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Objectives: Resective surgery in drug-resistant focal epilepsy (DRFE) requires extensive evaluation to localize the epileptogenic zone (EZ). When non-invasive phase 1 assessments (electroencephalography, EEG; magnetic resonance imaging, MRI; and 18 F-Fluorodeoxyglucose-positron emission tomography, [ 18 F]FDG-PET) are inconclusive for EZ localization, invasive investigations such as stereo-EEG (SEEG) are necessary. Epileptogenicity maps (Ems) visualize the EZ using SEEG-identified ictal high-frequency oscillations (iHFOs). PET imaging with radioligands targeting the18-kDa translocator protein (TSPO), a marker of glial activation, may aid EZ localization. This study investigates the correlation between TSPO-PET imaging and SEEG iHFOs in DRFE to determine the utility of TSPO-PET in pre-surgical assessments, especially in complex or non-lesional cases., Methods: Patients with DRFE and inconclusive phase 1 assessments were recruited from Bicêtre Hospital (AP-HP) for a prospective study (Eudract 2017-003381-27). They underwent SEEG and [ 18 F]DPA-714 (N,N-diethyl-2-(2-(4-(2-(fluoro- 18 F)ethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) (TSPO radioligand) PET imaging. Statistical parametric mapping (SPM) techniques analyzed significant [ 18 F]DPA-714-PET uptake (TSPO-map) and generated epileptogenicity maps (EM-map). Correlation analyses at regional and voxel-of-interest (VOI) levels assessed the relationship between TSPO-map and EM-map., Results: We were able to obtain and analyze both maps in 12 of 17 patients recruited. A significant positive correlation between EM-map and TSPO-map in focal epilepsies was found regionally (r = .81, p < .00004) and at the VOI level (r = .79, p < .00003). Temporal, insular, parietal, and occipital regions showed particularly strong correspondence. In frontal epilepsies, TSPO-map was more focal than EM-map, suggesting increased specificity for SEEG planning. This study also demonstrated the benefit of the TSPO-map in identifying multiple foci in multifocal epilepsies, with or without lesions., Significance: These findings suggest that neuroinflammation may be a molecular substrate of the EZ in non-lesional focal epilepsy. Identifying the EZ inpatients with complex DRFE and inconclusive MRI/[ 18 F]FDG-PET imaging is essential to improve resective surgery outcomes. Combining TSPO-PET imaging with SEEG recordings may help bridge this gap., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [ 11 C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [ 11 C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB., Methods: Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [ 11 C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K 1 ) and from brain to plasma (k 2 ), and the total volume of distribution (V T = K 1 /k 2 )., Results: DRE patients but not DSE patients showed significantly higher k 2 values and a trend towards lower V T values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k 2 : hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%)., Conclusions: [ 11 C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k 2 seems to be the most sensitive parameter to measure increased P-gp function with [ 11 C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [ 11 C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases., Trial Registration: EudraCT 2019-003137-42. Registered 28 February 2020., (© 2024. The Author(s).)

In patients suffering from focal drug-resistant epilepsy, intracranial explorations are the gold standard for identifying the epileptogenic zone and evaluating the possibility of a surgical resection. Amongst them, stereoelectroencephalography (SEEG), using depth electrodes, is a safe procedure. However, complications occur on average in 2% of cases, notably haemorrhages or infections. Vasogenic cerebral oedema constitutes a rarely reported complication. Amongst the 85 patients explored with SEEG between January 2017 and September 2023, three had a clinically and electrophysiologically relevant vasogenic cerebral oedema. In these three patients, the surgical procedure was uneventful. In all three as well, electrodes exploring areas away from the epileptogenic zone recorded some unexpected focal delta slowing with clinically asymptomatic superimposed discharges, a pattern so far only reported in cases of bleeding. Moreover, one patient experienced confusion 10 days after explantation. Post-explantation magnetic resonance imaging showed, in all three patients, a vasogenic oedema that fully resolved a few months later. We did not identify any contributing factors, and there were no particularities concerning the number of electrodes, their implantation site or the recording duration. Focal delta slowing and rhythmic discharges during SEEG can indicate a vasogenic oedema. Clinical consequences can occur after explantation. Evolution is favourable but this misleading pattern must be identified., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Prognostication of outcome in severe stroke patients necessitating invasive mechanical ventilation poses significant challenges. The objective of this study was to assess the prognostic significance and prevalence of early electroencephalogram (EEG) abnormalities in adult stroke patients receiving mechanical ventilation., Methods: This study is a pre-planned ancillary investigation within the prospective multicenter SPICE cohort study (2017-2019), conducted in 33 intensive care units (ICUs) in the Paris area, France. We included adult stroke patients requiring invasive mechanical ventilation, who underwent at least one intermittent EEG examination during their ICU stay. The primary endpoint was the functional neurological outcome at one year, determined using the modified Rankin scale (mRS), and dichotomized as unfavorable (mRS 4-6, indicating severe disability or death) or favorable (mRS 0-3). Multivariable regression analyses were employed to identify EEG abnormalities associated with functional outcomes., Results: Of the 364 patients enrolled in the SPICE study, 153 patients (49 ischemic strokes, 52 intracranial hemorrhages, and 52 subarachnoid hemorrhages) underwent at least one EEG at a median time of 4 (interquartile range 2-7) days post-stroke. Rates of diffuse slowing (70% vs. 63%, p = 0.37), focal slowing (38% vs. 32%, p = 0.15), periodic discharges (2.3% vs. 3.7%, p = 0.9), and electrographic seizures (4.5% vs. 3.7%, p = 0.4) were comparable between patients with unfavorable and favorable outcomes. Following adjustment for potential confounders, an unreactive EEG background to auditory and pain stimulations (OR 6.02, 95% CI 2.27-15.99) was independently associated with unfavorable outcomes. An unreactive EEG predicted unfavorable outcome with a specificity of 48% (95% CI 40-56), sensitivity of 79% (95% CI 72-85), and positive predictive value (PPV) of 74% (95% CI 67-81). Conversely, a benign EEG (defined as continuous and reactive background activity without seizure, periodic discharges, triphasic waves, or burst suppression) predicted favorable outcome with a specificity of 89% (95% CI 84-94), and a sensitivity of 37% (95% CI 30-45)., Conclusion: The absence of EEG reactivity independently predicts unfavorable outcomes at one year in severe stroke patients requiring mechanical ventilation in the ICU, although its prognostic value remains limited. Conversely, a benign EEG pattern was associated with a favorable outcome., (© 2024. The Author(s).)

Background: Although still incomplete, the epidemiology of epilepsy shows substantial variations in the burden of the condition according to demographic, social and territorial characteristics. This study aimed to estimate the prevalence of treated epilepsy and to investigate its demographic and spatial distribution in 2020 in France, a country where the nationwide epidemiological situation of the condition remains largely unknown., Methods: We used the French national health data system, which covers nearly the entire population residing in France (over 67 million of inhabitants in metropolitan and overseas departments). Prevalent cases were identified using long-term disease status, hospitalisation for epilepsy (ICD-10 codes G40 or G41), and reimbursements for antiseizure medications and electroencephalograms., Results: In 2020, we identified 685,122 epilepsy cases, corresponding to an overall prevalence of 10.2 per 1000 inhabitants [95% confidence interval 10.1-10.2], with similar rates in men and women. Estimates were found to increase with age, with an accelerated rise in the second half of the life, which occurred earlier in men than in women. We observed a monotonic gradient of variation with socio-economic deprivation (in non-military metropolitan subjects aged 18-54 years) as well as territorial heterogeneity, with the mountainous centre of France as well as some French overseas departments having the highest prevalence., Conclusions: Our results revise upwards the estimation of epilepsy prevalence in France, showing that it now ranks among the highest in developed countries. Our study also confirms the important socio-territorial heterogeneity of the condition that reflects health inequalities in this country., (© 2023. The Author(s).)

Several studies have shown that the retroinsular and posterior parietal operculum regions play a central role in vestibular processing. Electrical stimulations performed during stereoelectroencephalography (SEEG) in patients with focal drug-resistant epilepsy could contribute to the analysis of this area. Among the 264 SEEGs performed in both an adult and a paediatric epilepsy surgery centre, we retrospectively identified 24 patients (9%) reporting vertigo during electrical stimulations (ES). In seven of them (29% of patients experiencing vertigo during ES), it was evoked by stimulating the retroinsular region. The reported responses were mostly not rotatory sensations but actually illusions of body, limb or limb segment movement. The involved area is limited. Moreover, two patients reported having the same symptoms at the beginning of their seizures starting in the same region. Our case study confirms the pivotal role of the retroinsular and posterior parietal operculum areas in vestibular responses, and we therefore advise the exploration of this region when patients report an illusion of body movement at the beginning of their seizures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Translocator protein 18 kDa (TSPO) PET imaging is used to monitor glial activation. Recent studies have proposed TSPO PET as a marker of the epileptogenic zone (EZ) in drug-resistant focal epilepsy (DRFE). This study aims to assess the contributions of TSPO imaging using [ 18 F]DPA-714 PET and [ 18 F]FDG PET for localizing the EZ during presurgical assessment of DRFE, when phase 1 presurgical assessment does not provide enough information., Methods: We compared [ 18 F]FDG and [ 18 F]DPA-714 PET images of 23 patients who had undergone a phase 1 presurgical assessment, using qualitative visual analysis and quantitative analysis, at both the voxel and the regional levels. PET abnormalities (increase in binding for [ 18 F]DPA-714 vs decrease in binding for [ 18 F]FDG) were compared with clinical hypotheses concerning the localization of the EZ based on phase 1 presurgical assessment. The additional value of [ 18 F]DPA-714 PET imaging to [ 18 F]FDG for refining the localization of the EZ was assessed. To strengthen the visual analysis, [ 18 F]DPA-714 PET imaging was also reviewed by 2 experienced clinicians blind to the EZ location., Results: The study included 23 patients. Visual analysis of [ 18 F]DPA-714 PET was significantly more accurate than [ 18 F]FDG PET to both, show anomalies (95.7% vs 56.5%, p = 0.022), and provide additional information to refine the EZ localization (65.2% vs 17.4%, p = 0.019). All 10 patients with normal [ 18 F]FDG PET had anomalies when using [ 18 F]DPA-714 PET. The additional value of [ 18 F]DPA-714 PET seemed to be greater in patients with normal brain MRI or with neocortical EZ (especially if insula is involved). Regional analysis of [ 18 F]DPA-714 and [ 18 F]FDG PET provided similar results. However, using voxel-wise analysis, [ 18 F]DPA-714 was more effective than [ 18 F]FDG for unveiling clusters whose localization was more often consistent with the EZ hypothesis (87.0% vs 39.1%, p = 0.019). Nonrelevant bindings were seen in 14 of 23 patients in visual analysis and 9 patients of 23 patients in voxel-wise analysis., Discussion: [ 18 F]DPA-714 PET imaging provides valuable information for presurgical assessments of patients with DRFE. TSPO PET could become an additional tool to help to the localization of the EZ, especially in patients with negative [ 18 F]FDG PET., Trial Registration Information: Eudract 2017-003381-27. Inclusion of the first patient: September 24, 2018., Classification of Evidence: This study provides Class IV evidence on the utility of [ 18 F]DPA-714 PET compared with [ 18 F]FDG PET in identifying the epileptic zone in patients undergoing phase 1 presurgical evaluation for intractable epilepsy., (© 2023 American Academy of Neurology.)

Purpose: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [ 18 F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases., Methods: The non-metabolized fraction of [ 18 F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([ 18 F]DPA-714 70-90 ) and corresponding normalized plasma concentration (SUV 70-90 ) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [ 18 F]DPA-714 at equilibrium was investigated., Results: As no significant differences were observed between arterial and venous [ 18 F]DPA-714 70-90 and SUV 70-90 , venous plasma was used for correlations. [ 18 F]DPA-714 70-90 was not significantly different between patients and HC S (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [ 18 F]DPA-714 70-90 (up to 88% or down to 23%) and SUV 70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [ 18 F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VT IND ) or population-based input function derived from untreated HCs (VT PBIF ) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [ 18 F]DPA-714 70-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [ 18 F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase)., Conclusion: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [ 18 F]DPA-714 and consequently its human brain and peripheral uptake., Trial Registration: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Insular epilepsy (IE) is an increasingly recognized cause of drug-resistant epilepsy amenable to surgery. However, concerns of suboptimal seizure control and permanent neurological morbidity hamper widespread adoption of surgery for IE. We performed a systematic review and individual participant data meta-analysis to determine the efficacy and safety profile of surgery for IE and identify predictors of outcomes. Of 2483 unique citations, 24 retrospective studies reporting on 312 participants were eligible for inclusion. The median follow-up duration was 2.58 years (range, 0-17 years), and 206 (66.7%) patients were seizure-free at last follow-up. Younger age at surgery (≤18 years; HR = 1.70, 95% CI = 1.09-2.66, P = .022) and invasive EEG monitoring (HR = 1.97, 95% CI = 1.04-3.74, P = .039) were significantly associated with shorter time to seizure recurrence. Performing MR-guided laser ablation or radiofrequency ablation instead of open resection (OR = 2.05, 95% CI = 1.08-3.89, P = .028) was independently associated with suboptimal or poor seizure outcome (Engel II-IV) at last follow-up. Postoperative neurological complications occurred in 42.5% of patients, most commonly motor deficits (29.9%). Permanent neurological complications occurred in 7.8% of surgeries, including 5% and 1.4% rate of permanent motor deficits and dysphasia, respectively. Resection of the frontal operculum was independently associated with greater odds of motor deficits (OR = 2.75, 95% CI = 1.46-5.15, P = .002). Dominant-hemisphere resections were independently associated with dysphasia (OR = 13.09, 95% CI = 2.22-77.14, P = .005) albeit none of the observed language deficits were permanent. Surgery for IE is associated with a good efficacy/safety profile. Most patients experience seizure freedom, and neurological deficits are predominantly transient. Pediatric patients and those requiring invasive monitoring or undergoing stereotactic ablation procedures experience lower rates of seizure freedom. Transgression of the frontal operculum should be avoided if it is not deemed part of the epileptogenic zone. Well-selected candidates undergoing dominant-hemisphere resection are more likely to exhibit transient language deficits; however, the risk of permanent deficit is very low., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

[11C]metoclopramide PET imaging provides a sensitive and translational tool to explore P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Patients with neurological diseases are often treated with cytochrome (CYP) modulators which may impact the plasma and brain kinetics of [11C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [11C]metoclopramide was investigated in rats. Data obtained in a control group were compared with groups that were either orally pretreated with carbamazepine (45 mg/kg twice a day for 7 days before PET) or ritonavir (20 mg/kg, 3 h before PET) (n = 4 per condition). Kinetic modelling was performed to estimate the brain penetration (VT) of [11C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [11C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor VT of [11C]metoclopramide (p > 0.05). However, ritonavir significantly increased VT (p < 0.001), apparently behaving as an inhibitor of P-gp at the BBB. Our data suggest that treatment with potent CYP inducers such as carbamazepine does not bias the estimation of P-gp function at the BBB with [11C]metoclopramide PET. This supports further use of [11C]metoclopramide for studies in animals and patients treated with CYP inducers.

Objective: The semiology of temporo-basal epilepsy has rarely been analysed in the literature. In this paper, we report three patients with proven basal temporal epilepsy with somatomotor or somatosensory facial ictal semiology, highly suggestive of insulo-opercular onset., Methods: The three patients had a temporobasal lesion and their drugresistant epilepsy was cured with resection of the lesion (follow-up duration: 7-17 years). We reviewed the medical charts, non-invasive EEG data as well as the stereoelectroencephalography (SEEG) performed in two patients. Quantitative analysis of ictal fast gamma activity was performed for one patient., Results: Early ictal features were orofacial, either somatomotor in two patients or ipsilateral somatosensory in one. The three patients had prior sensations compatible with a temporal lobe onset. Interictal and ictal EEG pointed to the temporal lobe. The propagation of the discharge to the insula and operculum before the occurrence of facial features was seen on SEEG. Facial features occurred 7-20 seconds after electrical onset. Quantitative analysis of six seizures in one patient confirmed the visual analysis, showing statistically significant fast gamma activity originating from basal areas and then propagating to insuloopercular regions after a few seconds., Significance: We report three cases of lesional temporo-basal epilepsy responsible for orofacial semiology related to propagation of insulo-opercular ictal discharge. In MRI-negative patients with facial manifestations, this origin should be suspected when EEG is suggestive. These observations may contribute to our understanding of brain networks.

Epilepsy is one of the most common neurological disorders and affects both the young and adult populations. The question we asked for this review was how positron emission tomography (PET) imaging with translocator protein (TSPO) radioligands can help inform the epilepsy clinic and the development of future treatments targeting neuroinflammatory processes.Even though the first TSPO PET scans in epilepsy patients were performed over 20 years ago, this imaging modality has not seen wide adoption in the clinic. There is vast scientific evidence from preclinical studies in rodent models of temporal lobe epilepsy which have shown increased levels of TSPO corresponding to neuroinflammatory processes in the brain. These increases peaked sub-acutely (1-2 weeks) after the epileptogenic insult (e.g. status epilepticus) and remained chronically increased, albeit at lower levels. In addition, these studies have shown a correlation between TSPO levels and seizure outcome, pharmacoresistance and behavioural morbidities. Histological assessment points to a complex interplay between different cellular components such as microglial activation, astrogliosis and cell death changing dynamically over time.In epilepsy patients, a highly sensitive biomarker of neuroinflammation would provide value for the optimization of surgical assessment (particularly for extratemporal lobe epilepsy) and support the clinical development path of anti-inflammatory treatments. Clinical studies have shown a systematic increase in asymmetry indices of TSPO PET binding. However, region-based analysis typically does not yield statistical differences and changes are often not restricted to the epileptogenic zone, limiting the ability of this imaging modality to localise pathology for surgery. In this manuscript, we discuss the biological underpinnings of these findings and review for which applications in epilepsy TSPO PET could bring added value., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In stroke units, diagnosing seizures may be difficult, especially in aphasic patients. We discuss herein our systematic 4-hour video EEG monitoring of 61 patients with aphasia within the first 72hours after the onset of ischaemic stroke. Five electrographic seizures were identified in 3 patients, with no clinical signs apparent on the video and no symptoms reported by patients. We did not record status epilepticus nor generalized seizure. Comparative analyses disclosed a higher risk of early seizures in patients with haemorrhagic transformation. Video EEG monitoring detected electrographic seizures in 5% of stroke patients with aphasia. This monitoring could be useful for selected patients, especially those with haemorrhagic transformation., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Purpose: Interictal positron emission tomography (PET) with 18 F-FDG has largely proved its utility in presurgical evaluation of drug-resistant epilepsies (DRE) and in the surgical outcomes. Interictal hypometabolism topography is related to the neuronal networks involved in the seizure onset zone (SOZ) and spread pathways. 18 F-FDG PET has a good prognostic value for post-surgical outcome, especially in cases with unique focal ictal semiology and a limited extent of hypometabolism. Surprisingly few patients have similar limited ictal features but extended hypometabolism. The objective of this study is to show that stereoelectro encephalography (SEEG) provides an explanation for this large hypometabolism, which impacts the surgical strategy., Methods: A cohort of 248 patients underwent 18 F-FDG PET and SEEG to explore for refractory epilepsy in two close tertiary epilepsy centers between January 2009 and December 2017. From this cohort, a subset of patients was selected with extended PET metabolism despite showing unique and limited ictal features in scalp EEG. The surgical outcome of this subset of patients has been analysed with respect to their FDG-PET and SEEG to understand the relationship between PET/SEEG/ presentation and surgical outcome., Results: We report a series of seven patients with DRE and unique stereotyped ictal semiology but extensive 18 F-FDG-PET hypometabolism revealing unexpected multifocal SOZ using SEEG. All SOZ were encompassed by the hypometabolic area., Conclusion: Our results demonstrate the necessity of accounting for the discrepancy between limited symptoms and widespread hypometabolism which can reveal multifocal SOZ. In those patients, surgical possibilities should be considered carefully., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

Longitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging., Methods: Using dynamic, whole-body 18 F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (V T ) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The V T and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against V T and %ID parameters., Results: The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the V T estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans., Conclusion: We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling.

Objectives: Although rare, neurological manifestations in SARS-CoV-2 infection are increasingly being reported. We conducted a retrospective systematic study to describe the electroencephalography (EEG) characteristics in this disease, looking for specific patterns., Methods: EEGs performed in patients with positive PCR for SARS-CoV-2 between 25/03/2020 and 06/05/2020 in the University Hospital of Bicêtre were independently reviewed by two experienced neurologists. We used the American Clinical Neurophysiology Society's terminology for the description of abnormal patterns. EEGs were classified into five categories, from normal to critically altered. Interobserver reliability was calculated using Cohen's kappa coefficient. Medical records were reviewed to extract demographics, clinical, imaging and biological data., Results: Forty EEGs were reviewed in 36 COVID-19 patients, 18 in intensive care units (ICU) and 22 in medicine units. The main indications were confusion or fluctuating alertness for 23 (57.5%) and delayed awakening after stopping sedation in ICU in six (15%). EEGs were normal to mildly altered in 23 (57.5%) contrary to the 42.5% where EEG alterations were moderate in four (10%), severe in eight (20%) and critical in five (12.5%). Generalized periodic discharges (GPDs), multifocal periodic discharges (MPDs) or rhythmic delta activity (RDA) were found in 13 recordings (32.5%). EEG alterations were not stereotyped or specific. They could be related to an underlying morbid status, except for three ICU patients with unexplained encephalopathic features., Conclusion: In this first systematic analysis of COVID-19 patients who underwent EEG, over half of them presented a normal recording pattern. EEG alterations were not different from those encountered in other pathological conditions., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: A plethora of data show that the hippocampus and the amygdala are involved in post-traumatic stress disorder (PTSD). Neural dysfunctions leading to PTSD (e.g. how the amygdala and the hippocampus are altered) are only partially known. The unusual case of a patient presenting with refractory epilepsy and developing PTSD immediately after surgery is described. Such symptoms in epileptic patients may help to explore PTSD mechanisms., Case Report: A 41-year-old male suffering from partial refractory temporal lobe epilepsy was operated in May 2017. A right amygdala, hippocampus, and temporal pole selective resection was performed. He experienced intense PTSD symptoms 1 month after surgery. He complained about repetitive intrusive memories of abuse. The PTSD checklist score was equal to 62/80. He reported a history of childhood abuse: physical and emotional abuse as well as emotional negligence, assessed with the Childhood Trauma Questionnaire. No other medical history was recorded. He never complained about PTSD or any other psychiatric symptoms before surgery., Conclusion: this case indicates that PTSD may occur after temporal lobe epilepsy surgery and may specifically stem, as in this context, from the excision of part of the medial temporal lobe structures. Although rarely reported, PTSD may be undiagnosed when not selectively detected via multi-disciplinary neurological and psychiatric management, in the preoperative period and the immediate and delayed postoperative period., (Copyright © 2020 Yrondi, Valton, Bouilleret, Aghakhani, Curot and Birmes.)

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3-5 months concomitant with developmental arrest or regression, other seizure types and drug-resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1-related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1-related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epileptic and psychiatric diseases share overlaps. Indeed, anxiety and depression are common comorbidities in epilepsy, and patients with psychiatric disease are at risk of epilepsy. Some antiepileptic drugs (AED) have psychiatric side effects; conversely, some AED could be used to treat psychiatric pathologies. Based on current literature data, the aim of this study is to determine the psychiatric effects induced by the most frequently prescribed AED in epileptic adults. Some AED will have positive mood or anxiolytic effects like sodium channel blockers, valproate and benzodiazepines; conversely, others might induce negative psychiatric effect, especially depression, anxiety or aggression, like levetiracetam, perampanel, topiramate, zonisamide, and barbiturates. The main risk factor for presenting these side effects is a personal history of psychiatric pathology. We therefore recommend monitoring the occurrence of psychiatric side effects, especially when using the most at risk AED and/or in case of psychiatric history. Moreover, in this latter case, it is preferable to use AED with positive psychiatric effects. The use of anxiety and depression scales could be useful detection tools.

Objective: Mesiotemporal lobe epilepsy is the most common type of drug-resistant partial epilepsy, with a specific history that often begins with status epilepticus due to various neurological insults followed by a silent period. During this period, before the first seizure occurs, a specific lesion develops, described as unilateral hippocampal sclerosis (HS). It is still challenging to determine which drugs, administered at which time point, will be most effective during the formation of this epileptic process. Neuroinflammation plays an important role in pathophysiological mechanisms in epilepsy, and therefore brain inflammation biomarkers such as translocator protein 18 kDa (TSPO) can be potent epilepsy biomarkers. TSPO is associated with reactive astrocytes and microglia. A unilateral intrahippocampal kainate injection mouse model can reproduce the defining features of human temporal lobe epilepsy with unilateral HS and the pattern of chronic pharmacoresistant temporal seizures. We hypothesized that longitudinal imaging using TSPO positron emission tomography (PET) with 18 F-DPA-714 could identify optimal treatment windows in a mouse model during the formation of HS., Methods: The model was induced into the right dorsal hippocampus of male C57/Bl6 mice. Micro-PET/computed tomographic scanning was performed before model induction and along the development of the HS at 7 days, 14 days, 1 month, and 6 months. In vitro autoradiography and immunohistofluorescence were performed on additional mice at each time point., Results: TSPO PET uptake reached peak at 7 days and mostly related to microglial activation, whereas after 14 days, reactive astrocytes were shown to be the main cells expressing TSPO, reflected by a continuing increased PET uptake., Significance: TSPO-targeted PET is a highly potent longitudinal biomarker of epilepsy and could be of interest to determine the therapeutic windows in epilepsy and to monitor response to treatment., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Developmental venous anomalies (DVAs) are congenital anatomical variants of normal venous drainage of normal brain. Although DVAs are often discovered on the occasion of a seizure, their involvement in epilepsy is poorly studied. Our objective was to determine whether DVA can cause seizures, in the cases where there is no associated lesion, including no cavernoma or dysplasia. Based on clinical history, cerebral MRI, EEG recording, and 18 F-FDG PET, we report 4 patients with DVA revealed by seizures. The first patient had a convulsive seizure caused by a hemorrhagic infarction due to thrombosis of her DVA. The second patient had a left temporo-parietal DVA next to a nonspecific lesion, possibly a sequelae of a venous infarction. The last two patients disclosed an isolated and uncomplicated DVA with a concordant epileptic focus confirmed on ictal video EEG recording. We reviewed literature and identified 21 other published cases of seizures caused by complications of a DVA and 9 patients that may have a direct link between epilepsy and an isolated and uncomplicated DVA. Seizures are linked to a DVA in two main situations: presence of an associated epileptogenic lesion, such as cavernoma or dysplasia, and occurrence of a complication of the DVA. Before concluding that a seizure is caused by a DVA, it is essential to perform full MRI protocols to search them. It remains rare and uncertain that isolated and uncomplicated DVA can cause seizures. In this last situation, physiopathological processes are probably different in each patient.

Purpose: To analyze the semiological characteristics of the language and speech disorders arising during epileptic seizures, and to describe the patterns of language and speech disorders that can predict laterality of the epileptic focus., Method: This study retrospectively analyzed 95 consecutive videos of seizures with language and/or speech disorders in 44 patients admitted for diagnostic video-EEG monitoring. Laterality of the epileptic focus was defined according to electro-clinical correlation studies and structural and functional neuroimaging findings. Language and speech disorders were analyzed by a neurologist and a speech therapist blinded to these data., Results: Language and/or speech disorders were subdivided into eight dynamic patterns: pure anterior aphasia; anterior aphasia and vocal; anterior aphasia and "arthria"; pure posterior aphasia; posterior aphasia and vocal; pure vocal; vocal and arthria; and pure arthria. The epileptic focus was in the left hemisphere in more than 4/5 of seizures presenting with pure anterior aphasia or pure posterior aphasia patterns, while discharges originated in the right hemisphere in almost 2/3 of seizures presenting with a pure vocal pattern. No laterality value was found for the other patterns., Conclusion: Classification of the language and speech disorders arising during epileptic seizures into dynamic patterns may be useful for the optimal analysis of anatomo-electro-clinical correlations. In addition, our research has led to the development of standardized tests for analyses of language and speech disorders arising during seizures that can be conducted during video-EEG sessions., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Anti NMDA receptor (anti NMDAR) encephalitis is a well-characterized entity in children associating movement disorders, psychiatric features and speech difficulties. Novel phenotypes have been described in adults., Methods and Results: A 4-year-old girl presented partial seizures which evolved towards sudden and isolated Broca's aphasia. Anti NMDAR antibodies were positive in CSF and serum confirming anti NMDAR encephalitis. Clinical recovery was observed after a specific treatment., Conclusion: This case widens the clinical spectrum of anti-NMDAR encephalitis in children and awareness of this newly identified symptom is important as early treatment is a predictor of good outcome., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE., Methods: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5-25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6-4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data., Key Findings: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding., Significance: Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.

Unlabelled: Studies report that (11)C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than (18)F-FDG PET. However, practical aspects of (11)C use limit clinical application. We report a phase I/IIa study assessing the clinical use of (18)F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial sampling., Methods: Dynamic (18)F-FMZ PET and static interictal (18)F-FDG PET scans were compared in healthy controls (n = 17 for (18)F-FMZ and n = 20 for (18)F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n = 12) and with normal MR imaging (NL TLE, n = 19). Masked visual assessment of images was undertaken. Parametric images of (18)F-FMZ binding potential (BPND) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify (18)F-FMZ BPND and (18)F-FDG uptake in the temporal lobe., Results: The visual assessment of static standardized uptake value images showed (18)F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than (18)F-FDG PET. However, the (18)F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippocampal (18)F-FMZ BPND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippocampal (18)F-FMZ BPND was independent of both hippocampal volume and (18)F-FDG uptake, whereas ipsilateral hippocampal volume was correlated with (18)F-FDG uptake (r(2) = 0.69, P < 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with (18)F-FMZ PET and 18 of 29 (62%) with (18)F-FDG PET. Cluster size was significantly smaller on (18)F-FMZ than (18)F-FDG images (37 vs. 160 voxels, P < 0.01)., Conclusion: (18)F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to (18)F-FDG PET, with a more restricted region of abnormality.

Purpose: Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE., Methods: Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings., Key Findings: MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, (18) F-fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month (18) F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination., Significance: These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Background: Statistical parametric mapping (SPM) procedure is an objective tool to analyze 18F-fluoro-2-deoxy-d-glucose-positron-emission tomography (FDG-PET) images and a useful complement to visual analysis. However, SPM requires a comparison to control data set that cannot be obtained in healthy children for ethical reasons. Using adults as controls showed some limitations. The purpose of the present study was to generate and validate a group of pseudo-normal children as a control group for FDG-PET studies in pediatrics., Methods: FDG-PET images of 47 children (mean ± SD age 10.2 ± 3.1 years) with refractory symptomatic (MRI-positive, n = 20) and cryptogenic (MRI-negative, n = 27) focal epilepsy planned for surgery were analyzed using visual and SPM analysis. Performances of SPM analysis were compared using two different control groups: (1) an adult control group consisting of healthy young adults (n = 25, 30.5 ± 5.8 years, adult PET template) and (2) a pediatric pseudo-control group consisting of patients (n = 24, 10.6 ± 3.1 years, children PET template) with refractory focal epilepsy but with negative MRI and with PET considered normal not only on visual analysis but also on SPM., Results: Among the 47 children, visual analysis succeeded detecting at least one hypometabolic area in 87% of the cases (interobserver kappa = 0.81). Regarding SPM analysis, the best compromise between sensitivity and specificity was obtained with a threshold of p less than 0.001 as an extent of more than 40 voxels. There was a significant concordance to detect hypometabolic areas between both SPM analyses [kappa (K) = 0.59; p < 0.005] and between both SPM and visual analyses (K = 0.45; p < 0.005), in symptomatic (K = 0.74; p < 0.005) as in cryptogenic patients (K = 0.26; p < 0.01). The pediatric pseudo-control group dramatically improved specificity (97% vs. 89%; p < 0.0001) by increasing the positive predictive value (86% vs. 65%). Sensitivity remained acceptable although it was not better (79% vs. 87%, p = 0.039). The main impact was to reduce by 41% the number of hypometabolic cortical artifacts detected by SPM, especially in the younger epileptic patients, which is a key point in clinical practice., Conclusions: This age-matched pseudo-control group is a way to optimize SPM analysis of FDG-PET in children with epilepsy. It might also be considered for other brain pathologies in pediatrics in the future.

Purpose: To investigate changes in diffusion tensor imaging (DTI) measures in limbic system white matter of patients with temporal lobe epilepsy (TLE) using diffusion tensor tractography., Materials and Methods: DTI metrics including fractional anisotropy (FA), λ1, λ2, λ3, and trace (Tr) coefficients were obtained from tractography for bilateral fornix, superior and inferior cingulum fibers in 18 patients and 10 healthy controls. Hippocampal signal-to-noise ratio (SNR) quantitative analysis was performed in order to confirm the magnetic resonance imaging (MRI) hippocampal lesion presence or absence in TLE patients., Results: Nine patients presented unilateral hippocampal sclerosis (TLE+HS) and nine patients had no signal abnormalities on conventional MRI (TLE-HS). On the ipsilateral seizure side, all three investigated tracts showed significant DTI indices abnormalities in both patient groups when compared with controls, most marked on the inferior cingulum. Contralateral to the seizure side, the three tracts presented significant DTI parameters in only the TLE+HS group when compared with controls., Conclusion: The DTI abnormalities found in the TLE-HS group may suggest that in the inferior cingulum the structural integrity is more affected than in the fornix or superior cingulum white matter bundles. The eigenvalues taken separately add complementary information to the FA and Tr metrics and may be useful indices in better understanding the architectural reorganization of limbic system tracts in TLE patients without HS., (Copyright © 2012 Wiley Periodicals, Inc.)

Surgical outcome in patients with nonlesional refractory partial epilepsies could be improved by a more precise definition of the epileptogenic zone (EZ). The value of interictal FDG-PET hypometabolism, voxel-based-morphometry (VBM) and diffusion tensor imaging (DTI) is still debated. We compared the sensitivity and specificity of these noninvasive techniques in localizing the EZ with stereo-electroencephalography (SEEG) results. Twenty patients with nonlesional partial epilepsy (13 temporal lobe epilepsy (TLE) and 7 extra-temporal (extra-TLE)) underwent structural MRI, DTI and FDG-PET. FDG-PET was analyzed visually (vPET) blinded and unblinded and by statistical parametric mapping (SPM) (sPET). Individual modifications of grey matter volume and mean diffusivity increase were compared to a control group with SPM. The best sensitivity was provided by vPET unblinded (75%) and the best specificity (60%) by DTI. The sensitivity of vPET blinded (55%) was lower and those of sPET (40%) and VBM (35%) were still lower. In TLE, vPET analyzed either blinded or unblinded, performed the best and additional use of the other tools improved slightly the sensitivity. For extra-TLE, combining vPET and DTI results increased the number of pertinent abnormalities detected especially for circumscribed changes in frontal lobe epilepsy (FLE). Combining vPET and DTI was the more efficient strategy for extra-TLE, allowing the detection of pertinent abnormalities in FLE when FDG-PET alone was not contributive. Combining sPET or VBM with vPET was less useful., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model., Materials and Methods: Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl(2) (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning., Results: Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors., Conclusion: Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI., (Copyright © 2011 Wiley-Liss, Inc.)

Unlabelled: Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a recently described epileptic entity whose etiology remains unknown. Brain abnormalities shown by MRI are usually limited to mesial-temporal structures and do not account for the catastrophic neuropsychologic findings., Methods: We conducted FIRES studies in 8 patients, aged 6-13 y, using 18F-FDG PET to disclose eventual neocortical dysfunction. Voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping and an age-matched control group., Results: Group analysis revealed a widespread interictal hypometabolic network including the temporoparietal and orbitofrontal cortices bilaterally. The individual analyses in patients identified hypometabolic areas corresponding to the predominant electroencephalograph foci and neuropsychologic deficits involving language, behavior, and memory., Conclusion: Despite clinical heterogeneity, 18F-FDG PET reveals a common network dysfunction in patients with sequelae due to fever-induced refractory epileptic encephalopathy.

Unlabelled: Traumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial (18)F-FDG PET and 3-dimensional MRI in vivo., Methods: Rats underwent lateral fluid percussion injury (FPI; n = 16) or a sham procedure (n = 11). PET and MR images were acquired at 1 wk and at 1, 3, and 6 mo after injury. Morphologic changes were assessed using MRI-based regions of interest, and hippocampal shape changes were assessed with large-deformation high-dimensional mapping. Metabolic changes were assessed using region-of-interest analysis and statistical parametric mapping with the flexible factorial analysis. Anxiety-like behavior and learning were assessed at 1, 3, and 6 mo after injury., Results: PET analyses showed widespread hypometabolism in injured rats, in particular involving the ipsilateral cortex, hippocampus, and amygdalae, present at 1 wk after FPI, most prominent at 1 mo, and then decreasing. Compared with the sham group, rats in the FPI group had decreased structural volume which progressively increased over 3-6 mo, occurring in the ipsilateral cortex, hippocampus, and ventricles after FPI (P < 0.05). Large-deformation high-dimensional mapping showed evolving hippocampal shape changes across the 6 mo after FPI. Injured rats displayed increased anxiety-like behavior (P < 0.05), but there were no direct correlations between the severity of the behavior abnormalities and functional or structural imaging changes., Conclusion: In selected brain structures, FPI induces early hypometabolism and delayed progressive atrophic changes that are dynamic and continue to evolve for months. These findings have implications for the understanding of the pathophysiology and evolution of long-term neurologic morbidity following TBI, and indicate an extended window for targeted neuroprotective interventions.

Purpose: Diffusion tensor imaging (DTI) can provide quantitative information of brain abnormalities in patients with temporal lobe epilepsy (TLE) that are not detectable with conventional magnetic resonance imaging (MRI)., Methods: Seventeen patients with medically TLE were selected for the study. The patients and ten healthy subjects underwent 25 directions DTI acquisition. The patients were separated into two groups based on the MRI findings: eight TLE MRI-negative patients with no signal abnormalities on conventional MRI and nine TLE patients with hippocampal sclerosis (HS). Fractional anisotropy (FA), mean diffusivity (MD), and the three diffusivities (lambda(1), lambda(2) and lambda(3)) were measured in bilateral hippocampi of controls, MRI-negative, and HS patients. Comparisons between the three groups were performed for hippocampi ipsi- and contralateral to epileptogenic zone., Results: The ipsilateral hippocampus of MRI-negative patients presented statistical increased anisotropy and no significant difference in diffusivities versus controls. Significant differences in anisotropy and diffusivities were detected between the ipsilateral hippocampus of HS when compared with controls., Conclusion: DTI depicted hippocampal abnormalities in TLE patients with a normal conventional MRI different from those found in patients with HS. Diffusivity and anisotropy indices provide significant differences inside hippocampus and should be jointly considered to improve the DTI measurements specificity in TLE patients.

Traumatic brain injury (TBI) has a high incidence of long-term morbidity. Manganese-enhanced MRI (MEMRI) provides high contrast structural and functional detail of the brain in-vivo. The study utilized serial MEMRI scanning in the fluid percussion injury (FPI) rat's model to assess long-term changes in the brain following TBI. Rats underwent a left-sided craniotomy and a 3.5 atmosphere FPI pulse (n = 23) or sham procedure (n = 22). MEMRI acquisition was performed at baseline, 1 day, 1 month, and 6 months after FPI. Volume changes and MnCl(2) enhancement were measured blindly using region-of-interest analysis and the results analyzed with repeated measures MANOVA. Compared to the shams, FPI animals showed a progressive decrease in brain volume from 1 (right, p = 0.02; left, p = 0.008) to 6 months (right, p = 0.04; left, p = 0.006), with progression over time (F = 7.16, p = 0.00018). Similar changes were found in the cortex and the hippocampus. Conversely, the ventricular volume was increased at 1 (p = 0.02) and 6 months (p = 0.003), with progression over time (F = 7.27, p = 0.0001). There were no differences in thalamic or amygdalae volumes. The severity of the early neuromotor deficits and the T2 signal intensity of the subacute focal lesion were highly predictive of the severity of the long-term hippocampal decrease, and the former was also associated with the degree of neuronal sprouting. Differential MnCl(2) enhancement occurred only in the dentate gyrus at 1 month on the side of trauma (p = 0.04). Progressive functional and structural changes occur in specific brain regions post-FPI. The severity of the neuromotor deficit and focal signal changes on MRI subacutely post-injury are predictive of severity of these long-term neurodegenerative changes.

Purpose: To report the detection of structural and functional biological changes in living animals using small animal in vivo MRI that complements traditional ex vivo histological techniques. We report the development and validation of the application of large deformation high dimensional mapping (HDM-LD) segmentation for the hippocampus in the rat., Materials and Methods: High resolution volumetric T2 weighted MRI images were acquired at 4.7 Tesla from six male in-breed nonepileptic Wistar rats. Two HDM-LD segmentations of the hippocampus (automated 1 and automated 2) were compared with the manual segmentations of two investigators who independently segmented the hippocampi (manual 1 and manual 2)., Results: The mean overlap for the hippocampi between automated 1 and automated 2 for the right hippocampi was 94.4% (SD 1.0) and for the left hippocampi was 94.3% (SD 2.5), while the mean overlap between automated 1 and manual 1 for the right hippocampi was 91.4% (SD 1.3) and for the left hippocampi was 91.9% (SD 1.4). Mean values for absolute differences for comparisons of all the segmentations were the following: automated 1 versus automated 2, 3.2% (SD 1.0); manual 1 versus manual 2 6.82% (SD 5.22); automated 1 versus manual 1 13.0% (SD 1.8)., Conclusion: HDM-LD can be applied to obtain accurate and reproducible three-dimensional segmentations of the hippocampus from rat MR images. HDM-LD will be a useful tool for investigations of hippocampal structural changes in vivo in rat models of human disease.

Background: Imaging studies of epilepsy patients with comorbid affective disturbance demonstrate morphometric changes in limbic brain regions implicated in psychiatric disease. Genetic Absence Epilepsy Rats from Strasbourg (GAERS), specifically bred for their epilepsy phenotype, also exhibit elevated anxiety-like behaviors suggesting a common causality. Here we examined whether relevant cerebral morphological alterations exist in this rat strain using volumetric measurements and large deformation high dimensional mapping (HDM-LD), a tool recently validated to produce accurate three-dimensional surface representations of the hippocampus., Methods: Volumetric MRI and the Open Field test of anxiety were performed in adult female GAERS (n=12) and Non-Epileptic Controls (NEC; n=11). The volumes of selected brain regions, including cortex, hippocampus, amygdala, thalamus, hypothalamus and lateral ventricles, were measured using Region-Of-Interest analysis from the MRI data and total volumes compared between the two strains., Results: GAERS had increased amygdala (right: p=0.003; left p<0.001), cortices (right: p=0.006; left p=0.012) and ventricular volumes (p=0.002) when compared with NEC rats. Further, HDM-LD showed GAERS to have hippocampal volume loss in two regions: the medial hippocampal surface immediately caudal to the hippocampal commissure, and the lateral hippocampal surface over the mid-portion of the septotemporal axis. GAERS exhibited increased anxiety in the Open Field compared with NEC rats: reduced distance traveled (p<0.001) and reduced time in the centre area (p=0.042)., Conclusions: Morphometric brain changes in GAERS could be relevant to their hyperanxious and epileptic phenotypes. This model may be useful in illuminating the pathogenesis of affective disorders generally, as well as modeling psychiatric comorbidities of epilepsy.