Prognostic value of early EEG abnormalities in severe stroke patients requiring mechanical ventilation: a pre-planned analysis of the SPICE prospective multicenter study.

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.

Deep retroinsular and parieto-opercular origin of vestibular symptoms: A stereoelectrocenphalography (SEEG) study.

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.

What value can TSPO PET bring for epilepsy treatment?

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.

Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene.

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.

Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling.

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 18F-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 (VT) 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 VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT 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 VT 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.

Longitudinal positron emission tomography imaging of glial cell activation in a mouse model of mesial temporal lobe epilepsy: Toward identification of optimal treatment windows.

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.

Prevalence, demographic and spatial distribution of treated epilepsy in France in 2020: a study based on the French national health data system.

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.

[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients.

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 [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]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 [11C]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 (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2). RESULTS: DRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%). CONCLUSIONS: [11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]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. [11C]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.

Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?

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.

[18F]DPA-714 PET Imaging in the Presurgical Evaluation of Patients With Drug-Resistant Focal Epilepsy.

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 [18F]DPA-714 PET and [18F]FDG PET for localizing the EZ during presurgical assessment of DRFE, when phase 1 presurgical assessment does not provide enough information. METHODS: We compared [18F]FDG and [18F]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 [18F]DPA-714 vs decrease in binding for [18F]FDG) were compared with clinical hypotheses concerning the localization of the EZ based on phase 1 presurgical assessment. The additional value of [18F]DPA-714 PET imaging to [18F]FDG for refining the localization of the EZ was assessed. To strengthen the visual analysis, [18F]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 [18F]DPA-714 PET was significantly more accurate than [18F]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 [18F]FDG PET had anomalies when using [18F]DPA-714 PET. The additional value of [18F]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 [18F]DPA-714 and [18F]FDG PET provided similar results. However, using voxel-wise analysis, [18F]DPA-714 was more effective than [18F]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: [18F]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 [18F]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 [18F]DPA-714 PET compared with [18F]FDG PET in identifying the epileptic zone in patients undergoing phase 1 presurgical evaluation for intractable epilepsy.

Predictors of outcomes after surgery for medically intractable insular epilepsy: A systematic review and individual participant data meta-analysis.

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.

Diffusion tensor imaging tractography parameters of limbic system bundles in temporal lobe epilepsy patients.

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.

Somatomotor or somatosensory facial manifestations in patients with temporobasal epilepsies.

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.

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier.

[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.

Confounding neurodegenerative effects of manganese for in vivo MR imaging in rat models of brain insults.

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.

18 F-FDG-PET hypometabolic pattern reveals multifocal epileptic foci despite limited unique stereotyped seizures.

PURPOSE: Interictal positron emission tomography (PET) with 18F-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. 18F-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 18F-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 18F-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.

Electroencephalogram (EEG) in COVID-19: A systematic retrospective study.

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.

Post-traumatic Stress Disorder With Flashbacks of an Old Childhood Memory Triggered by Right Temporal Lobe Epilepsy Surgery in Adulthood.

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.

Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.

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.

Morphometric abnormalities and hyperanxiety in genetically epileptic rats: a model of psychiatric comorbidity?

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.