Temporal Lobe Seizures Research Articles

Identifying the characteristics of brain glucose metabolism using normal 18F-FDG PET database in patients with temporal lobe epilepsy

This study aimed to measure the global brain glucose metabolism of patients with temporal lobe epilepsy (TLE) using MIMneuro software based on the normal brain glucose metabolism database. In this cross-sectional study, 23 patients (11 males and 12 females, mean age 25.6 ± 10.1years) with TLE who underwent 18F-labeled fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) were enrolled. 18F-FDG PET images were then imported into MIMneuro software, which can automatically analyze the differences in regional brain glucose metabolism between patients and a normal database, and the results of different brain regions were presented by values of Z-score. In patients with TLE, 18F-FDG PET imaging showed that in addition to the presence of temporal lobe hypometabolism, there was hypometabolism in the ipsilateral hippocampus, parahippocampal gyrus, insula, amygdala, temporal operculum, and bilateral cerebellar hemisphere, while hypermetabolism was found in the contralateral temporal lobe, frontal lobe, parietal lobe, parietal lobule, angular gyrus, and precentral gyrus. There was no significant difference in brain areas between the left and the right temporal lobe seizures (P > 0.05). We found that TLE has a specific characteristic in terms of brain glucose metabolism, and the underlying mechanism needs to be further studied that may be helpful to localize seizure focus.

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.

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures.

On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy. In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50ms pulse of light is able to significantly inhibit seizures. On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures. Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity. Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells - the fastigial nucleus - in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

Factors associated with obsessive–compulsive symptoms in people with epilepsy

PurposeObsessive–compulsive disorder (OCD) is a common but underrecognized psychiatric condition comorbid with epilepsy. We thus investigated clinical factors associated with obsessive–compulsive symptoms (OCS) in adults with epilepsy. MethodsThis was a cross-sectional multicenter study in Republic of Korea. Obsessive–compulsive symptoms were assessed using the Obsessive–Compulsive Inventory—Revised (OCI-R). Clinical factors that were assessed included age, sex, seizure-related variables, and the number and use of antiepileptic drugs (AEDs) prescribed. Data were analyzed by stepwise linear regression and adjusted according to anxiety and depressive symptoms as assessed by Hospital Anxiety Depression Scale (HADS). ResultsThe study population comprised 221 adults with epilepsy (42.1% male, 39.7 ± 11.9 years of age). The mean OCI-R score was 18.0 (standard deviation, 12.7), and an OCI-R score of ≥21 was obtained for 40.3% of the study sample. On a stepwise linear regression analysis, epilepsy severity, temporal lobe seizures, the use of topiramate, and the use of lamotrigine were identified as independent factors associated with OCI-R score after adjusting for anxiety according to the HADS. All factors except topiramate usage were positively associated with OCS. The total explained variance was 37.3%. ConclusionsObsessive–compulsive symptoms are common in persons with epilepsy and are associated with severe epilepsy, temporal lobe seizures, and the use of topiramate and lamotrigine. Specifically, the use of lamotrigine may aggravate OCS, whereas the use of topiramate may have beneficial effects on OCS.

Up and Down States of Cortical Neurons in Focal Limbic Seizures.

Recent work suggests an important role for cortical-subcortical networks in seizure-related loss of consciousness. Temporal lobe seizures disrupt subcortical arousal systems, which may lead to depressed cortical function and loss of consciousness. Extracellular recordings show ictal neocortical slow waves at about 1Hz, but it is not known whether these simply represent seizure propagation or alternatively deep sleep-like activity, which should include cortical neuronal Up and Down states. In this study, using in vivo whole-cell recordings in a rat model of focal limbic seizures, we directly examine the electrophysiological properties of cortical neurons during seizures and deep anesthesia. We found that during seizures, the membrane potential of frontal cortical secondary motor cortex layer 5 neurons fluctuates between Up and Down states, with decreased input resistance and increased firing rate in Up states when compared to Down states. Importantly, Up and Down states in seizures are not significantly different from those in deep anesthesia, in terms of membrane potential, oscillation frequency, firing rate, and input resistance. By demonstrating these fundamental similarities in cortical electrophysiology between deep anesthesia and seizures, our results support the idea that a state of decreased cortical arousal may contribute to mechanisms of loss of consciousness during seizures.

High-frequency oscillations mirror severity of human temporal lobe seizures.

ObjectiveMany patients with epilepsy have both focal and bilateral tonic‐clonic seizures (BTCSs), but it is largely unclear why ictal activity spreads only sometimes. Previous work indicates that interictal high‐frequency oscillations (HFOs), traditionally subdivided into ripples (80–250 Hz) and fast ripples (250–500 Hz), are a promising biomarker of epileptogenicity. We aimed to investigate whether HFOs correlate with the emergence of seizure activity and whether they differ between focal seizures (FSs) with impaired awareness and BTCSs.MethodsWe retrospectively analyzed 15 FSs and 13 BTCSs from seven patients with mesial temporal lobe epilepsy, each of them with at least one BTCS and at least one FS. Representative intervals of intracranial electroencephalography from the seizure onset zone (SOZ) and remote non‐SOZ areas were selected to compare pre‐ictal, complex focal, tonic‐clonic, and postictal periods. Ripples and fast ripples were visually identified and their density, that is, percentage of time occupied by the respective events, computed.ResultsRipple and fast ripple densities increased inside the SOZ after seizure onset (P < 0.01) and in remote areas after progression to BTCSs (P < 0.01). Postictal SOZ ripple density dropped below pre‐ictal levels (P < 0.001). Prior to onset of bilateral tonic‐clonic movements, ripple density inside the SOZ is higher in BTCSs than in FSs (P < 0.05).InterpretationRipples and fast ripples correlate with onset and spread of ictal activity. Abundant ripples inside the SOZ may reflect the activation of specific neuronal networks related to imminent spread of seizure activity.

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.

Hand posture as localizing sign in adult focal epileptic seizures.

The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy. In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization. We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ. Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800.

Ictal lid movements - Blinks and lid saccades

Two types of lid movements, lid saccades and blinks, have discrete kinematic properties and physiology. These differences are reflected in distinct phenomenology of disorders affecting their neural substrate. Proof of this principle was seen in two cases, one with parietal eyefield epileptiform discharges and the other with temporal lobe seizures. The lid movements in the patient with epileptiform discharges in the eyefield were rhythmic, yoked, and had rapid upward component that instantaneously followed slow downward drift. These cyclic movements strikingly resembled nystagmus, but unlike typical eye nystagmus, the rapid upward component was pathological and seemed to involve saccadic mechanism. We suggest terms “ictal lid saccade” or “ictal lid nystagmus” to describe such phenomenology. In contrast, the patient with temporal lobe seizures had ipsilateral lid movements with rapid downward trajectories resembling reflex or spontaneous blinks. The term “ictal blink” is appropriate for this phenomenology. Schematic organization of the underlying neural circuit for lid saccade (A) and blink (B). The caricature of trajectory of lid saccade (C) and blink (D). In the caricature of the lid saccade caricature, vertical lid position is schematized in blue color, while corresponding lid velocity is schematized in brown color. The bottom row schematized EMG activity from levator palpebrae (LP, green color) and orbicularis oculi (OO, light brown color). In schematic in panel C, D, the x-axis always represents time, and schematized EMG activity is temporally matched with schematized lid position and lid velocity.

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.

Worldwide survey of neurologists on approach to autoimmune encephalitis.

To explore practice differences in the diagnosis and management of autoimmune encephalitis (AE), which is complicated by issues with sensitivity/specificity of antibody testing, nonspecific MRI/EEG/CSF findings, and competing differential diagnoses. We used a worldwide electronic survey with practice-related demographic questions and clinical questions about 2 cases: (1) a 20-year-old woman with a neuropsychiatric presentation strongly suspicious of AE and (2) a 40-year-old man with new temporal lobe seizures and cognitive impairment. Responses among different groups were compared using multivariable logistic regression. We received 1,333 responses from 94 countries; 12.0% identified as neuroimmunologists. Case 1: those treating >5 AE cases per year were more likely to send antibodies in both serum and CSF (adjusted odds ratio [aOR] vs 0 per year: 3.29, 95% CI 1.31-8.28, p = 0.011), pursue empiric immunotherapy (aOR: 2.42, 95% CI 1.33-4.40, p = 0.004), and continue immunotherapy despite no response and negative antibodies at 2 weeks (aOR: 1.65, 95% CI 1.02-2.69, p = 0.043). Case 2: neuroimmunologists were more likely to send antibodies in both serum and CSF (aOR: 1.80, 95% CI 1.12-2.90, p = 0.015). Those seeing >5 AE cases per year (aOR: 1.86, 95% CI 1.22-2.86, p = 0.004) were more likely to start immunotherapy without waiting for antibody results. Our results highlight the heterogeneous management of AE. Neuroimmunologists and those treating more AE cases generally take a more proactive approach to testing and immunotherapy than peers. Results highlight the need for higher-quality cohorts and trials to guide empiric immunotherapy, and evidence-based guidelines aimed at both experts and nonexperts. Because the average AE patient is unlikely to be first seen by a neuroimmunologist, ensuring greater uniformity in our approach to suspected cases is essential to ensure that patients are appropriately managed.

Brain connectivity changes during ictal coughing.

Coughing is a reflex phenomenon that is protective for the upper airways, involving both a reflex arc in the brainstem and cortical control. Ictal coughing has been prominently reported in temporal lobe seizures, but precise anatomo-electrical correlations are lacking. We report a patient who presented with persistent coughing at seizure onset. We studied intracerebrally recorded seizures (using stereo-electroencephalography) in order to describe the anatomo-functional correlations associated with this sign. Coughing followed seizure onset in the medial temporal lobe. A functional connectivity study (h2 estimation of interdependencies) showed that during coughing, a network of cortical and subcortical regions was involved, particularly the perisylvian cortices and the caudate nucleus.

Ictal Central Apnea (ICA) may be a useful semiological sign in invasive epilepsy surgery evaluations

IntroductionIctal central apnea (ICA) occurs in up to 44% focal seizures (temporal > extratemporal) and precedes scalp electrographic (EEG) seizure onset in 54% of them. Central apnea can be elicited by electrical stimulation of mesial temporal structures (amygdala, hippocampus, and anteromesial parahippocampal and fusiform gyri), known symptomatogenic anatomical substrates for ICA. We aimed to analyze ICA value as an early semiological sign in invasive evaluation of suspected mesial temporal lobe epilepsy (MTLE). MethodsWe examined seizure records of intractable, suspected MTLE patients undergoing intracranial EEG (ICEEG) evaluations who had simultaneous respiratory belts with artifact-free signal. ResultsWe analyzed 32 seizures (11 patients). ICA was seen in 22/32 (68.7%) seizures in 9 patients, was the first clinical manifestation in all of them, and the only clinical sign in 5/32 (15.6%). ICA onset occurred simultaneously or after ICEEG seizure onset in 20/22 (91%) seizures by 4.9 +4.6 [0–14] seconds. In one patient with bilateral amygdalar and hippocampal implantation, ICA occurred before ICEEG seizure onset, indicating seizure discharge in an untargeted, probably extra amygdalohippocampal, symptomatogenic location. ConclusionsICA incidence in mesial temporal lobe (MTL) seizures is 68.7%. ICA is often the first clinical sign and sometimes the only clinical manifestation in MTLE, but usually goes unrecognized. ICA recognition may help anatomo-electro-clinical localization of clinical seizure onset to known symptomatogenic areas. ICA preceding ICEEG onset may indicate inadequate putative epileptogenic zone coverage, and may impact surgical outcomes. Respiratory monitoring in surgical evaluations is of critical importance and should be carried out as standard of care.

Clinical implications of scalp ictal EEG pattern in patients with temporal lobe epilepsy

ObjectiveTo determine the clinical implications of scalp ictal EEG pattern in patients with temporal lobe epilepsy (TLE). MethodsScalp EEG ictal patterns were retrospectively determined in 27 consecutive patients with medically refractory temporal lobe epilepsy who underwent phase-1 scalp video-EEG and phase-2 simultaneous scalp and intracranial video-EEG recordings for pre-surgical evaluation. ResultsOf the 192 temporal lobe seizures recorded during phase-1 and phase-2 scalp video-EEG studies, 124 (65%) seizures were associated with theta/alpha (5–9 Hz) ictal onset pattern, and 68 (35%) seizures were associated with delta (2–5 Hz) ictal onset pattern. Fourteen (52%) patients had exclusively theta/alpha ictal onset, 3 (11%) patients had exclusively delta ictal onset, and 10 (37%) patients had mixed theta/alpha and delta ictal onsets. MTLE was observed in 26 patients who had 124 seizures with theta/alpha ictal onset and 59 seizures with delta ictal onset. LTLE was observed in one patient who had 9 seizures with delta ictal onset. Scalp ictal EEG pattern was not significantly correlated with postsurgical seizure outcomes. ConclusionsBoth scalp delta and theta/alpha ictal onset patterns can be commonly found in patients with MTLE. SignificanceScalp delta ictal onset is not a unique EEG pattern for LTLE as commonly believed.

Implication of Anterior Nucleus of the Thalamus in Mesial Temporal Lobe Seizures

Deep brain stimulation of the anterior nucleus of the thalamus has been proposed as novel therapy to treat intractable epilepsy. To optimize this approach, we proposed to study the involvement of this nucleus in a non-human primate model of mesial temporal lobe seizure.Two macaques were implanted with one chronic electrode into the hippocampus allowing to monitor the ictal activity. Neurons of the anterior nucleus of the thalamus were recorded with a microelectrode inserted acutely. To induce seizures, penicillin was injected into the hippocampus and neuronal activities of the anterior nucleus were analyzed during ictal and interictal periods. The effects of the chemical neuromodulation of the anterior nucleus on the ictal hippocampal activities were studied and electron microscopy analysis was carried out to study morphological modifications induced in the anterior nucleus of the thalamus. Our results demonstrate that the anterior nucleus of the thalamus is directly involved in the pathophysiology of induced seizures since: (1) Electrophysiological study showed an heterogenous excitation during seizure characterized by the appearance of 2 types of neuronal firing response; (2) chemical neuromodulation of the anterior nucleus of the thalamus changed the severity of seizures; (3) morphological modification of the ultrastructure as well as a reduction of synapse density were observed within the ipsilateral anterior nucleus of the thalamus. This study demonstrates that the anterior nucleus of the thalamus is part of the epileptic network activated during temporal lobe seizures and suggests that this nucleus would be valid target for seizure control using deep brain stimulation.

Association between serum apolipoprotein E and cognitive functions in Egyptian patients with temporal lobe epilepsy.

Memory, cognition and visuospatial aspects of temporal lobe epilepsy (TLE) have not been fully analyzed yet. From among the huge growing population of circulating apoproteins analyzed in TLE, apolipoprotein E (APOE) was discovered; however, its role in TLE has not been fully elucidated yet. This study was designed to investigate the relation between the serum level of APOE and cognition in TLE patients. Sixty-five subjects (35 TLE patients and 30 healthy matched controls) were included. Evaluation of cognitive functions was done using Addenbrooke's Cognitive Examination Revised (ACE-R) scale. Serum APOE level was measured by ELISA. The mean total score, memory and visuospatial scores of ACE-R were significantly lower in TLE patients compared to healthy subjects. The mean total score and memory score of ACE-R were significantly lower in seizures originating from mesial temporal lobe (MTL) and left temporal lobe seizures. Serum APOE levels were significantly higher in TLE patients compared to healthy subjects. Serum APOE levels significantly negatively correlated with total score, memory, and visuospatial ability scores of ACE-R. Serum APOE was significantly higher in MTL seizures compared to lateral lobe seizures and in left temporal lobe seizures compared to right temporal seizures. Memory and visuospatial aspects were significantly affected in TLE patients. So, the serum APOE level can possibly contribute to cognitive dysfunction in such patients.

Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression

Autoantibodies against CASPR2 (contactin-associated protein-like 2) have been linked to autoimmune limbic encephalitis that manifests with memory disorders and temporal lobe seizures. According to the growing number of data supporting a role for CASPR2 in neuronal excitability, CASPR2 forms a molecular complex with transient axonal glycoprotein-1 (TAG-1) and shaker-type voltage-gated potassium channels (Kv1.1 and Kv1.2) in compartments critical for neuronal activity and is required for Kv1 proper positioning. Whereas the perturbation of these functions could explain the symptoms observed in patients, the pathogenic role of anti-CASPR2 antibodies has been poorly studied. In the present study, we find that patient autoantibodies alter Caspr2 distribution at the cell membrane promoting cluster formation. We confirm in a HEK cellular model that the anti-CASPR2 antibodies impede CASPR2/TAG-1 interaction and we identify the domains of CASPR2 and TAG-1 taking part in this interaction. Moreover, introduction of CASPR2 into HEK cells induces a marked increase of the level of Kv1.2 surface expression and in cultures of hippocampal neurons Caspr2-positive inhibitory neurons appear to specifically express high levels of Kv1.2. Importantly, in both cellular models, anti-CASPR2 patient autoAb increase Kv1.2 expression. These results provide new insights into the pathogenic role of autoAb in the disease.