Mesial Temporal Lobe Seizures Research Articles

Involvement of the posterior cingulate gyrus in temporal lobe epilepsy: A study using stereo-EEG

ObjectiveTo analyze the involvement of the posterior cingulate gyrus (PCG) during mesial temporal lobe seizures (MTLS). MethodsWe retrospectively reviewed the stereo-EEG (SEEG) recordings of patients with MTLS performed in our institution from February 2013 to December 2020. Only patients who had electrode implantation in the PCG were included. Patients with lesions that could potentially alter the seizure spread pathways were excluded. We assessed the propagation patterns of MTLS with respect to the different structures sampled. ResultsNine of 97 patients who had at least one seizure originating in the mesial temporal region met the inclusion criteria. A total of 174 seizures were analyzed. The PCG was the first site of propagation in most of the cases (8/9 patients and 77.5% of seizures, and 7/8 patients and 65.6% of seizures after excluding an outlier patient). The fastest propagation times were towards the contralateral mesial temporal region and ipsilateral PCG. Seven patients underwent standard anterior temporal lobectomy and, of these, all but one were Engel 1 at last follow up. ConclusionWe found the PCG to be the first propagation site of MTLS in this group of patients. These results outline the relevance of the PCG in SEEG planning strategies. Further investigations are needed to corroborate whether fast propagation to the PCG predicts a good surgical outcome.

Seizure and anatomical outcomes of repeat laser amygdalohippocampotomy for temporal lobe epilepsy: A single-institution case series

ObjectiveIn patients with treatment-refractory temporal lobe epilepsy (TLE), a single stereotactic laser interstitial thermotherapy (LITT) procedure is sometimes insufficient to ablate epileptogenic tissue, particularly the medial structures often implicated in TLE. In patients with seizure recurrence after initial ablation, the extent to which a second ablation may achieve improved seizure outcomes is uncertain. The objective of this study was to investigate the feasibility and potential efficacy of repeat LITT amygdalohippocampotomy as a worthwhile strategy for intractable temporal lobe epilepsy by quantifying changes to targeted mesial temporal lobe structures and seizure outcomes. MethodsPatients who underwent two LITT procedures for drug-resistant mesial TLE at our institution were included in the study. Lesion volumes for both procedures were calculated by comparing post-ablation intraoperative sequences to preoperative anatomy. Clinical outcomes after the initial procedure and repeat procedure were classified according to Engel scores. ResultsFive consecutive patients were included in this retrospective case series: 3 with right- and 2 with left-sided TLE. The median interval between LITT procedures was 294 days (range: 227–1918). After the first LITT, 3 patients experienced class III outcomes, 1 experienced a class IV, and 1 experienced a class IB outcome. All patients achieved increased seizure freedom after a second procedure, with class I outcomes (3 IA, 2 IB). ConclusionsRepeat LITT may be sufficient to achieve satisfactory seizure outcomes in some individuals who might otherwise be considered for more aggressive resection or palliative neuromodulation. A larger study to establish the potential value of repeat LITT amygdalohippocampotomy vs. other re-operation strategies for persistent, intractable temporal lobe epilepsy is worth pursuing.

Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis.

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [18F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [18F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

The anterior and pulvinar thalamic nuclei interactions in mesial temporal lobe seizure networks

ObjectiveTo evaluate the respective roles of the anterior thalamic nucleus (ANT) and the medial pulvinar (PuM) during mesial temporal lobe seizures recorded by stereoelectroencephalography (SEEG). MethodsWe assessed functional connectivity (FC) in 15 SEEG recorded seizures from 6 patients using a non-linear correlation method. Functional interactions were explored between the mesial temporal region, the temporal neocortex, ANT and PuM. The node total-strength (the summed connectivity of the node with all other nodes) as well as the directionality of the links (IN and OUT strengths) were calculated to estimate drivers and receivers during the cortico-thalamic interactions. ResultsSignificant increased thalamo-cortical FC during seizures was observed, with the node total-strength reaching a maximum at seizure end. There was no significant difference in global connectivity values between ANT and PuM. Regarding directionality, significantly higher thalamic IN strength values were observed. However, compared to ANT, PuM appeared to be the driver at the end of seizures with synchronous termination. ConclusionsThis work demonstrates that during temporal seizures, both thalamic nuclei are highly connected with the mesial temporal region and that PuM could play a role in seizure termination. SignificanceUnderstanding functional connectivity between the mesial temporal and thalamic nuclei could contribute to the development of target-specific deep brain stimulation strategies for drug-resistant epilepsy.

Surgical Treatment for mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis. Our Experience.

Introduction; Epilepsy is one of the most common neurological chronic disorders, with an estimated prevalence of 0. 5 – 1%. Partial focal epilepsy (PE) is one of the most common types of epilepsies that originates from a relatively limited number of neurons, whose malfunction generates epileptic attacks. Partial focal epilepsies make up 60% of the whole spectrum of epilepsies. Recent studies show that 25% of patient who suffer from PE show a resistance against medication. The duration of symptoms on the one hand and AED treatment on the other hand cause the cognitive dysfunctions in the patients suffering from epileptic seizures, especially children, to suffer progressive damage. Patients suffering from epilepsy have a cost that at the moment is difficult to calculate accurately, but it is still very high. Mesial Temporal lobe seizures are the most common form of partial epileptic seizures originating in the temporal lobe, and they are frequently resistant to anti-epileptic drug treatment.
 Materials and Methods, At Neurosurgical Department, University Hospital “Mother Theresa”, since 2013 there is a team consisting of different medical specialists, for the study and selection of candidates, who can benefit from surgery. At the same time, since many years now in neurological department there is already a successful tradition in the medicament treatment of epilepsy.
 The team of medical doctors in our Department, which makes the treatment of these diseases by means of surgery, is made up of: neuro-epileptologist, radiologists, neurologists, psychologists and neurosurgeons.
 During the period, from 2013 until the year 2021, 35 patients have undergone an operation. All the patients were considered, based on protocols, as pharmacoresistant.
 Conclusions; The post-surgical results were 80% of the patient’s seizure free and without need to use any antiepileptic treatment, meaning Engel 1. 15% of the patients were seizure free but with the need of antiepileptic treatment and meaning Engel 2 and 5% of patients were not able to be cured by achieving only a modification of the semiology of the crisis and frequency, meaning Engel 3.
 Anterior temporal lobectomy in majority of the cases is the best surgical treatment of drug-resistant HS-TLE and long-term seizure free patients in this group have been reported about 70% (62-83%).

Localizing seizure onset zones in surgical epilepsy with neurostimulation deep learning.

In drug-resistant temporal lobe epilepsy, automated tools for seizure onset zone (SOZ) localization that use brief interictal recordings could supplement presurgical evaluations and improve care. Thus, the authors sought to localize SOZs by training a multichannel convolutional neural network on stereoelectroencephalography (SEEG) cortico-cortical evoked potentials. The authors performed single-pulse electrical stimulation in 10 drug-resistant temporal lobe epilepsy patients implanted with SEEG. Using 500,000 unique poststimulation SEEG epochs, the authors trained a multichannel 1-dimensional convolutional neural network to determine whether an SOZ had been stimulated. SOZs were classified with mean sensitivity of 78.1% and specificity of 74.6% according to leave-one-patient-out testing. To achieve maximum accuracy, the model required a 0- to 350-msec poststimulation time period. Post hoc analysis revealed that the model accurately classified unilateral versus bilateral mesial temporal lobe seizure onset, as well as neocortical SOZs. This was the first demonstration, to the authors' knowledge, that a deep learning framework can be used to accurately classify SOZs with single-pulse electrical stimulation-evoked responses. These findings suggest that accurate classification of SOZs relies on a complex temporal evolution of evoked responses within 350 msec of stimulation. Validation in a larger data set could provide a practical clinical tool for the presurgical evaluation of drug-resistant epilepsy.

Seizures in autoimmune encephalitis: specific features based on a systematic comparative study.

To highlight specific characteristics of seizure semiology and EEG features associated with different subtypes of autoimmune encephalitis (AE). We systematically reviewed the seizure semiology and all the EEG recordings from patients with AE managed in a tertiary referral centre for epilepsy and a neuro-intensive care unit. Each characteristic across the different subtypes of AE was compared by post hoc analysis. We identified 66 patients with anti-neuronal antibody-mediated AE or Rasmussen's encephalitis (RE) experiencing seizures, which were the most frequent symptom at onset. Anti-NMDAR and anti-LGI1 AE accounted for the majority of patients; 41% and 24%, respectively. We isolated specific semiological features, such as early tonic-clonic seizures (TCS) in anti-NMDAR AE, early mesial temporal lobe seizures with emotional symptoms in anti-GAD AE, somatosensory seizures in RE, and a lower frequency of TCS in anti-LGI1 AE. EEG analysis also provided additional insights into distinguishing the subtypes based on: (1) generalized rhythmic delta activity, which was more sensitive than extreme delta brush in identifying anti-NMDAR AE among all subtypes; and (2) temporal interictal epileptiform activity and temporal seizures on EEG in anti-GAD AE. We identified a new EEG pattern consisting of temporal low-voltage and periodic spikes associated with ipsilateral hippocampal abnormalities on MRI, which could be a sign of inflammatory mesial temporal involvement. Specific clinical and EEG features can be useful in guiding the diagnosis of a subtype of AE with acute symptomatic seizures, particularly before the results of anti-neuronal antibody testing are available.

Deep Learning of Simultaneous Intracranial and Scalp EEG for Prediction, Detection, and Lateralization of Mesial Temporal Lobe Seizures.

In people with drug resistant epilepsy (DRE), seizures are unpredictable, often occurring with little or no warning. The unpredictability causes anxiety and much of the morbidity and mortality of seizures. In this work, 102 seizures of mesial temporal lobe onset were analyzed from 19 patients with DRE who had simultaneous intracranial EEG (iEEG) and scalp EEG as part of their surgical evaluation. The first aim of this paper was to develop machine learning models for seizure prediction and detection (i) using iEEG only, (ii) scalp EEG only and (iii) jointly analyzing both iEEG and scalp EEG. The second goal was to test if machine learning could detect a seizure on scalp EEG when that seizure was not detectable by the human eye (surface negative) but was seen in iEEG. The final question was to determine if the deep learning algorithm could correctly lateralize the seizure onset. The seizure detection and prediction problems were addressed jointly by training Deep Neural Networks (DNN) on 4 classes: non-seizure, pre-seizure, left mesial temporal onset seizure and right mesial temporal onset seizure. To address these aims, the classification accuracy was tested using two deep neural networks (DNN) against 3 different types of similarity graphs which used different time series of EEG data. The convolutional neural network (CNN) with the Waxman similarity graph yielded the highest accuracy across all EEG data (iEEG, scalp EEG and combined). Specifically, 1 second epochs of EEG were correctly assigned to their seizure, pre-seizure, or non-seizure category over 98% of the time. Importantly, the pre-seizure state was classified correctly in the vast majority of epochs (>97%). Detection from scalp EEG data alone of surface negative seizures and the seizures with the delayed scalp onset (the surface negative portion) was over 97%. In addition, the model accurately lateralized all of the seizures from scalp data, including the surface negative seizures. This work suggests that highly accurate seizure prediction and detection is feasible using either intracranial or scalp EEG data. Furthermore, surface negative seizures can be accurately predicted, detected and lateralized with machine learning even when they are not visible to the human eye.

The comparative study of invasive electroencephalography modalities in temporal lobe epilepsy

Introduction. Invasive video-EEG monitoring (invasive EEG) is indicated in patients with refractory focal epilepsy while localization of the epileptogenic zone is unclear. Methods of invasive EEG in different groups of patients demonstrate variable results.Objective: to analyse the results of invasive EEG via subdural and depth electrodes in patients with refractory temporal lobe epilepsy with mesial temporal lobe seizures.Materials and methods. The series of 37 patients who underwent invasive EEG from 2013 to 2020 was retrospectively analysed. The study includes primary adult patients with structural refractory focal epilepsy with mesial temporal lobe seizures without tumor and vascular pathology. Patients were divided onto 3 groups: 1) with foramen ovale electrodes 2) subdural strip electrodes and 3) combination of subdural strips and depths electrodes. The results of anteromedial temporal lobectomy after 6 months were classified according to Engel scale.Results. A group with foramen ovale electrodes included 7 patients, subdural strips – 23, combination – 7. The seizure onset zone was detected in 36 (97 %) cases. Serious complications were observed in 2 (29 %) cases in the group with foramen ovale electrodes. The mean follow-up in 23 (76 %) patients after resective surgery was 28.3 months. Favourable results (Engel I, II) were observed in 4 (80 %) patients with foramen ovale electrodes, in 8 (67 %) patients with subdural electrodes, in 6 (100 %) with combination. Unfavourable results (Engel III, IV) were noted in 1 (20 %) patient with foramen ovale electrode, in 4 (33 %) patients with subdural strips.Conclusion. All the presented modalities of invasive EEG are effective for localizing of seizure onset zone in this category of patients. Foramen ovale electrode using may be limited due to increased risk of complications.

Slow oscillations open susceptible time windows for epileptic discharges.

ObjectiveIn patients with epilepsy, interictal epileptic discharges are a diagnostic hallmark of epilepsy and represent abnormal, so‐called “irritative” activity that disrupts normal cognitive functions. Despite their clinical relevance, their mechanisms of generation remain poorly understood. It is assumed that brain activity switches abruptly, unpredictably, and supposedly randomly to these epileptic transients. We aim to study the period preceding these epileptic discharges, to extract potential proepileptogenic mechanisms supporting their expression.MethodsWe used multisite intracortical recordings from patients who underwent intracranial monitoring for refractory epilepsy, the majority of whom had a mesial temporal lobe seizure onset zone. Our objective was to evaluate the existence of proepileptogenic windows before interictal epileptic discharges. We tested whether the amplitude and phase synchronization of slow oscillations (.5–4 Hz and 4–7 Hz) increase before epileptic discharges and whether the latter are phase‐locked to slow oscillations. Then, we tested whether the phase‐locking of neuronal activity (assessed by high‐gamma activity, 60–160 Hz) to slow oscillations increases before epileptic discharges to provide a potential mechanism linking slow oscillations to interictal activities.ResultsChanges in widespread slow oscillations anticipate upcoming epileptic discharges. The network extends beyond the irritative zone, but the increase in amplitude and phase synchronization is rather specific to the irritative zone. In contrast, epileptic discharges are phase‐locked to widespread slow oscillations and the degree of phase‐locking tends to be higher outside the irritative zone. Then, within the irritative zone only, we observe an increased coupling between slow oscillations and neuronal discharges before epileptic discharges.SignificanceOur results show that epileptic discharges occur during vulnerable time windows set up by a specific phase of slow oscillations. The specificity of these permissive windows is further reinforced by the increased coupling of neuronal activity to slow oscillations. These findings contribute to our understanding of epilepsy as a distributed oscillopathy and open avenues for future neuromodulation strategies aiming at disrupting proepileptic mechanisms.

Atrioventricular Conduction in Mesial Temporal Lobe Seizures.

Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE).Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD.Results: Fifty-six seizures of 14 patients (5 men, age 34.7 ± 9.8 years) were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure.Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE.

Non-lesional mesial temporal lobe epilepsy requires bilateral invasive evaluation

Mesial temporal lobe epilepsy (MTLE) usually responds well to surgical treatment, although in non-lesional cases up to 50% of patients experience seizure relapse. The possibility of bilateral independent seizure onset should be considered as a reason for epilepsy surgery failure. In a cohort of 177 patients who underwent invasive presurgical evaluation with stereo-tactically placed electrodes in two level four epilepsy centers, 29 had non-lesional MTLE. Invasive evaluation results are described. Among 29 patients with non-lesional MRI and mesial temporal lobe seizure onset recorded during stereo-EEG (SEEG) evaluation, four patients with unilateral preimplantation hypothesis had independent bilateral mesial temporal seizures on SEEG despite of unilateral non-invasive evaluation data. Three of these patients were treated with bitemporal responsive neurostimulator system (RNS). Independent bilateral mesial temporal seizures have been confirmed on RNS ECoG (electrocorticography). The fourth patient underwent right anterior temporal lobectomy. We propose that patients with non-lesional mesial temporal lobe epilepsy would benefit from bilateral invasive evaluation of mesial temporal structures to predict those patients who would be at most risk for surgical failure. Neurostimulaiton could be an initial treatment option for patients with independent bitemporal seizure onset.

Electrical Stimulation of Subiculum for the Treatment of Refractory Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A 2-Year Follow-Up Study

Introduction: Evidence has been provided that the subiculum may play an important role in the generation of seizures. Electrical stimulation at this target has been reported to have anticonvulsive effects in kindling and pilocarpine rat models, while in a clinical study of hippocampal deep brain stimulation (DBS), contacts closest to the subiculum were associated with a better anticonvulsive effect. Objectives: To evaluate the effect of electrical stimulation of the subiculum in patients with refractory mesial temporal lobe epilepsy (MTLE) who have hippocampal sclerosis (HS). Methods: Six patients with refractory MTLE and HS, who had focal impaired awareness seizures (FIAS) and focal to bilateral tonic-clonic seizures (FBTCS), had DBS electrodes implanted in the subiculum. During the first month after implantation, all patients were OFF stimulation, then they all completed an open-label follow-up of 24 months ON stimulation. DBS parameters were set at 3 V, 450 µs, 130 Hz, cycling stimulation 1 min ON, 4 min OFF. Results: There was a mean reduction of 49.16% (±SD 41.65) in total seizure number (FIAS + FBTCS) and a mean reduction of 67.93% (±SD 33.33) in FBTCS at 24 months. FBTCS decreased significantly with respect to baseline, starting from month 2 ON stimulation. Conclusions: Subiculum stimulation is effective for FBTCS reduction in patients with MTLE and HS, suggesting that the subiculum mediates the generalization rather than the genesis of mesial temporal lobe seizures. Better results are observed at longer follow-up times.

Ictal central apneas in temporal lobe epilepsies

The objective of the study was to examine the frequency and characteristics of ictal central apnea (ICA) in a selective cohort of patients with mesial or neocortical temporal lobe epilepsy (TLE) undergoing surface video-electroencephalography (EEG) and multimodal recording of cardiorespiratory parameters. We retrospectively screened 453 patients who underwent EEG in a single center including nasal airflow measurements, respiratory inductance plethysmography of thoracoabdominal excursions, peripheral capillary oxygen saturation, and electrocardiography. Patients with confirmed TLE subtype, either by magnetic resonance imaging (MRI) lesions limited to the temporal neocortex or mesial structures and concordant neurophysiologic data, or patients who underwent invasive explorations were included. Ictal central apnea frequency and characteristics were analyzed in 41 patients with 164 seizures that had multimodal respiratory monitoring. The total occurrence of ICA in all seizures in this cohort was 79.9%. No significant difference was seen between mesial and neocortical temporal lobe seizures (79.8% and 80.0%, respectively). Ictal central apnea preceded EEG onset by 13 ± 11 s in 33.3% of seizures and was the first clinical sign by 18 ± 14 s in 48.7%. Longer ICA duration trended towards a more severe degree of hypoxemia. In a selective cohort of TLE defined by MRI lesion and/or intracranial recordings, the frequency of ICA was higher than previously reported in the literature. Multimodal respiratory monitoring has localizing value and is generally well tolerated. Ictal central apnea preceded both EEG on scalp recordings as well as clinical seizure onset in a substantial number of patients. Respiratory monitoring and ICA detection is even more paramount during invasive monitoring to confirm that the recorded seizure onset is seen before the first clinical sign.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

ObjectiveTo describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain‐responsive neurostimulator (RNS) system.MethodsWe retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3‐month follow‐up after MTL resection compared to seizure frequency 3 months before MTL resection.ResultsWe identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty‐five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow‐up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow‐up was 100% (mean: 94%; range: 50%‐100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure‐free at last follow‐up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%‐100%) at last follow‐up, with eight of fifteen seizure‐free. For those with more than 1 year of follow‐up (N = 21), 15 patients (71%) were seizure‐free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets.SignificanceChronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury.

The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for α2/3-containing GABAA receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED50 = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the α1β3γ2L GABAA receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with α1His102, providing a structural rationale for its low affinity for α1-containing GABAA receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy.

New Approaches to Studying Silent Mesial Temporal Lobe Seizures in Alzheimer's Disease.

Silent seizures were discovered in mouse models of Alzheimer's disease over 10 years ago, yet it remains unclear whether these seizures are a salient feature of Alzheimer's disease in humans. Seizures that arise early in the course of Alzheimer's disease most likely originate from the mesial temporal lobe, one of the first structures affected by Alzheimer's disease pathology and one of the most epileptogenic regions of the brain. Several factors greatly limit our ability to identify mesial temporal lobe seizures in patients with Alzheimer's disease, however. First, mesial temporal lobe seizures can be difficult to recognize clinically, as their accompanying symptoms are often subtle or even non-existent. Second, electrical activity arising from the mesial temporal lobe is largely invisible on the scalp electroencephalogram (EEG), the mainstay of diagnosis for epilepsy in this population. In this review, we will describe two new approaches being used to study silent mesial temporal lobe seizures in Alzheimer's disease. We will first describe the methodology and application of foramen ovale electrodes, which captured the first recordings of silent mesial temporal lobe seizures in humans with Alzheimer's disease. We will then describe machine learning approaches being developed to non-invasively identify silent mesial temporal lobe seizures on scalp EEG. Both of these tools have the potential to elucidate the role of silent seizures in humans with Alzheimer's disease, which could have important implications for early diagnosis, prognostication, and development of targeted therapies for this population.

Spectral organization of focal seizures within the thalamotemporal network.

ObjectiveTo investigate dynamic changes in neural activity between the anterior nucleus of the thalamus (ANT) and the seizure onset zone (SOZ) in patients with drug‐resistant temporal lobe epilepsy (TLE) based on anatomic location, seizure subtype, and state of vigilance (SOV).MethodsEleven patients undergoing stereoelectroencephalography for seizure localization were recruited prospectively for local field potential (LFP) recording directly from the ANT. The SOZ was identified using line length and epileptogenicity index. Changes in power spectral density (PSD) were compared between the two anatomic sites as seizures (N = 53) transitioned from interictal baseline to the posttermination stage.ResultsAt baseline, the thalamic LFPs were significantly lower and distinct from the SOZ with the presence of higher power in the fast ripple band (P < 0.001). Temporal changes in ictal power of neural activity within ANT mimic those of the SOZ, are increased significantly at seizure onset (P < 0.05), and are distinct for seizures that impaired awareness or that secondarily generalized (P < 0.05). The onset of seizure was preceded by a decrease in the mean power spectral density (PSD) in ANT and SOZ (P < 0.05). Neural activity correlated with different states of vigilance at seizure onset within the ANT but not in the SOZ (P = 0.005).InterpretationThe ANT can be recruited at the onset of mesial temporal lobe seizures, and the recruitment pattern differs with seizure subtypes. Furthermore, changes in neural dynamics precede seizure onset and are widespread to involve temporo‐thalamic regions, thereby providing an opportunity to intervene early with closed‐loop DBS.

Robotic Orthogonal Implantation of Responsive Neurostimulation (RNS) Depth Electrodes in Patients With Unilateral Mesial Temporal Lobe Seizure Onset

Abstract INTRODUCTION Responsive neurostimulation (RNS) is a closed-loop neurostimulation modality for treating intractable epilepsy in patients who are not candidates for resection. A high number of patients have ictal onsets originating in the temporal lobe. In the past, implantation of depth electrodes have been placed using a transoccipital approach that transverses the long axis of the hippocampus. However, there have been no description of orthogonal approaches to RNS electrode placement into the medial temporal structures in the literature. We aimed to describe our initial experience with placing RNS depth electrodes using an orthogonal approach to target the short axis of the mesial temporal lobe. METHODS Presurgical work up included magnetic resonance imaging (MRI), video electroencephalography (vEEG), and neuropsychological testing. During the procedure, patients were placed with their heads in a neutral position. Electrodes were placed via stereotactic robotic assistance using a unilateral orthogonal approach targeting the amygdala or hippocampus. Patients who underwent RNS electrode implantation via orthogonal approach were identified after a retrospective review of all RNS patients at our institution. Multiple variables were collected, including age, disease onset, complications, follow-up, semiology, and seizure reduction. RESULTS There were 4 patients who underwent RNS implantation with orthogonal electrode placement. The mean age and follow-up were 44.8 and 1.2 yr, respectively. One of 8 patients was seizure free at last follow-up and 2 experienced over 50% reduction in seizures. There was one surgical complication but no mortality. CONCLUSION The initial experience using an orthogonal approach for depth electrode placement for RNS implantation was described. The potential advantages may include better safety, accuracy, and positioning in comparison to a transoccipital approach. Limitations included the retrospective nature of the study and a low sample size. Further research and experience are required to determine the best indications for an orthogonal approach.

The Positive Allosteric Modulator of Alpha-2/3-Containing γ-Aminobutyric Acid Type A Receptors, KRM-II-81, Is Active in Pharmacoresistant Models of Epilepsy and in Human Epileptic Tissue

Abstract INTRODUCTION Epilepsy patients continue to suffer from the lack of efficacious medications. Recent attention has been directed toward the potential advantages of developing positive allosteric modulators of alpha-2/3-containing γ-aminobutyric acid type A (GABAA) receptors as antiepileptic drugs. A proof of principle has been reported with one such molecule in patients with photosensitive epilepsy. KRM-II-81 (5- (8-ethynyl-6- (pyridin-2-yl)-4H-benzo[f]imidazole[1,5-alpha][1,4]diazepin-3-yl)oxazole) is an orally-bioavailable compound recently designed for selectivity at alpha-2/3-containing GABAA receptors over the alpha-1-subtype involved in motor-impairing effects. KRM-II-81 has recently been reported to dampen seizure activity in rodents induced by acute and chronic seizure provocation. KRM-II-81 was often more efficacious than diazepam as an anticonvulsant while producing less motor impairment than diazepam. The reduced motor impact of KRM-II-81 is hypothesized to enable higher central target exposure and hence increased efficacy. METHODS The effects of KRM-II-81 were investigated in a mouse mesial temporal lobe model and a rat lamotrigine-resistant kindling model. We also explored the antiepileptic electrophysiological effects of KRM-II-81 in cortical slices from epileptic pediatric patients to help guide the development of novel compounds that might be valuable against antiepileptic drug-resistant epilepsies. RESULTS Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges (16.8 +/–2.5). KRM-II-81 significantly reduced the discharge frequency to 5.5 +/–1.4 after oral dosing at 15 mg/kg. KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine. In slices of epileptic cortex, KRM-II-81 produced a concentration-dependent dampening of network activity engendered by the GABAA receptor antagonist picrotoxin or the K+-channel modulator 4-aminopyridine. CONCLUSION This study provides increased levels of confidence regarding the unique anticonvulsant profile of KRM-II-81 and its potential as an improved antiepileptic drug. The data also help to solidify the veracity of alpha-2/3-containing GABAA receptors as a novel molecular target for antiepileptic drugs.