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Resective Surgery Prevents Progressive Cortical Thinning in Temporal Lobe Epilepsy Galovic M, de Tisi J, McEvoy AW, et al. Brain. 2020;43(11):3262-3272. doi:10.1093/brain/awaa284Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal aging. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case–control neuroimaging study, we included patients with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural magnetic resonance imaging scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to aging-related cortical thinning in healthy patients, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 vs healthy volunteers 0.0032 ± 0.0013 mm/year, P < .0001) and right (right TLE 0.0198 ± 0.0016 vs healthy volunteers 0.0037 ± 0.0016 mm/year, P < .0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = .0006) or right (0.0052 ± 0.0020 mm/year, P = .0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal aging. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal aging. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.

GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI (‘MRI-negative’) and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. ‘Bandpass’ exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [VF; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (VS; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of VF and VS measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher VS in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P

Impairment of naming function is a critical problem for temporal lobe epilepsy patients, yet the neural correlates of the disruption of temporal lobe language networks are poorly understood. Using functional MRI, we investigated the activation and task-related functional connectivity of left temporal lobe language networks and their relation to clinical naming performance and disease characteristics. We studied 59 adult patients with temporal lobe epilepsy (35 left temporal lobe epilepsy) and 32 healthy controls with auditory and visual naming functional MRI tasks. Time series of activation maxima in the left posterior inferior temporal lobe were extracted to create a psychophysiological interaction regressor for subsequent seed-based whole-brain task-related functional connectivity analyses. Correlational analyses were performed to assess the association of functional MRI activation and functional connectivity with clinical naming scores, age of onset of epilepsy, and duration of epilepsy. Auditory naming elicited activation in the left posterior inferior temporal gyrus and visual naming in the left fusiform gyrus across all groups. Activations in the left inferior temporal gyrus, left thalamus and left supplementary motor region during auditory naming as well as left fusiform activations during picture naming correlated with better clinical naming performance. Functional connectivity analyses indicated coupling of left posterior inferior temporal regions to bilateral anterior and posterior temporal lobe regions and the bilateral inferior precentral gyrus as well as contralateral occipital cortex. Stronger functional connectivity was associated with better clinical naming performance in all groups. In patients with left temporal lobe epilepsy only, functional connectivity increased with later age of onset of epilepsy and shorter disease duration. This suggests that onset of seizures early in life and prolonged disease duration lead to disrupted recruitment of temporal lobe networks ipsilateral to the seizure focus, which might account for naming deficits in temporal lobe epilepsy.

SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug-refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III-IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting, a feature of temporal lobe epilepsy. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning (Spearman correlation, r = -0.63), recall (r = -0.44) and graded naming test scores (r = -0.50) over 1-year post-temporal lobe resection (P < 0.05). This relationship with tau burden was also present when examining decline in verbal learning from 3 months to 1 year post-resection (r = -0.54). We found an association between modified tau score and history of secondary generalized seizures (likelihood-ratio χ(2), P < 0.05) however there was no clear relationship between tau pathology and other clinical risk factors assessed. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications.

The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P

Anterior temporal lobe resection is an effective treatment for refractory temporal lobe epilepsy. The structural consequences of such surgery in the white matter, and how these relate to language function after surgery remain unknown. We carried out a longitudinal study with diffusion tensor imaging in 26 left and 20 right temporal lobe epilepsy patients before and a mean of 4.5 months after anterior temporal lobe resection. The whole-brain analysis technique tract-based spatial statistics was used to compare pre- and postoperative data in the left and right temporal lobe epilepsy groups separately. We observed widespread, significant, mean 7%, decreases in fractional anisotropy in white matter networks connected to the area of resection, following both left and right temporal lobe resections. However, we also observed a widespread, mean 8%, increase in fractional anisotropy after left anterior temporal lobe resection in the ipsilateral external capsule and posterior limb of the internal capsule, and corona radiata. These findings were confirmed on analysis of the native clusters and hand drawn regions of interest. Postoperative tractography seeded from this area suggests that this cluster is part of the ventro-medial language network. The mean pre- and postoperative fractional anisotropy and parallel diffusivity in this cluster were significantly correlated with postoperative verbal fluency and naming test scores. In addition, the percentage change in parallel diffusivity in this cluster was correlated with the percentage change in verbal fluency after anterior temporal lobe resection, such that the bigger the increase in parallel diffusivity, the smaller the fall in language proficiency after surgery. We suggest that the findings of increased fractional anisotropy in this ventro-medial language network represent structural reorganization in response to the anterior temporal lobe resection, which may damage the more susceptible dorso-lateral language pathway. These findings have important implications for our understanding of brain injury and rehabilitation, and may also prove useful in the prediction and minimization of postoperative language deficits. peerReviewed

Animal and limited human data suggest an important anticonvulsant role for opioid peptides and their receptors. We aimed to provide direct human in vivo evidence for changes in opioid receptor availability following spontaneous seizures. We scanned nine patients within hours of spontaneous temporal lobe seizures and compared their postictal binding of the non-subtype selective opioid receptor PET radioligand [11C]diprenorphine (DPN), quantified as a volume-of-distribution (VD), with interictal binding and with binding changes in 14 healthy controls, controlling for a range of behavioural variables associated with opioid action. A regionally specific increase of opioid receptor availability was evident in the temporal pole and fusiform gyrus ipsilateral to the seizure focus following seizures (Z 5.01, P < 0.001, 16 432 mm3). Within this region, there was a negative correlation between VD and log10 time since last seizure (r = -0.53, P < 0.03), compatible with an early increase and gradual return to baseline. [11C]DPN VD did not undergo systematic changes between time points in controls. This study provides direct human in vivo evidence for changes in opioid receptor availability over a time course of hours following spontaneous seizures, emphasizing an important role of the opioid system in seizure control.

Maintaining language functions after left hemisphere lesions has been associated with compensatory right hemisphere activation. It remains unclear whether recruitment of right hemisphere regions necessarily provides an effective mechanism to compensate for language deficits. To investigate the compensatory mechanisms that mediate good reading skills in patients after left anterior temporal lobe resection for mesial temporal lobe epilepsy (mTLE), we tested for the effect of their reading ability on the regional fMRI (functional MRI) signal elicited by sentence reading. Sixteen control subjects and 16 patients participated in the study. In the activation condition, they silently read nine-word sentences, and in the baseline condition they viewed nine-word sentences after all the letters were transformed into false fonts. Reading ability in controls and patients significantly (P < 0.05, corrected) predicted activations in a left hemisphere middle temporal region that was part of the normal sentence reading system. In addition, reading ability in patients, but not controls, significantly predicted activation in the right inferior frontal sulcus, right hippocampus and right inferior temporal sulcus. Right inferior frontal activation was only observed in the patients. In contrast, right hippocampal and inferior temporal activation was observed in all controls and in patients whose reading ability was within the normal range, indicating the importance of these regions for efficient encoding during normal sentence reading. We conclude that proficient reading skills following left anterior temporal lobe resection for mTLE rely on two mechanisms: (i) integrating regions from the normal system (i.e. the left middle temporal, right hippocampus and anterior superior temporal sulcus); and (ii) recruiting right hemisphere regions (i.e. the right inferior frontal sulcus) that are not activated in control subjects.

Psychosis of epilepsy (POE) has been recognized as a severe complication of chronic intractable epilepsy for more than a century. Most of the clinical symptoms of POE are reminiscent of schizophrenia. Nevertheless, there is general agreement that the phenomenology of POE differs from classical schizophrenia. The temporal lobe hypothesis of schizophrenia put forward in the 1960s notes that episodes with paranoid psychoses are more prevalent in temporal lobe epilepsy (TLE). However, the aetiology and pathogenesis of POE are poorly understood. One of the strongest biological findings in schizophrenia is volume loss of temporal lobe structures and the hippocampus in particular. In order to test the hypothesis that atrophy of the hippocampus and the amygdala is found in patients with TLE and POE, we performed a retrospective study of all patients with TLE who were admitted to the assessment unit of the Chalfont Centre for Epilepsy from 1995 until 1999. Twenty-six (2.6%) of these 1008 patients fulfilled inclusion criteria and were compared with 24 patients with TLE without psychopathology and 20 healthy volunteers. All patients underwent extensive MRI investigations, including volumetric data sets and quantitative T(2 )relaxometry. We found that patients with TLE and POE differed from patients with TLE alone and healthy volunteers in that the total brain volumes were significantly smaller. While there were no differences in hippocampal volumes between the three study groups, there was a significant 16-18% enlargement of the amygdala on both sides in patients with POE. Our findings support the notion that POE is a distinct nosologic entity differing from schizophrenia not only in clinical details but also in neurobiological aspects. The finding of amygdala enlargement agrees with the observation of an association between dysphoric disorders of epilepsy and POE described nearly 100 years ago.

Regional cerebral phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) was performed in 10 non- demented Parkinson's disease patients and nine age-matched control subjects. Five of the patients undergoing (31)P-MRS and four additional Parkinson's disease patients had cerebral 2-[(18)F]fluoro-2-deoxy-D-glucose PET ((18)FDG-PET), the results of which were compared with those of eight age-matched control subjects. All Parkinson's disease patients underwent neuropsychological testing including performance and verbal subtests of the Wechsler Adult Intelligence Scale-Revised, Boston Naming Test, Controlled Oral Word Association test (FAS Test) and California Learning Test to exclude clinical dementia. (31)P MR spectra from right and left temporo-parietal cortex, occipital cortex and a central voxel incorporating basal ganglia and brainstem were obtained. (31)P MR peak area ratios of signals from phosphomonoesters (PMEs), inorganic phosphate (P(i)), phosphodiesters (PDEs), alpha-ATP, gamma-ATP and phosphocreatine (PCr) relative to beta-ATP were measured. Relative percentage peak areas of PMEs, P(i), PDEs, PCr, and alpha-, beta- and gamma-ATP signals were also measured with respect to the total (31)P-MRS signal. Significant bilateral increases in the P(i)/beta-ATP ratio were found in temporoparietal cortex (P = 0.002 right and P = 0.014 left cortex) for the non-demented Parkinson's disease patients compared with controls. In the right temporoparietal cortex, there was also a significant increase in the mean relative percentage P(i) (P = 0.001). (18)FDG-PET revealed absolute bilateral reductions in glucose metabolism after partial volume effect correction in posterior parietal and temporal cortical grey matter (P < 0.01 and P < 0.05, respectively) for the Parkinson's disease group, using both volume of interest analysis and statistical parametric mapping. There were significant correlations between right temporoparietal P(i)/beta-ATP ratios and estimated reductions in performance IQ (r = 0.96, P < 0.001). Left temporoparietal P(i)/beta-ATP ratios correlated with full scale IQ and verbal IQ (r = -0.82, P = 0.006, r = -0.86, P = 0.003, respectively). In summary, temporoparietal cortical hypometabolism was seen in non-demented Parkinson's disease patients with both (31)P-MRS and (18)FDG-PET, suggesting that both glycolytic and oxidative pathways are impaired. This dysfunction may reflect either the presence of primary cortical pathology or deafferentation of striato-cortical projections. (31)P-MRS and (18)FDG-PET may both provide useful predictors of future cognitive impairment in a subset of Parkinson's disease patients who go on to develop dementia.

MRI scans of patients with idiopathic generalized epilepsy (IGE) are normal on visual assessment. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that patients with IGE had significantly larger cortical grey matter than control subjects. Further, 40% of individual patients with juvenile myoclonic epilepsy (JME), a syndrome of IGE in adolescence, had significant abnormalities of cerebral structure. In this study, we applied the automated and objective technique of statistical parametric mapping (SPM) to the analysis of structural MRI from 20 patients with JME and 30 control subjects. The cortical grey matter of each individual JME patient and the group of JME patients was contrasted with that of the group of 30 normal subjects. The voxel-based SPM comparison between the group of JME patients and the control subjects showed an increase in cortical grey matter in the mesial frontal lobes of the patients. Analysis of individual patients revealed significant abnormalities of cortical grey matter in five out of 20 JME patients, four of whom had been shown to have widespread abnormalities using the previous volume of interest technique. These findings indicate a structural cerebral abnormality in JME, with involvement of mesiofrontal cortical structures.

Malformations of cortical development (MCD) are an important aetiology of localization-related epilepsy. Previous MRI and [11C]flumazenil PET studies have demonstrated widespread structural and neuroreceptor abnormalities beyond the region of MCD that is visually apparent on MRI. We investigated the ability of brain regions affected by MCD to participate in normal cognitive and motor tasks and compared the responses seen in such patients with those in normal subjects. We studied five patients known to have MCD affecting the occipital region and seven normal subjects using H2 (15)O PET whilst they were performing a visual attention task. We also studied five right-handed patients known to have MCD affecting the left frontal lobe and seven right-handed normal subjects, using H2 (15)O PET whilst they were performing a motor learning task with the right hand. The patient and normal control data were examined using statistical parametric mapping to determine the ability of the brain region affected by MCD to participate in the task and also to detect evidence for atypical organization of cortical function in association with the MCD. Eight of the ten patients with MCD showed significant alteration of relative regional cerebral blood flow during the task compared with 'rest' in the affected brain region. These regions included focally dysgenetic cortex, the cortex lining schizencephalic clefts, heterotopic bands, subependymal grey matter heterotopia, and the cortex overlying band and subependymal heterotopia. In addition there was a significant alteration in the overall activation pattern in five patients compared with the normal control groups; in all five patients this atypical organization involved regions of cortex that appeared entirely normal on MRI. We conclude that regions of MCD may participate in normal cognitive functions but widespread cortical atypical organization may be seen. These findings have implications for surgical planning in any such patients.