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Abstract: In the present study patients with previously diagnosed MRI-negative temporal lobe epilepsy (TLE) on long-term video electroencephalography (VEEG) monitoring were re-evaluated with high resolution 3T MRI brain to look out for a skull base temporal lobe encephalocoele (TE). A total of 234 VEEGs were analyzed. TLE had been diagnosed in 104 patients based on semiology, ictal, interictal EEG data, and brain positron emission tomography (PET) studies. Of these, 99 patients had temporal lobe abnormality (78 had mesial temporal sclerosis, 8 had tumor, 3 had focal cortical dysplasia, and 10 had mixed pathology). Out of the five 1.5T MRI-negative TLE patients, two patients were diagnosed with TE on subsequent 3T MRI brain scans and one patient underwent electrocorticography-guided tailored resection for complete removal of epileptogenic tissue; with Engels class I seizure freedom at one year follow-up. We propose that TE should be carefully searched for, as a cause of refractory TLE, using high-resolution MRI sequences., (Copyright © 2023 Copyright: © 2023 Journal of Postgraduate Medicine.)

Purpose: To identify patients with adult-onset temporal lobe epilepsy (TLE) at risk of developing cognitive decline. Detecting which patients, aetiologies, or factors are most closely related with memory decline would allow us to identify patients that would eventually benefit from more specific treatment., Methods: Single centre, retrospective analysis of a prospectively followed-up cohort study, including all patients with the diagnosis of adult-onset TLE during 2013, with a minimum follow-up of five years. Memory and cognitive decline were analysed at 5 years and at last follow-up., Results: Of 89 initially selected patients, 71 were included. After 5 years, 11/71 (15.5%) patients suffered cognitive decline, of which 1/71 (4%) developed dementia. At last follow-up (range 65-596 m) a total of 34/71 (47.8%) patients were diagnosed with cognitive decline, specifically either memory decline or dementia. Cognitive decline at 5 years was related to: 1. Age at onset: 62.65 years (SD 9.04) in the group with cognitive decline vs 50.33 y. (SD 13.02 in the group without cognitive decline; p=0.004); 2. Onset as status epilepticus (3/6 in patients with memory decline vs 8/65 in patients without cognitive decline; p=0.04); 3. Immune aetiology: 42% compared with unknown (10%) and structural (10%) aetiologies; p=0.036; 4. Hippocampal sclerosis on MRI: 5/11 patients with cognitive decline vs 9/51 patients without cognitive decline; p=0.035. Cognitive decline was not related to seizure frequency, sex, or age (p=0.78; p=0.40; p=0.95, respectively)., Conclusions: Older age at epilepsy onset, onset as status epilepticus, immune aetiology, and hippocampal sclerosis are risk factors for developing cognitive decline in patients with adult-onset temporal lobe epilepsy., Competing Interests: Declaration of Competing Interest All authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Eating-induced seizures (EIS) are a rare form of reflex seizures. The objective of this study was to report a series of cases of EIS involving patients admitted to our epilepsy unit, and to analyze the clinical characteristics, etiology, and treatment response of this type of infrequent seizure., Methods: We performed a single-center retrospective analysis of all consecutive patients diagnosed with epilepsy with eating-induced seizures between 2008 and 2020., Results: We included eight patients (six women) with mean age 54.75 years (range: 40-79), and mean age at epilepsy onset 30.75 years (range: 9-58 years). EIS were triggered during a meal in 5/8 (at dinner 1/8, at breakfast in 1/8, and without time preference in 3/8), by a certain flavor in 1/8, by eating different textures or drinking soft drinks in 1/8, and by slicing food in 1/8. All patients suffered nonreflex seizures and 3/8 other types of reflex seizures. In 6/8 of patients, EIS originated in the right hemisphere. In 5/8, the EIS progressed to impaired awareness with oromandibular automatisms. In 6/8, the epilepsy was drug-resistant. Temporopolar encephalocele was the most frequent etiology, in 4/8. Three of the eight underwent surgical treatment, with Engel IA 1 year in 3/3. Three of the eight were treated with vagal stimulation therapy, with McHugh A 1 year in 2/3., Significance: In our series, eating-induced seizures were observed in patients with focal epilepsy. It was frequently drug-resistant and started predominantly in the right hemisphere, due to temporal pole involvement in half of the patients., (© 2023 International League Against Epilepsy.)

Background: Temporal lobe encephaloceles (TEs) are a rare cause of drug-resistant temporal lobe epilepsy (DR-TLE), with head trauma and obesity identified as risk factors in adults. This study evaluated the clinical characteristics of childhood-onset DR-TLE due to TE., Methods: This is a single-institution retrospective review of childhood-onset DR-TLE with radiographic TE identified between 2008 and 2020. The epilepsy history, brain imaging features, and surgical outcomes were collected., Results: Eleven children with DR-TLE due to TE were included (median age at epilepsy onset was 11 years, interquartile range 8.5 to 13.5 years). Median latency between epilepsy diagnosis and TE detection was 3 years (range of 0 to 13 years). None had history of head trauma. Body mass index greater than 85 percentile for age and sex was seen in 36% of the children. No patient had bilateral TE identified. TEs were diagnosed based on epilepsy surgery conference re-review of imaging in 36% of cases. All herniations were contained defects without osseous dehiscence. Regional fluorodeoxyglucose (FDG) hypometabolism ipsilateral to the encephalocele was seen in all children who had FDG-positron emission tomography (PET) of the brain. Of the children who had surgery, 70% were seizure free or had nondisabling seizures at last follow-up (mean follow-up 52 months)., Conclusions: TE is a surgically remediable etiology of DR-TLE in childhood. TEs are often overlooked at pediatric epilepsy diagnosis, calling for the need to increase awareness of this entity. FDG-PET temporal hypometabolism in children with presumed nonlesional DR-TLE should be carefully examined for occult TEs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Anterior temporal lobectomy (ATL) is a safe and well-validated procedure in the treatment of temporal lobe epilepsy (TLE), but is a challenging technique to master and still confers a risk of morbidity and mortality due to the complex anatomy of the mesial temporal lobe structures. Automated robotic 3D exoscopes have been developed to address limitations traditionally associated with microscopic visualization, allowing for ergonomic, high-definition 3D visualization with hands-free control of the robot. Given the potential advantages of using such a system for visualization of complex anatomy seen during mesial structure resection in ATL, this group sought to investigate impact on the percentage of hippocampal resection in both exoscope and microscope guided procedures., Methods: We conducted a retrospective analysis of 20 consecutive patients undergoing standard ATL for treatment of medically refractory TLE at our institution. Using pre-operative and post-operative imaging, the coronal plane cuts in which either the head, body, or tail of the hippocampus appeared were counted. The number of cuts in which the hippocampus appeared were multiplied by slice thickness to estimate hippocampal length., Results: Mean percentage of hippocampal resection was 61.1 (SD 13.1) and 76.5 (SD 6.5) for microscope and exoscope visualization, respectively (p = 0.0037)., Conclusion: Use of exoscope for mesial resection during ATL has provided good visualization for those in the operating room and the potential for a safe increase in hippocampal resection in our series. Further investigation of its applications should be evaluated to see if it will improve outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Epileptic seizure is the common symptom associated with lipomas in the Sylvian fissure (Sylvian lipomas). Removal of these lipomas carries risks of hemorrhage and brain damage. We report a surgical strategy of not removing the lipoma in a case of intractable temporal lobe epilepsy associated with Sylvian lipoma. We performed anterior temporal lobectomy with preservation of the pia mater of the Sylvian fissure and achieved seizure freedom. Focal cortical dysplasia type 1 of the epileptic neocortex adjacent to the Sylvian lipoma was pathologically diagnosed. We recommend our surgical procedure in similar cases to avoid complications and achieve adequate seizure control., (© 2022. The Author(s).)

In recent years there has been increased attention to the proposed entity of feline temporal lobe epilepsy (TLE). Epileptic discharges in certain parts of the temporal lobe elicit very similar semiology, which justifies grouping these epilepsies under one name. Furthermore, feline TLE patients tend to have histopathological changes within the temporal lobe, usually in the hippocampus. The initial aetiology is likely to be different but may result in hippocampal necrosis and later hippocampal sclerosis. The aim of this article was not only to summarise the clinical features and the possible aetiology, but also being work to place TLE within the veterinary epilepsy classification. Epilepsies in cats, similar to dogs, are classified based on the aetiology into idiopathic epilepsy, structural epilepsy and unknown cause. TLE seems to be outside of this classification, as it is not an aetiologic category, but a syndrome, associated with a topographic affiliation to a certain anatomical brain structure. Magnetic resonance imaging, histopathologic aspects and current medical therapeutic considerations will be summarised, and emerging surgical options are discussed., Competing Interests: Conflict of interest statement None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Although rare, temporal encephalocele is an important causative agent in surgically remediable drug-refractory epilepsy. The ideal treatment for temporal encephalocele remains unclear with a variety of resective surgeries recommended. Here, we analyse patient data on temporal encephalocele with a view to highlighting diagnostic clues and management strategies., Methods: Comprehensive databases at Deenanath Mangeshkar Hospital, Pune from January 2015 to June 2019 were reviewed for this observational study. Of 107 temporal lobe epilepsy surgery patients, nine individuals with temporal encephalocele were identified, who formed the study cohort. Their clinical, neuropsychological, EEG, imaging and long-term outcome data were analysed., Results: The study cohort consisted of seven males and two females with a mean age of 22 years. Epilepsy onset age varied from 4.5 to 19 years. Seven patients had focal non-motor seizures with impaired awareness, while two patients had focal motor seizures. Temporal encephalocele detection by MRI was reported in only two patients, and was missed in seven individuals. Three patients underwent standard anterior temporal lobectomy while the remaining six underwent resection of the temporal encephalocele with surrounding temporal pole. Eight patients showed Engel Class I outcome and one showed Class IIa outcome after a mean follow-up duration of 27 months (17-44 months). Histopathology confirmed gliosis in seven, hippocampal sclerosis type I in one and suspicious dyslamination with prominent gliosis in one patient. Six of eight patients reported an improvement in their psychological state (mood, anxiety and motivation) over time., Significance: A careful review of MRI in patients with temporal lobe epilepsy is necessary, followed by investigations for the presence of an encephalocele. When temporal lobe epilepsy is associated with encephalocele, tailored resection of the encephalocele and the surrounding temporal pole, sparing mesial temporal structures, demonstrates excellent long-term clinical and neuropsychological outcome.

Case Series Summary: Seven cases of feline hippocampal and piriform lobe necrosis (FHN) are described, with particular emphasis on clinical, radiographic and histopathological correlations. FHN is an uncommon acute epileptic condition resembling human autoimmune limbic encephalitis and temporal lobe epilepsy. Seizures are typically focal and feature uni- or bilateral orofacial or head twitching, hypersalivation, lip smacking, mydriasis, vocalisation and motionless staring, with inter-ictal behavioural changes such as unprovoked aggression and rapid running. Emerging evidence supports an autoimmune aetiology, although disruption of hippocampal architecture secondary to brain neoplasia has also been recognised. Most commonly, however, the underlying cause remains unknown. Diagnosis is achieved clinically and with brain MRI; electroencephalography and voltage-gated potassium channel-complex autoantibodies are currently the subject of research. Affected cats are frequently refractory to conventional antiepileptic treatment., Relevance and Novel Information: Following a review of the literature, including potential complicating factors and comparisons with human medicine, the hippocampus and piriform lobe are proposed as the neuroanatomical localisation for focal seizures with orofacial involvement in cats, regardless of aetiology.

Epilepsy and Alzheimer's disease (AD) incidence increases with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age, and abnormal AD biomarkers in PET and/or CSF are frequently found in late-onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes, including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation, leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies, suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy, share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology, such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate the progression of cognitive decline, and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly patients without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with an altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASMs). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.

A 31-year-old male with history of bipolar disorder, suicidal attempts requiring inpatient hospitalization, and seizures on antiepileptic medications presented with increasing seizure frequency. He was neurologically intact yet had multiple facial, axillary, and inguinal flat pigmented macules (cafe au lait spots) and ophthalmologic examination with iris hamartomas (Lisch nodules) consistent with neurofibromatosis type 1. Electroencephalogram was notable for multiple right temporal lobe seizures with anterior temporal interictal epileptiform discharges. Magnetic resonance imaging revealed a T2 hyperintense mass centered in the right amygdala, contiguous with the cystic area. Preoperative intracarotid sodium amobarbital testing showed left-sided language and memory dominance. The patient was operated on for right amygdalohippocampectomy, and initial pathology was consistent with a low-grade neuroepithelial neoplastic process. Further pathologic examination found hypercellular proliferation of predominantly bland, spindled cells with scattered, embedded neurocytic elements with dysplastic appearance, consistent with low-grade glioma. The patient was clinically diagnosed with neurofibromatosis type 1., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease. Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n  = 8) or pure water ( n  = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures. Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition. Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.

This article analyzes data from scientific publications (mainly reviews) concerning the link between human neurocysticercosis and epilepsy. Along with data from our own studies on experimental hippocampal sclerosis induced by a Taenia crassiceps metacestode factor in mice, it explores the connection between mechanisms that likely favor the development of epilepsy in cases of human neurocysticercosis. The data from both sources suggest the idea that the T. solium metacestode factor causes hippocampal sclerosis and later epilepsy in humans with neurocysticercosis.

Prevention or modification of acquired epilepsy in patients at risk is an urgent, yet unmet, clinical need. Following acute brain insults, there is an increased risk of mesial temporal lobe epilepsy (mTLE), which is often associated with debilitating comorbidities and reduced life expectancy. The latent period between brain injury and the onset of epilepsy may offer a therapeutic window for interfering with epileptogenesis. The pilocarpine model of mTLE is widely used in the search for novel antiepileptogenic treatments. Recent biochemical studies indicated that cholinergic mechanisms play a role in the epileptogenic alterations induced by status epilepticus (SE) in this and other models of mTLE, which prompted us to evaluate whether treatment with the muscarinic antagonist scopolamine during the latent period after SE is capable of preventing or modifying epilepsy and associated behavioral and cognitive alterations in female Sprague-Dawley rats. First, in silico pharmacokinetic modeling was used to select a dosing protocol by which M-receptor inhibitory brain levels of scopolamine are maintained during prolonged treatment. This protocol was verified by drug analysis in vivo. Rats were then treated twice daily with scopolamine over 17 days after SE, followed by drug wash-out and behavioral and video/EEG monitoring up to ~6 months after SE. Compared to vehicle controls, rats that were treated with scopolamine during the latent period exhibited a significantly lower incidence of spontaneous recurrent seizures during periods of intermittent recording in the chronic phase of epilepsy, less behavioral excitability, less cognitive impairment, and significantly reduced aberrant mossy fiber sprouting in the hippocampus. The present data may indicate that scopolamine exerts antiepileptogenic/disease-modifying activity in the lithium-pilocarpine rat model, possibly involving increased remission of epilepsy as a new mechanism of disease-modification. For evaluating the rigor of the present data, we envision a study that more thoroughly addresses the gender bias and video-EEG recording limitations of the present study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood-brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events., (© 2021. The Author(s).)

Introduction: Bitemporal epilepsy (biTLE), a potential cause of failure in TLE surgery, is rarely associated with unilateral HS and could be suggested by not lateralizing ictal scalp EEG/interictal PET-FDG findings. We evaluated the proportion of biTLE in a population of drug-resistant TLE-HS subjects who underwent intracranial investigation for lateralizing purpose., Methods: We retrospectively included all consecutive refractory TLE-HS patients and not lateralizing ictal scalp EEG/interictal PET-FDG findings, investigated by intracranial bilateral longitudinal hippocampal electrodes. Demographic characteristics, electroclinical findings and seizure outcome were evaluated., Results: We identified 14 subjects (7 males; mean age 39.5 years; mean age at disease onset 14.4 years), 7 of them had biTLE diagnosed after intracranial investigations. In the remaining 7 with unilateral epileptogenesis (uniTLE) anterior temporal lobectomy was performed (6/7 were in Engel class I). Preoperative neuropsychological assessment differentiated biTLE from uniTLE, as it was normal in six uniTLE patients but only in one with biTLE (p < 0.05)., Conclusions: Not lateralizing ictal scalp EEG and functional imaging findings in TLEHS should alert about the possibility of a true biTLE also in presence of unilateral findings at MRI. Intracranial investigations with bilateral longitudinal hippocampal electrodes can localize the EZ with a good risk-benefit profile. Consistently with the warning on memory functions in TLE patients explored by using longitudinal hippocampal electrodes, further studies are needed to better define the optimal investigation strategy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Various factors have been considered as potential seizure precipitants. We here assessed the temporal association of food intake and seizure occurrence, and characteristics of seizures and epilepsy syndromes involved. 596 seizures from 100 consecutive patients undergoing long-term video-EEG monitoring were analyzed. Preictal periods of 60 min were assessed as to the occurrence of food intake, and latencies between food intake and seizure onset were analyzed. Seizures of temporal origin were highly significantly more frequently preceded by food intake compared to those of extratemporal origin; and were associated with shorter food intake-seizure latency. Seizure precipitation by food intake showed male predominance. Shorter food intake-seizure latency was associated with less severe seizures and less frequent contralateral spread of epileptic discharges. We here show for the first time that not only in specific rare reflex epilepsies but in the most frequent form of focal epilepsy, temporal lobe epilepsy, seizures are significantly precipitated by food intake. Seizure occurrence was increased over a period of up to one hour following food intake, and remained more localized in terms of both ictal EEG spread and as reflected by seizure severity. This finding supports the emerging concepts of ictogenesis, implying a continuum between reflex and spontaneous seizures-instead a dichotomy between them., (© 2021. The Author(s).)

G-protein coupled estrogen receptor 1 (GPER1) is a novel type of estrogen receptor. Several studies have shown that it has an anti-inflammatory action,which plays an important role in remyelination and cognitive ability adjustment. However, whether it is involved in the development of temporal lobe epilepsy (TLE) is still unknown. The present study established a TLE model by intraperitoneal injection of lithium chloride (3 mmol/kg) and pilocarpine (50 mg/kg) in rats to study the effect of GPER1 in the synaptic plasticity during the development of temporal lobe epilepsy. A microinjection cannula was implanted into the lateral ventricle region of rats via a stereotaxic instrument. G-1 is the specific GPER1 agonist and G15 is the specific GPER1 antagonist. The G1 or G15 and Dimethyl sulfoxide were injected into the rat brains in the intervention groups and control group, respectively. After G1 intervention, the learning and memory abilities and hippocampal neuron damage in epileptic rats were significantly improved, while G15 weakened the neuroprotective effect of GPER1. Meanwhile, G1 controlled the abnormal formation of hippocampal mossy fiber sprouting caused by seizures, and participated in the regulation of synaptic plasticity by reducing the expression of Synapsin I and increasing the expression of gephyrin. Inhibitory synapse gephyrin may play a significant role in synaptic plasticity.

Temporal lobe epilepsy (TLE) is the most common epilepsy type. TLE onset in infancy aggravates features like severity, drug responsiveness, or development of comorbidities. These aggravations may arise from altered micro RNA (miRNA) expression specific to the early onset of the disease. Although the miRNA involvement in TLE is widely studied, the relationship between the onset-age and miRNA expression has not been addressed. Here, we investigated the miRNA profile of infantile and adult-onset TLE in rats combining sequencing and PCR. Since miRNA expression changes with the disease progression, we scrutinized miRNA dynamics across three stages: acute, latent, and chronic. We report that infantile-onset TLE leads to changes in the expression of fewer miRNAs across these stages. Interestingly, the miRNA profile in the acute stage of infantile-onset TLE overlaps in dysregulation of miR-132-5p, -205, and -211-3p with the chronic stage of the disease starting in adulthood. The analysis of putative targets linked the majority of dysregulated miRNAs with pathways involved in epilepsy. Our profiling uncovered miRNA expression characteristic for infantile and adulthood-onset epileptogenesis, suggesting the distinct biology underlying TLE in the onset age-dependent matter. Our results indicate the necessity of addressing the onset age as an important parameter in future epilepsy research.

The present study performed a detailed analysis of behavior in a rat model of epilepsy using both established and novel methodologies to identify behavioral impairments that may differentiate between animals with a short versus long latency to spontaneous seizures and animals with a low versus high number of seizures. Temporal lobe epilepsy was induced by electrical stimulation of the amygdala. Rats were stimulated for 25 min with 100-ms trains of 1-ms biphasic square-wave pluses that were delivered every 0.5 s. Electroencephalographic recordings were performed to classify rats into groups with a short latency (< 20 days, n = 7) and long latency (> 20 days, n = 8) to the first spontaneous seizure and into groups with a low number of seizures (62 ± 64.5, n = 8) and high number of seizures (456 ± 185, n = 7). To examine behavioral impairments, we applied the following behavioral tests during early and late stages of epilepsy: behavioral hyperexcitability, open field, novel object exploration, elevated plus maze, and Morris water maze. No differences in stress levels (e.g., touch response in the behavioral hyperexcitability test), activity (e.g., number of entries into the open arms of the elevated plus maze), or learning (e.g., latency to find the platform in the Morris water maze test during training days) were observed between animals with a short versus long latency to develop spontaneous seizures or between animals with a low versus high number of seizures. However, we found a higher motor activity measured by higher number of entries into the closed arms of the elevated plus maze at week 26 post-stimulation in animals with a high number of seizures compared with animals with a low number of seizures. The analysis of the Morris water maze data categorized the strategies that the animals used to locate the platform showing that the intensity of epilepsy and duration of epileptogenesis influenced swimming strategies. These findings indicate that behavioral impairments were relatively mild in the present model, but some learning strategies may be useful biomarkers in preclinical studies.

A 24-year-old woman was referred to us for an intracranial haemorrhage in the left temporal lobe caused by a ruptured cavernous malformation; the bleeding extended over the left Heschl's gyrus and Wernicke area. On admission, the patient had global aphasia. A few days later, she spontaneously improved but remained with mild residual comprehensive dysphasia. She reported hearing, in her right ear, recently heard words, which is consistent with palinacousis. Auditory acuity testing was normal. EEG showed focal slowing in the left temporal region with no epileptiform activity. During awake surgery for resection of the cavernous malformation, stimulation of the superior temporal gyrus did not provoke palinacousis. The patient made good recovery with complete resolution of the aphasia and no recurrence of palinacousis. We aimed to review this phenomenon and to provide a systematic review of the current literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models.

Objective: Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved., Methods: Here, we scrutinized pathogenic consequences emerging from CD8 + T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1 -/- mice (termed "OVA-CD8 + LE model")., Results: Viral-mediated antigen transfer caused dense CD8 + T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8 + T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8 + LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8 + T cells specifically targeted OVA-expressing, SIINFEKL-H-2K b -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8 + T cells escorted by NK cells., Interpretation: These data indicate that a CD8 + T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8 + T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

This case was a 50-year-old healthy woman. After repeated transient amnesia, she developed tonic-clonic seizures and was admitted to our hospital. The brain MRI showed FLAIR hyperintensities in the left temporal lobe and EEG showed an epileptic discharge starting from the left temporal region. Based on these findings, we diagnosed temporal lobe epilepsy associated with acute limbic encephalitis. While she experienced recurrent transient amnesia, her cognitive functions were preserved except for her memory. These symptoms and EEG findings were consistent with transient epileptic amnesia (TEA). Acute limbic encephalitis that occurred in a healthy middle-aged woman may be antibody-mediated encephalitis, requiring immediate immunotherapies. In this case, GABA B receptor antibodies in cerebrospinal fluid were found positive. This is the first report showing that TEA was caused by GABA B receptor autoimmune encephalitis.

Background: Hippocampal sclerosis (HS) may be associated with focal cortical dysplasia IIIa (FCD IIIa) in patients undergoing surgery for temporal lobe epilepsy (TLE)., Objective: To investigate whether the anatomo-electro-clinical profile and surgical outcome in patients with HS-related TLE are affected by coexisting FCD IIIa., Methods: A total of 220 patients, operated in 5 centers, with at least 24 mo follow-up (FU), were retrospectively studied. Preliminary univariate and subsequent multivariate analyses were performed to investigate possible associations between several potential presurgical, surgical, and postsurgical predictors and different variables (Engel's class I and Engel's class Ia, co-occurrence of FCD IIIa)., Results: At last available postoperative control (FU: range 24-95 mo, median 47 mo), 182 (82.7%) patients were classified as Engel's class I and 142 (64.5%) as Engel's class Ia. At multivariate analysis, extension of neocortical resection and postoperative electroencephalogram were significantly associated with Engel's class I, whereas length of FU had a significant impact on class Ia in the whole cohort and in isolated HS (iHS) patients, but not in the FCD IIIa group. No differences emerged in the anatomo-electro-clinical profile and surgical results between patients with FCD IIIa and with iHS., Conclusion: Coexistence of FCD IIIa did not confer a distinct anatomo-electro-clinical profile to patients with HS-related epilepsy. Postoperative seizure outcome was similar in FCD IIIa and iHS cases. These findings indicate limited clinical relevance of FCD IIIa in HS-related epilepsy and might be useful for refining future FCD classifications. Further studies are needed to clarify the correlation of class Ia outcome with the duration of FU., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Aim: To investigate the relationship between clinical features and prognosis of the hippocampal sclerosis (HS) cases and International League Against Epilepsy (ILAE) histopathology classification., Material and Methods: A hundred patients with refractory epilepsy who were operated with the diagnosis of the Mesial Temporal Lobe Epilepsy were included in the study. Socio-demographic characteristics, clinical and family histories, post-operative ILAE and Engel epilepsy scores and diagnostic tests were recorded. At the same time, all of the pathological specimens were classified according to the new semi-quantitative ILAE classification. A significant statistical relationship was investigated between clinical data and HS-ILAE groups., Results: There were 36 male 64 female patients. The mean follow-up period was 6.5 years. 75% of the cases were HS-ILAE type 1, 19% HS-ILAE type 2, 6% were unidentifiable. FCD3A was detected in 3 patients. The HS-ILAE Type 2 ratio was high on the rightsided cases. In addition, HS-ILAE Type 1 ratio was high in patients with early seizure onset and long duration of epilepsy. There was no significant relationship between long-term ILAE and Engel epilepsy outcome scores and HS-ILAE types., Conclusion: Resection of mesiotemporal structures in hippocampal sclerosis provides seizure control in at least two-thirds of cases. Histopathological findings may help us understand the epileptogenicity-prognosis of HS. The relationship between ILAE histopathology classification and clinical factors will become more obvious in the future. According to our study, there was a relationship between onset age of epilepsy, epilepsy duration, lesion side and HS-ILAE types. The reinforcement of these relationships with larger series will benefit clinicians.

Surgery is an effective approach for drug-resistant temporal lobe epilepsy following hippocampal sclerosis. There is still no clear and unanimous opinion about advantages and disadvantages of certain surgical technique., Material and Methods: There were 103 surgical interventions in 101 patients. Females prevailed (1.45:1). Age of patients ranged from 16 to 56 years (median 28). Anteromedial temporal lobectomy and selective amygdaloghippocampectomy were performed in 49 (47.6%) and 54 (52.4%) patients, respectively. In the latter group, 30 patients were operated via a 14-mm burr hole-subtemporal approach. Postoperative outcomes were assessed using the Engel grading system. The follow-up period ranged from 2 to 8 years (median 4 years)., Results: By the 2 nd year, Engel class I was observed in 74 (72%) patients, Engel II, III and IV - in 20 (19.4%), 6 (5.8%) and 3 (2.9%) patients, respectively. Engel class I was achieved after anteromedial temporal lobectomy in 68% of cases, selective amygdaloghippocampectomy via standard approaches in 75% of cases, amygdaloghippocampectomy via subtemporal burr hole approach - in 80% of cases. Neurocognitive impairments after anteromedial lobectomy and selective amygdaloghippocampectomy were similar. At the same time, mental disorders de novo prevailed in the group of anteromedial lobectomy ( p <0.05). There were no severe visual field disorders after subtemporal burr-hole access. In other cases, these disorders occurred in 36.2% of patients ( p <0.05). There were 8 (7.8%) postoperative complications: 5 (10.2%) - after anterior temporal lobectomy, 3 (5.5%) - after selective surgeries via standard approaches. There were no complications after burr-hole surgery., Conclusion: Selective amygdaloghippocampectomy is not inferior to anteromedial lobectomy. Moreover, this procedure is associated with a lower risk of complications and adverse events.

The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with epilepsy and those from animal models of epilepsy have revealed that microglia are excessively activated, especially in the hippocampus. These findings suggest that microglia may contribute to the onset and aggravation of epilepsy; however, direct evidence for microglial involvement or the underlying mechanisms by which this occurs remain to be fully discovered. To date, neuron-microglia interactions have been vigorously studied in adult epilepsy models; such studies have clarified microglial responses to excessive synchronous firing of neurons. In contrast, the role of microglia in the postnatal brain of patients with epileptic seizures remain largely unclear. Some early-life seizures, such as complex febrile seizures, have been shown to cause structural and functional changes in the brain, which is a risk factor for future development of epilepsy. Because brain structure and function are actively modulated by microglia in both health and disease, it is essential to clarify the role of microglia in early-life seizures and its impact on epileptogenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

To investigative whether radiomics features in bilateral hippocampi from MRI can identify temporal lobe epilepsy (TLE). A total of 131 subjects with MRI (66 TLE patients [35 right and 31 left TLE] and 65 healthy controls [HC]) were allocated to training (n = 90) and test (n = 41) sets. Radiomics features (n = 186) from the bilateral hippocampi were extracted from T1-weighted images. After feature selection, machine learning models were trained. The performance of the classifier was validated in the test set to differentiate TLE from HC and ipsilateral TLE from HC. Identical processes were performed to differentiate right TLE from HC (training set, n = 69; test set; n = 31) and left TLE from HC (training set, n = 66; test set, n = 30). The best-performing model for identifying TLE showed an AUC, accuracy, sensitivity, and specificity of 0.848, 84.8%, 76.2%, and 75.0% in the test set, respectively. The best-performing radiomics models for identifying right TLE and left TLE subgroups showed AUCs of 0.845 and 0.840 in the test set, respectively. In addition, multiple radiomics features significantly correlated with neuropsychological test scores (false discovery rate-corrected p-values < 0.05). The radiomics model from hippocampus can be a potential biomarker for identifying TLE.

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and hippocampal sclerosis (HS) is the most common pathological substrate of TLE. Considering the significant consequences of uncontrolled seizures (e.g. increased morbidity and mortality), epilepsy prevention remains a necessity that potentially could save many lives. Human herpes virus-6 (HHV-6) has been linked to TLE in humans. The relationship between HHV-6 and HS-TLE could be attributed to a neuro-inflammatory cascade triggered by the infection, involving direct neuronal damage and production of several pro-inflammatory cytokines under certain conditions that are still incompletely understood. Hepatitis B virus (HBV) infection is another chronic viral infection with a life-long latency. HBV infection is linked to various clinical conditions, including liver cirrhosis. There are currently three ways to fight HBV infection and its consequences; primary prevention (by vaccination), secondary prevention (by drug therapy), and tertiary prevention (by liver transplantation). Considering the similarities between the natural histories of HHV-6 and HBV infections, and also the successful strategies which are currently available to fight HBV infection and its long-term consequences, here, we propose three strategies to fight HHV-6 and its possible long-term consequence (i.e. HS-TLE): Primary prevention: by developing vaccines to prevent HHV-6 infection; Secondary prevention: by considering trials of antiviral drugs to treat HHV-6 infection, when it happens in the childhood to hopefully prevent its long-term consequences; and, Tertiary prevention: by stem cell therapy for drug-resistant epilepsy.

Introduction: The distribution of hippocampal sclerosis (HS) subtypes, according to the classification of the International League Against Epilepsy (ILAE), has been reported mainly in adult patients. We aimed to review the pathological findings in children who had anterior temporal lobectomy accompanied with amygdalohippocampectomy, in view of the current classification, and evaluate postsurgical outcome with respect to HS subtypes in childhood., Methods: Seventy children who underwent temporal resections for treatment of medically refractory epilepsy, with a minimum follow-up of 2 years, were included; the surgical hippocampus specimens were re-evaluated under the HS ILAE classification., Results: Neuropathological evaluations revealed HS type 1 in 38 patients (54.3%), HS type 2 in 2 (2.8%), HS type 3 in 21 patients (30%), and no HS in 9 patients (12.9%). Of 70 patients, 23 (32.9%) had dual pathology, and the most common pattern was HS type 3 with low-grade epilepsy-associated brain tumors (LEAT). The distribution of HS types with respect to age revealed that HS type 3 and no HS subgroups had significantly more patients younger than 12 years, compared with those of HS type 1 (90.5%, 77.8% vs 47.4%, respectively). History of febrile seizures was higher in HS type 1. Prolonged/recurrent febrile seizures were most common in patients 12 years and older, whereas LEAT was the most common etiology in patients under 12 years of age (p < 0.001). Patients with HS type 1 had longer duration of epilepsy and an older age at the time of surgery compared with patients with HS type 3 and no HS (p: 0.031, p: 0.007). At final visit, 74.3% of the patients were seizure-free. Seizure outcome showed no significant difference between pathological subtypes., Conclusions: Our study presents the distribution of HS ILAE subtypes in an exclusively pediatric series along with long-term seizure outcome. The study reveals that the leading pathological HS subgroup in children is HS type 1, similar with adult series. Hippocampal sclerosis type 2 is significantly less in children compared with adults; however, HS type 3 emerges as the second most predominant group because of dual pathology, particularly LEAT. Further studies are required regarding clinicopathological features of isolated HS in pediatric cohort. Seizure-free outcome was favorable and similar in all HS types in children. The proportion of HS types may be better defined in pediatric patients with temporal resections, as the current HS ILAE classification becomes more widely used, and may help reveal the surgical and cognitive outcome with respect to HS types., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Excessive activation of mammalian target of rapamycin (mTOR) signaling is epileptogenic in genetic epilepsy. However, the exact role of microglial mTOR in acquired epilepsy remains to be clarified. In the present study, we found that mTOR is strongly activated in microglia following excitatory injury elicited by status epilepticus. To determine the role of microglial mTOR signaling in excitatory injury and epileptogenesis, we generated mice with restrictive deletion of mTOR in microglia. Both male and female mice were used in the present study. We found that mTOR-deficient microglia lost their typical proliferative and inflammatory responses to excitatory injury, whereas the proliferation of astrocytes was preserved. In addition, mTOR-deficient microglia did not effectively engulf injured/dying neurons. More importantly, microglial mTOR-deficient mice displayed increased neuronal loss and developed more severe spontaneous seizures. These findings suggest that microglial mTOR plays a protective role in mitigating neuronal loss and attenuating epileptogenesis in the excitatory injury model of epilepsy. SIGNIFICANCE STATEMENT The mammalian target of rapamycin (mTOR) pathway is strongly implicated in epilepsy. However, the effect of mTOR inhibitors in preclinical models of acquired epilepsy is inconsistent. The broad presence of mTOR signaling in various brain cells could prevent mTOR inhibitors from achieving a net therapeutic effect. This conundrum has spurred further investigation of the cell type-specific effects of mTOR signaling in the CNS. We found that activation of microglial mTOR is antiepileptogenic. Thus, microglial mTOR activation represents a novel antiepileptogenic route that appears to parallel the proepileptogenic route of neuronal mTOR activation. This may explain why the net effect of mTOR inhibitors is paradoxical in the acquired models of epilepsy. Our findings could better guide the use of mTOR inhibitors in preventing acquired epilepsy., (Copyright © 2020 the authors.)

Temporal plus epilepsy is defined as focal epilepsy in which the primary epileptogenic area extends beyond the temporal lobe. It involves the neighboring regions such as the insula, the suprasilvian opercular cortex, the orbitofrontal cortex and the temporo-parieto-occipital junction. The objective of this review is to provide an update in temporal plus epilepsy. A previous history of brain trauma, a history of tonic clonic seizures, and previous central nervous system infection are risk factors. They likely allowed the generation of complex hippocampal and extrahypocampic neural networks. Clinical manifestations will depend on the location of the epileptogenic zone as well as the rapid propagation into temporal mesial structures. Video-electroencephalography usually shows involvement of the temporal lobe, with rapid propagation into the perisilvian, orbitofrontal or temporo-parieto-occipital regions. The magnetoelectroencephaography has lesser muscle contamination and could be considered as a biomarker of early states in the diagnosis process. Brain MRI is usually negative or shows non-specific mesial temporal abnormalities. Stereoelectroencephalography is the invasive method of choice. Temporal plus epilepsy is considered to be the most common cause of temporal lobe epilepsy surgery failure and represents up to 30%.

Objective: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS)., Background: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies., Design/methods: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B., Results: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results., Interpretation: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies., (Published 2020. This article is a U.S Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11 C-methionine uptake and a region with homogenous low 18 F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

Objective: To investigate if there is an association between consanguinity and hippocampal sclerosis (HS) in the Saudi population., Methods: A retrospective case-control study was conducted by assessing the prevalence of consanguinity in patients with pathologically proven HS, who underwent epilepsy surgery at King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between January 2004 and December 2015. We reviewed the medical records to extract data, which included; age, gender, duration of epilepsy, history of febrile seizure, family history of epilepsy in a first or second-degree relative, and pathology reports., Results: A total of 120 patients, out of which 40 patients (65% male) having mesial temporal lobe epilepsy due to HS, and 80 controls (56% male) with cryptogenic epilepsy, were identified. Twenty-two patients (53.5%) in the HS group had a history of consanguinity. In the control group, 30 patients (37.5%) had a history of consanguinity. The odds ratio was 2.04 (95% confidence interval = 0.94 - 4.4, p=0.052). A family history of epilepsy was found in 28% of the patients with HS and 32.5% cryptogenic epilepsy. Only 8 patients (19.5%) with HS reported a history of febrile seizure., Conclusion: Our retrospective case-control study suggests that consanguinity might increase the likelihood of developing HS.

Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming α-subunits and two auxiliary β-subunits, several of which have been well studied in epileptic conditions. However, despite the β4-subunits' role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4β in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K + channels activated by Ca 2+ , or K + two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B . These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs.

Background: Patients with a lesion within the amygdala and uncus may develop temporal lobe epilepsy despite having functional mesial structures. Resection of functional hippocampus and surrounding structures may lead to unacceptable iatrogenic deficits. To our knowledge, there is limited descriptions of surgical techniques for selectively resecting the amygdala and uncus lesions while preserving the hippocampus in patients with language-dominant temporal lobe pathology., Methods: Thirteen patients with language-dominant temporal lobe epilepsy related to amygdala-centric lesions were identified. Patients with sclerosis of the mesial structures or evidence of pathology outside of the amygdala-uncus region were excluded. Neuropsychological evaluation confirmed normal function of the mesial structures ipsilateral to the lesion. All patients were worked up with video-EEG, high-resolution brain MRI, neuro-psychology evaluation, and either Wada or functional MRI testing., Results: All patients underwent selective resection of the lesion including amygdala and uncus with preservation of the hippocampus via a transcortical inferior temporal gyrus approach to the mesial temporal lobe. Pathology was compatible with glioneuronal tumors. Post-operative MRI demonstrated complete resection in all patients. Eight of the thirteen patients underwent post-operative neuropsychology evaluations and did not demonstrate any significant decline in tasks of delayed verbal recall or visual memory based on the Rey Auditory Verbal Learning Test (RAVLT). One patient showed a slight decrease in confrontation naming using the Boston Naming Test (BNT). Seizure freedom (Engel class I) was achieved in 12 of 13 patients., Conclusion: Selective transcortical amygdala and uncus resection with hippocampus preservation may be a reasonable way to achieve seizure control while sparing functional mesial structures.

We report the case of a 25-year-old woman who developed temporal lobe epilepsy associated with systemic lupus erythematosus (SLE). Serum and cerebrospinal fluid samples showed high titers of anti-ribosomal P (anti-P) antibodies with negative anti-NMDAR antibodies. She was receiving prednisone and azathioprine, with normalization of SLE serum markers, but without changes in titers of anti-P antibodies. No seizure control was achieved using valproic acid, levetiracetam and lamotrigine. However, she had a selective response to topiramate, an AMPAR blocker, maintained during 6 years of follow-up. We discuss the pathophysiology of this autoimmune epilepsy associated with high titer anti-P antibodies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus sub-regions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system.

Microglia exhibit multiple, phenotype-dependent motility patterns often triggered by purinergic stimuli. However, little data exist on motility of human microglia in pathological situations. Here we examine motility of microglia stained with a fluorescent lectin in tissue slices from female and male epileptic patients diagnosed with mesial temporal lobe epilepsy or cortical glioma (peritumoral cortex). Microglial shape varied from ramified to amoeboid cells predominantly in regions of high neuronal loss or closer to a tumor. Live imaging revealed unstimulated or purine-induced microglial motilities, including surveillance movements, membrane ruffling, and process extension or retraction. At different concentrations, ADP triggered opposing motilities. Low doses triggered process extension. It was suppressed by P2Y12 receptor antagonists, which also reduced process length and surveillance movements. Higher purine doses caused process retraction and membrane ruffling, which were blocked by joint application of P2Y1 and P2Y13 receptor antagonists. Purinergic effects on motility were similar for all microglia tested. Both amoeboid and ramified cells from mesial temporal lobe epilepsy or peritumoral cortex tissue expressed P2Y12 receptors. A minority of microglia expressed the adenosine A2A receptor, which has been linked with process withdrawal of rodent cells. Laser-mediated tissue damage let us test the functional significance of these effects. Moderate damage induced microglial process extension, which was blocked by P2Y12 receptor antagonists. Overall, the purine-induced motility of human microglia in epileptic tissue is similar to that of rodent microglia in that the P2Y12 receptor initiates process extension. It differs in that retraction is triggered by joint activation of P2Y1/P2Y13 receptors. SIGNIFICANCE STATEMENT Microglial cells are brain-resident immune cells with multiple functions in healthy or diseased brains. These diverse functions are associated with distinct phenotypes, including different microglial shapes. In the rodent, purinergic signaling is associated with changes in cell shape, such as process extension toward tissue damage. However, there are little data on living human microglia, especially in diseased states. We developed a reliable technique to stain microglia from epileptic and glioma patients to examine responses to purines. Low-intensity purinergic stimuli induced process extension, as in rodents. In contrast, high-intensity stimuli triggered a process withdrawal mediated by both P2Y1 and P2Y13 receptors. P2Y1/P2Y13 receptor activation has not previously been linked to microglial morphological changes., (Copyright © 2020 the authors.)

Dysregulation of the PI3K/Akt/mTOR pathway has been implicated in several brain disorders, including epilepsy. Rapamycin and similar compounds inhibit mTOR. complex 1 and have been reported to decrease seizures, delay seizure development, or prevent epileptogenesis in different animal models of genetic or acquired epilepsies. However, data for acquired epilepsy are inconsistent, which, at least in part, may be due to the poor brain penetration and long brain persistence of rapamycin and the fact that it blocks only one of the two cellular mTOR complexes. Here we examined the antiepileptogenic or disease-modifying effects of two novel, brain-permeable and well tolerated 1,3,5-triazine derivatives, the ATP-competitive mTORC1/2 inhibitor PQR620 and the dual pan-PI3K/mTORC1/2 inhibitor PQR530 in the intrahippocampal kainate mouse model, in which spontaneous seizures develop after status epilepticus (SE). Following kainate injection, the two compounds were administered over 2 weeks at doses previously been shown to block mTORC1/2 or PI3K/mTORC1/2 in the mouse brain. When spontaneous seizures were recorded by continuous (24/7) video-EEG recording starting 6 weeks after termination of treatment, no effects on incidence or frequency of seizures were observed. Drug treatment suppressed the epilepsy-induced activation of the PI3K/Akt/mTOR pathway in the hippocampus, but granule cell dispersion in the dentate gyrus was not prevented. When epilepsy-associated behavioral alterations were determined 12-14 weeks after kainate, mice pretreated with PQR620 or PQR530 exhibited reduced anxiety-related behavior in the light-dark box, indicating a disease-modifying effect. Overall, the data indicate that mTORC1/C2 or PI3K/mTORC1/C2 inhibition may not be an antiepileptogenic strategy for SE-induced epilepsy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To characterise bilateral temporal encephalocele (BTE)-associated epilepsy relative to unilateral temporal encephalocele (UTE)-associated epilepsy as a rare but curable cause of structural epilepsy using demographics, epilepsy status and imaging findings., Method: In this single-centre retrospective study we included all patients from June 2015 to August 2018, who suffered from epilepsy and were diagnosed with a temporal encephalocele. Data were systematically collected and analysed for differences between BTE and UTE., Results: Seventeen epilepsy patients diagnosed with temporal encephaloceles (TE) were identified. One-third exhibited BTE. The age of epilepsy onset was higher in patients with BTE compared to UTE (median 51 vs. 37 years, p = 0.074). Latency between epilepsy diagnosis and definitive TE diagnosis differed considerably with a median five-fold shorter duration for the BTE-group when compared to the UTE-group (2-10 years, p = 0.02). Five of seven (81%) patients with BTE were pharmacoresistant, while this applied to only five out of ten (50%) patients with a UTE., Conclusion: When compared to UTE-associated epilepsy, BTE-associated epilepsy is characterised by a later age at onset, shorter delay in TE diagnosis and more frequent drug-resistance. As epilepsy surgery is a valid treatment option for both syndromes, a standardised diagnostic workup should be implemented for temporal lobe epilepsy (TLE) patients with unknown aetiology to facilitate early detection of UTE and BTE., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Temporal lobe epilepsy is most prevalent among focal epilepsies, and nearly one-third of patients are refractory to pharmacological intervention. Persistent cognitive and neurobehavioral comorbidities also occur due to the recurrent nature of seizures and medication-related side effects., Hypothesis: Electrical neuromodulation is an effective strategy to reduce seizures both in animal models and clinically, but its efficacy to modulate cognition remains unclear. We hypothesized that theta frequency stimulation of the medial septum would increase septohippocampal oscillations, increase seizure threshold, and improve spatial learning in a rat model of pilocarpine-induced epilepsy., Methods: Sham and pilocarpine rats were implanted with electrodes in the medial septum, hippocampus and prefrontal cortex. EEG was assessed days prior to and following stimulation. Sham and pilocarpine-treated rats received either no stimulation, continuous (throughout each behavior), or pre-task (one minute prior to each behavior) 7.7 Hz septal stimulation during the Barnes maze spatial navigation test and also during assessment of flurothyl-induced seizures., Results: Both continuous and pre-task stimulation prevented epilepsy-associated reductions in theta oscillations over time. Additionally, both stimulation paradigms significantly improved spatial navigation in the Barnes maze, reducing latency and improving search strategy. Moreover, stimulation led to significant increases in seizure threshold in pilocarpine-treated rats. There was no evidence of cognitive enhancement or increased seizure threshold in stimulated sham rats., Conclusion: These findings have profound implications as theta stimulation of the septum represents a single frequency and target that has the potential to both improve cognition and reduce seizures for patients with refractory epilepsy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multinodular and vacuolating neuronal tumour (MVNT) of the cerebrum is a relatively new, well defined histopathological and neuroradiological entity, in many cases associated with an early adult-onset epilepsy. These lesions have an indolent course and resemble both malformative and neoplastic processes, combining a focal developmental anomaly and a low-grade tumour. Herein, we report a case of a 48-year-old female patient with left temporal lobe epilepsy associated with MVNT. In addition, a comprehensive review of all the previously published cases is provided with a focus on seizure-related cases, surgical treatment, and postoperative outcome.

Rationale and Objectives: To test whether an image-processing algorithm can aid in visualization of mesial temporal sclerosis on magnetic resonance imaging by selectively increasing contrast-to-noise ratio (CNR) between abnormal hippocampus and normal brain., Materials and Methods: In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, baseline coronal fluid-attenuated inversion recovery images of 18 adults (10 females, eight males; mean age 41.2 years) with proven mesial temporal sclerosis were processed using a custom algorithm to produce corresponding enhanced images. Average (Hmean) and maximum (Hmax) CNR for abnormal hippocampus were calculated relative to normal ipsilateral white matter. CNR values for normal gray matter (GM) were similarly calculated using ipsilateral cingulate gyrus as the internal control. To evaluate effect of image processing on visual conspicuity of hippocampal signal alteration, a neuroradiologist masked to the side of hippocampal abnormality rated signal intensity (SI) of hippocampi on baseline and enhanced images using a five-point scale (definitely abnormal to definitely normal). Differences in Hmean, Hmax, GM, and SI ratings for abnormal hippocampi on baseline and enhanced images were assessed for statistical significance., Results: Both Hmean and Hmax were significantly higher in enhanced images as compared to baseline images (p < 0.0001 for both). There was no significant difference in the GM between baseline and enhanced images (p = 0.9375). SI ratings showed a more confident identification of abnormality on enhanced images (p = 0.0001)., Conclusion: Image-processing resulted in increased CNR of abnormal hippocampus without affecting the CNR of normal gray matter. This selective increase in conspicuity of abnormal hippocampus was associated with more confident identification of hippocampal signal alteration., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Epilepsy associated with neurocutaneous disorders is well known, and the prevalence of epilepsy among patients with neurofibromatosis type 1 (NF1) ranges from 4% to 13%. However, epilepsy surgery for patients with NF1 is not commonly performed., Case Description: We report the case of a patient with medically intractable mesial temporal lobe epilepsy (mTLE) concomitant NF1 and moyamoya syndrome (MMS) who had already undergone bilateral superficial temporal artery-middle cerebral artery anastomosis at 17 years old. As the standard temporal approach was unavailable, we evaluated the patient with neurologists, radiologists, neurosurgeons and neuropsychologists to identify the safest trajectory for epilepsy surgery. The patient underwent the right selective amygdala hippocampectomy from the posterior auricle part at 32 years old and obtained freedom from seizures., Conclusion: To the best of our knowledge, this represents the first surgical case report for mTLE concomitant with NF1 and MMS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)