern separation and rapid pattern completion, whereas hippocampal CA1 neurons are implicated in place memory and autobiographical memory retrieval. Patients with temporal lobe epilepsy present with a broad spectrum of memory impairment, which can be assessed during clinical examination. Although long seizure histories may contribute to a pathophysiological reorganization of functional connectivity, surgical resection of the epileptic hippocampus offers a unique possibility to anatomically study the differential contribution of hippocampal subfields to compromised learning and memory in humans. Herein, we tested the hypothesis of hippocampal subfield specialization in a series of 100 consecutive patients with temporal lobe epilepsy submitted to epilepsy surgery. Memory profiles were obtained from intracarotid amobarbital testing and non-invasive verbal memory assessment before surgery, and correlated with histopathologically quantified cell loss pattern in hippocampal subfields obtained from the same patients using the new international consensus classification for hippocampal sclerosis proposed by the International League against Epilepsy (HS ILAE). Interestingly, patients with CA1 predominant cell loss (HS ILAE Type 2; n = 13) did not show declarative memory impairment and were indistinguishable from patients without any hippocampal cell loss (n = 19). In contrast, 63 patients with neuronal loss affecting all hippocampal subfields including CA1, CA4 and dentate gyrus (HS ILAE Type 1), or predominant cell loss in CA4 and partially affecting also CA3 and dentate gyrus (HS ILAE Type 3, n = 5) showed significantly reduced declarative memory capacities (intracarotid amobarbital testing: P < 0.001; verbal memory: P < 0.05). Our results suggested an alternative model of how memory processing can be organized amongst hippocampal subfields, and that CA1 pyramidal cells are less critically involved in declarative human memory acquisition compared to dentate gyrus granule cells or CA4/CA3 pyramidal cells.

The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 ± 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 ± 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R²(adjusted) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R²(adjusted) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.