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Aims Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). Methods and results We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011–17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. Conclusion In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.

Objective To identify functional and structural alterations in language networks of people with temporal lobe epilepsy (TLE), who frequently present with naming and word‐finding difficulties. Methods Fifty‐five patients with unilateral TLE (29 left) and 16 controls were studied with auditory and picture naming functional magnetic resonance imaging (fMRI) tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole‐brain functional connectivity analyses (psychophysiological interaction). White matter language pathways were investigated using diffusion tensor imaging and neurite orientation dispersion and density imaging metrics extracted along fiber bundles starting from fMRI‐guided seeds. Regression analyses were performed to investigate the correlation of functional connectivity with diffusion MRI metrics. Results In the whole group of patients and controls, weaker functional connectivity from the left posterobasal temporal lobe (1) to the bilateral anterior temporal lobe, precentral gyrus, and lingual gyrus during auditory naming and (2) to the bilateral occipital cortex and right fusiform gyrus during picture naming was associated with decreased neurite orientation dispersion and higher free water fraction of white matter tracts. Compared to controls, TLE patients exhibited fewer structural connections and an impaired coupling of functional and structural metrics. Significance TLE is associated with an impairment and decoupling of functional and structural language networks. White matter damage, as evidenced by diffusion abnormalities, may contribute to impaired functional connectivity and language dysfunction in TLE.

The piriform cortex, at the confluence of the temporal and frontal lobes, generates seizures in response to chemical convulsants and electrical stimulation. Resection of more than 50% of the piriform cortex in anterior temporal lobe resection for refractory temporal lobe epilepsy (TLE) was associated with a 16-fold higher chance of seizure freedom. The objectives of the current study were to implement a robust protocol to measure piriform cortex volumes and to quantify the correlation of these volumes with clinical characteristics of TLE. Sixty individuals with unilateral TLE (33 left) and 20 healthy controls had volumetric analysis of left and right piriform cortex and hippocampi. A protocol for segmenting and measuring the volumes of the piriform cortices was implemented, with good inter-rater and test-retest reliability. The right piriform cortex volume was consistently larger than the left piriform cortex in both healthy controls and patients with TLE. In controls, the mean volume of the right piriform cortex was 17.7% larger than the left, and the right piriform cortex extended a mean of 6 mm (Range: -4 to 12) more anteriorly than the left. This asymmetry was also seen in left and right TLE. In TLE patients overall, the piriform cortices were not significantly smaller than in controls. Hippocampal sclerosis was associated with decreased ipsilateral and contralateral piriform cortex volumes. The piriform cortex volumes, both ipsilateral and contralateral to the epileptic temporal lobe, were smaller with a longer duration of epilepsy. There was no significant association between piriform cortex volumes and the frequency of focal seizures with impaired awareness or the number of anti-seizure medications taken. Implementation of robust segmentation will enable consistent neurosurgical resection in anterior temporal lobe surgery for refractory TLE..

Objective To investigate alterations of language networks and their relation to impaired naming performance in temporal lobe epilepsy (TLE) using functional MRI. Methods Seventy-two adult TLE patients (41 left) and 36 controls were studied with overt auditory and picture naming fMRI tasks to assess temporal lobe language areas, and a covert verbal fluency task to probe frontal lobe language regions. Correlation of fMRI activation with clinical naming scores, and alteration of language network patterns in relation to epilepsy duration, age at onset and seizure frequency, were investigated with whole-brain multiple regression analyses. Results Auditory and picture naming fMRI activated the left posterior temporal lobe, and stronger activation correlated with better clinical naming scores. Verbal fluency MRI mainly activated frontal lobe regions. In left and right TLE, a later age of epilepsy onset related to stronger temporal lobe activations, while earlier age of onset was associated with impaired deactivation of extratemporal regions. In left TLE patients, longer disease duration and higher seizure frequency were associated with reduced deactivation. Frontal lobe language networks were unaffected by disease characteristics. Conclusions While frontal lobe language regions appear spared, temporal lobe language areas are susceptible to dysfunction and reorganisation, particularly in left TLE. Early onset and long duration of epilepsy, and high seizure frequency, were associated with compromised activation and deactivation patterns of task-associated regions, which might account for impaired naming performance in individuals with TLE.

Funder: Helmholts International BigBrain Analytics & Learning Laboratory, Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization., For the Cambridge authors (Coles, Fryer & Aigbirhio): This work was funded by an MRC PET Neuroscience programme grant (Training and Novel Probes Programme in PET Neurochemistry - MR/K02308X/1) and by an MRC Developmental Pathway Funding Scheme grant (MR/L013215/1). This research in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JPC was supported by a British Journal of Anaesthesia/Royal College of Anaesthetists grant from the National Institute of Academic Anaesthesia.

Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing [18F]GE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p

Highlights • We found a high asymptomatic rate in vulnerable people with epilepsy. • Enhanced surveillance allows to quickly contain outbreaks. • We report a low rate of COVID-19 morbidity and mortality in a long-term care facility. • Preventative measures allow reducing resident-to-resident and -to-caregiver transmission. • Children and young adults appear to have lower infection rates., In this cohort study, we aim to compare outcomes from coronavirus disease 2019 (COVID-19) in people with severe epilepsy and other co-morbidities living in long-term care facilities which all implemented early preventative measures, but different levels of surveillance. During 25-week observation period (16 March–6 September 2020), we included 404 residents (118 children), and 1643 caregivers. We compare strategies for infection prevention, control, and containment, and related outcomes, across four UK long-term care facilities. Strategies included early on-site enhancement of preventative and infection control measures, early identification and isolation of symptomatic cases, contact tracing, mass surveillance of asymptomatic cases and contacts. We measured infection rate among vulnerable people living in the facilities and their caregivers, with asymptomatic and symptomatic cases, including fatality rate. We report 38 individuals (17 residents) who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive, with outbreaks amongst residents in two facilities. At Chalfont Centre for Epilepsy (CCE), 10/98 residents tested positive: two symptomatic (one died), eight asymptomatic on weekly enhanced surveillance; 2/275 caregivers tested positive: one symptomatic, one asymptomatic. At St Elizabeth’s (STE), 7/146 residents tested positive: four symptomatic (one died), one positive during hospital admission for symptoms unrelated to COVID-19, two asymptomatic on one-off testing of all 146 residents; 106/601 symptomatic caregivers were tested, 13 positive. In addition, during two cycles of systematically testing all asymptomatic carers, four tested positive. At The Meath (TM), 8/80 residents were symptomatic but none tested; 26/250 caregivers were tested, two positive. At Young Epilepsy (YE), 8/80 children were tested, all negative; 22/517 caregivers were tested, one positive. Infection outbreaks in long-term care facilities for vulnerable people with epilepsy can be quickly contained, but only if asymptomatic individuals are identified through enhanced surveillance at resident and caregiver level. We observed a low rate of morbidity and mortality, which confirmed that preventative measures with isolation of suspected and confirmed COVID-19 residents can reduce resident-to-resident and resident-to-caregiver transmission. Children and young adults appear to have lower infection rates. Even in people with epilepsy and multiple co-morbidities, we observed a high percentage of asymptomatic people suggesting that epilepsy-related factors (anti-seizure medications and seizures) do not necessarily lead to poor outcomes.

International audience; OBJECTIVES:Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE) but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface-shape patterns to verbal and visual learning.METHODS:We analysed hippocampal surface shapes on high-resolution MRI images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients and 39 age- and sex-matched healthy volunteers.RESULTS:Both left (LTLE) and right (RTLE) TLE patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8; RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8; visual 39 ± 6; p

OBJECTIVE Hippocampal sclerosis (HS) is the most common cause of drug-resistant temporal lobe epilepsy, and its accurate detection is important to guide epilepsy surgery. Radiological features of HS include hippocampal volume loss and increased T2 signal, which can both be quantified to help improve detection. In this work, we extend these quantitative methods to generate cross-sectional area and T2 profiles along the hippocampal long axis to improve the localization of hippocampal abnormalities. METHODS T1-weighted and T2 relaxometry data from 69 HS patients (32 left, 32 right, 5 bilateral) and 111 healthy controls were acquired on a 3-T magnetic resonance imaging (MRI) scanner. Automated hippocampal segmentation and T2 relaxometry were performed and used to calculate whole-hippocampal volumes and to estimate quantitative T2 (qT2) values. By generating a group template from the controls, and aligning this so that the hippocampal long axes were along the anterior-posterior axis, we were able to calculate hippocampal cross-sectional area and qT2 by a slicewise method to localize any volume loss or T2 hyperintensity. Individual patient profiles were compared with normative data generated from the healthy controls. RESULTS Profiling of hippocampal volumetric and qT2 data could be performed automatically and reproducibly. HS patients commonly showed widespread decreases in volume and increases in T2 along the length of the affected hippocampus, and focal changes may also be identified. Patterns of atrophy and T2 increase in the left hippocampus were similar between left, right, and bilateral HS. These profiles have potential to distinguish between sclerosis affecting volume and qT2 in the whole or parts of the hippocampus, and may aid the radiological diagnosis in uncertain cases or cases with subtle or focal abnormalities where standard whole-hippocampal measurements yield normal values. SIGNIFICANCE Hippocampal profiling of volumetry and qT2 values can help spatially localize hippocampal MRI abnormalities and work toward improved sensitivity of subtle focal lesions.

β-Lactam antibiotics are proconvulsive. In laboratory animals, this effect seems to be predominantly mediated through inhibition of GABA-A receptors, but it has not been demonstrated in humans in vivo. We report images of a [C]Ro15-4513 PET from a 40-year-old man who had completed a 1-week course of flucloxacillin before it. Relative to healthy controls, the participant had significantly lower mean gray matter binding. These novel data suggest that, in humans, the proconvulsive effect of β-lactam antibiotics is mediated via either competition for the same benzodiazepine-binding site as [C]Ro15-4513 or downregulation of GABA-A receptor expression.

Background Thirty-percent of patients with epilepsy are drug-resistant, and might benefit from effective noninvasive therapeutic interventions. Evidence is accumulating on the efficacy of autonomic biofeedback therapy using galvanic skin response (GSR; an index of sympathetic arousal) in treating epileptic seizures. This study aimed to extend previous controlled clinical trials of autonomic biofeedback therapy with a larger homogeneous sample of patients with temporal lobe epilepsy. In addition, we used neuroimaging to characterize neural mechanisms of change in seizure frequency following the therapy. Methods Forty patients with drug-resistant temporal lobe epilepsy (TLE) (age: 18 to 70 years old), on stable doses of anti-epileptic medication, were recruited into a controlled and parallel-group trial from three screening centers in the UK. Patients were allocated to either an active intervention group, who received therapy with GSR biofeedback, or a control group, who received treatment as usual. Allocation to the group was informed, in part, by whether patients could travel to attend repeated therapy sessions (non-randomized). Measurement of outcomes was undertaken by an assessor blinded to the patients' group membership. Resting-state functional and structural MRI data were acquired before and after one month of therapy in the therapy group, and before and after a one-month interval in the control group. The percentage change of seizure frequency was the primary outcome measure. The analysis employed an intention–to–treat principle. The secondary outcome was the change in default mode network (DMN) and limbic network functional connectivity tested for effects of therapy. The trial was registered with the National Institute for Health Research (NIHR) portfolio (ID 15967). Findings Data were acquired between May 2014 and October 2016. Twenty participants were assigned to each group. Two patients in the control group dropped out before the second scan, leaving 18 control participants. There was a significant difference in reduction of seizure frequency between the therapy and control groups (p 50%. Neuroimaging analysis revealed that post-therapy seizure reduction was linearly correlated with enhanced functional connectivity between right amygdala and both the orbitofrontal cortex (OFC) and frontal pole (FP). Interpretation Our clinical study provides evidence for autonomic biofeedback therapy as an effective and potent behavioral intervention for patients with drug-resistant epilepsy. This approach is non-pharmacological, non-invasive and seemingly side-effect free., Highlights • Autonomic biofeedback using GSR significantly reduced seizure frequencies in patients with drug resistant TLE. • The effect of GSR biofeedback in reducing seizures was mediated by increased fronto-limbic functional connectivity. • Autonomic biofeedback is a potent bio-behavioral therapy for patients with drug resistant epilepsy. Biofeedback training therapy is non-invasive and apparently side-effect free. The positive clinical findings of the current study carry significant translational implications for patients with epilepsy and for medical professionals. Beyond demonstrating the efficacy of autonomic biofeedback, our study provides fresh insight into neural mechanisms mediating the expression of seizures. We identified a key relationship wherein the strength of neural coupling between frontal cortex and right amygdala enhances the capacity to suppress seizures. The finding also implies that abnormal function of this network may promote the spread of seizures across the brain in a manner that is influenced by autonomic, and probably, emotional state.

Pharmacological treatment with antiepileptic medications (AEDs) in epilepsy is associated with a variety of neurocognitive side effects. However, the mechanisms underlying these side effects, and why certain brain anatomies are more affected still remain poorly understood. Advanced functional magnetic resonance imaging (fMRI) methods, such as pharmaco-fMRI, can investigate medication-related effects on brain activities using task and resting state fMRI and showing reproducible activation and deactivation patterns. This methodological approach has been used successfully to complement neuropsychological studies of AEDs. Here we review pharmaco-fMRI studies in people with epilepsy targeting the most-widely prescribed AEDs. Pharmco-fMRI has advanced our understanding of the impact of AEDs on specific brain networks and thus may provide potential biomarkers to move beyond the current "trial and error" approach when commencing anti-epileptic medication.

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013-2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three-dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences-HARNESS-MRI protocol. As these sequences are available on most MR scanners, the HARNESS-MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer-aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy.

Schoenberger and colleagues ( Schoenberger et al. ( 2018 ) ACS Chem. Neurosci. 9 , 298 - 305 ) recently reported attempts to demonstrate specific binding of the positron emission tomography (PET) radiotracer, [18F]GE-179, to NMDA receptors in both rats and Rhesus macaques. GE-179 did not work as expected in animal models; however, we disagree with the authors' conclusion that "the [18F]GE-179 signal seems to be largely nonspecific". It is extremely challenging to demonstrate specific binding for the use-dependent NMDA receptor intrachannel ligands such as [18F]GE-179 in animals via traditional blocking, due to its low availability of target sites ( Bmax'). Schoenberger and colleagues anesthetized rats and Rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the Bmax'. The extent of glutamate release achieved in the provocation experiments is uncertain, as is whether a significant increase in NMDA receptor channel opening can be expected under anesthesia. Prior data suggest that the uptake of disubstituted arylguanidine-based ligands such as GE-179 can be reduced by phencyclidine binding site antagonists, if injection is performed in the absence of ketamine and isoflurane anesthesia, e.g., with GE-179's antecedent, CNS 5161 ( Biegon et al. ( 2007 ) Synapse 61 , 577 - 586 ), and with GMOM ( van der Doef et al. ( 2016 ) J. Cereb. Blood Flow Metab. 36 , 1111 - 1121 ). However, the extent of nonspecific uptake remains uncertain.

Aims Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP. Methods We reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings. Results Macroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P

Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development.

Functional magnetic resonance imaging has demonstrated reorganization of memory encoding networks within the temporal lobe in temporal lobe epilepsy, but little is known of the extra-temporal networks in these patients. We investigated the temporal and extra-temporal reorganization of memory encoding networks in refractory temporal lobe epilepsy and the neural correlates of successful subsequent memory formation. We studied 44 patients with unilateral temporal lobe epilepsy and hippocampal sclerosis (24 left) and 26 healthy control subjects. All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words with subsequent out-of-scanner recognition assessments. A blocked analysis was used to investigate activations during encoding and neural correlates of subsequent memory were investigated using an event-related analysis. Event-related activations were then correlated with out-of-scanner verbal and visual memory scores. During word encoding, control subjects activated the left prefrontal cortex and left hippocampus whereas patients with left hippocampal sclerosis showed significant additional right temporal and extra-temporal activations. Control subjects displayed subsequent verbal memory effects within left parahippocampal gyrus, left orbitofrontal cortex and fusiform gyrus whereas patients with left hippocampal sclerosis activated only right posterior hippocampus, parahippocampus and fusiform gyrus. Correlational analysis showed that patients with left hippocampal sclerosis with better verbal memory additionally activated left orbitofrontal cortex, anterior cingulate cortex and left posterior hippocampus. During face encoding, control subjects showed right lateralized prefrontal cortex and bilateral hippocampal activations. Patients with right hippocampal sclerosis showed increased temporal activations within the superior temporal gyri bilaterally and no increased extra-temporal areas of activation compared with control subjects. Control subjects showed subsequent visual memory effects within right amygdala, hippocampus, fusiform gyrus and orbitofrontal cortex. Patients with right hippocampal sclerosis showed subsequent visual memory effects within right posterior hippocampus, parahippocampal and fusiform gyri, and predominantly left hemisphere extra-temporal activations within the insula and orbitofrontal cortex. Correlational analysis showed that patients with right hippocampal sclerosis with better visual memory activated the amygdala bilaterally, right anterior parahippocampal gyrus and left insula. Right sided extra-temporal areas of reorganization observed in patients with left hippocampal sclerosis during word encoding and bilateral lateral temporal reorganization in patients with right hippocampal sclerosis during face encoding were not associated with subsequent memory formation. Reorganization within the medial temporal lobe, however, is an efficient process. The orbitofrontal cortex is critical to subsequent memory formation in control subjects and patients. Activations within anterior cingulum and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment.

Anterior temporal lobe resection controls seizures in 50-60% of patients with intractable temporal lobe epilepsy but may impair memory function, typically verbal memory following left, and visual memory following right anterior temporal lobe resection. Functional reorganization can occur within the ipsilateral and contralateral hemispheres. We investigated the reorganization of memory function in patients with temporal lobe epilepsy before and after left or right anterior temporal lobe resection and the efficiency of postoperative memory networks. We studied 46 patients with unilateral medial temporal lobe epilepsy (25/26 left hippocampal sclerosis, 16/20 right hippocampal sclerosis) before and after anterior temporal lobe resection on a 3 T General Electric magnetic resonance imaging scanner. All subjects had neuropsychological testing and performed a functional magnetic resonance imaging memory encoding paradigm for words, pictures and faces, testing verbal and visual memory in a single scanning session, preoperatively and again 4 months after surgery. Event-related analysis revealed that patients with left temporal lobe epilepsy had greater activation in the left posterior medial temporal lobe when successfully encoding words postoperatively than preoperatively. Greater pre- than postoperative activation in the ipsilateral posterior medial temporal lobe for encoding words correlated with better verbal memory outcome after left anterior temporal lobe resection. In contrast, greater postoperative than preoperative activation in the ipsilateral posterior medial temporal lobe correlated with worse postoperative verbal memory performance. These postoperative effects were not observed for visual memory function after right anterior temporal lobe resection. Our findings provide evidence for effective preoperative reorganization of verbal memory function to the ipsilateral posterior medial temporal lobe due to the underlying disease, suggesting that it is the capacity of the posterior remnant of the ipsilateral hippocampus rather than the functional reserve of the contralateral hippocampus that is important for maintaining verbal memory function after anterior temporal lobe resection. Early postoperative reorganization to ipsilateral posterior or contralateral medial temporal lobe structures does not underpin better performance. Additionally our results suggest that visual memory function in right temporal lobe epilepsy is affected differently by right anterior temporal lobe resection than verbal memory in left temporal lobe epilepsy.

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

Functional magnetic resonance imaging can demonstrate the functional anatomy of cognitive processes. In patients with refractory temporal lobe epilepsy, evaluation of preoperative verbal and visual memory function is important as anterior temporal lobe resections may result in material specific memory impairment, typically verbal memory decline following left and visual memory decline after right anterior temporal lobe resection. This study aimed to investigate reorganization of memory functions in temporal lobe epilepsy and to determine whether preoperative memory functional magnetic resonance imaging may predict memory changes following anterior temporal lobe resection. We studied 72 patients with unilateral medial temporal lobe epilepsy (41 left) and 20 healthy controls. A functional magnetic resonance imaging memory encoding paradigm for pictures, words and faces was used testing verbal and visual memory in a single scanning session on a 3T magnetic resonance imaging scanner. Fifty-four patients subsequently underwent left (29) or right (25) anterior temporal lobe resection. Verbal and design learning were assessed before and 4 months after surgery. Event-related functional magnetic resonance imaging analysis revealed that in left temporal lobe epilepsy, greater left hippocampal activation for word encoding correlated with better verbal memory. In right temporal lobe epilepsy, greater right hippocampal activation for face encoding correlated with better visual memory. In left temporal lobe epilepsy, greater left than right anterior hippocampal activation on word encoding correlated with greater verbal memory decline after left anterior temporal lobe resection, while greater left than right posterior hippocampal activation correlated with better postoperative verbal memory outcome. In right temporal lobe epilepsy, greater right than left anterior hippocampal functional magnetic resonance imaging activation on face encoding predicted greater visual memory decline after right anterior temporal lobe resection, while greater right than left posterior hippocampal activation correlated with better visual memory outcome. Stepwise linear regression identified asymmetry of activation for encoding words and faces in the ipsilateral anterior medial temporal lobe as strongest predictors for postoperative verbal and visual memory decline. Activation asymmetry, language lateralization and performance on preoperative neuropsychological tests predicted clinically significant verbal memory decline in all patients who underwent left anterior temporal lobe resection, but were less able to predict visual memory decline after right anterior temporal lobe resection. Preoperative memory functional magnetic resonance imaging was the strongest predictor of verbal and visual memory decline following anterior temporal lobe resection. Preoperatively, verbal and visual memory function utilized the damaged, ipsilateral hippocampus and also the contralateral hippocampus. Memory function in the ipsilateral posterior hippocampus may contribute to better preservation of memory after surgery.

Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist [11C]diprenorphine (DPN) did not detect any changes in mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE. Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures ( Hammers et al., 2007a ). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); ( Shidahara et al., 2012 )). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; ( Heckemann et al., 2010 )). [11C]diprenorphine volume-of-distribution (VT) was quantified in six regions of interest. Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in [11C]DPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in [11C]DPN VT. This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures.

2-[18F]Fluoroethyl azide ([18F]FEA) can readily be obtained by nucleophilic substitution of 2-azidoethyl-4-toluenesulfonate with [18F]fluoride (half-life 110 min), and has become widely used as a reagent for ‘click’ labeling of PET tracers. However, distillation of [18F]FEA is typically required, which is time-consuming and unpractical for routine applications. In addition, copper(I)-catalyzed cycloaddition of [18F]FEA with non-activated alkynes, and with substrates containing labile functional groups, can be challenging. Herein, we report a highly efficient and practical ligand-accelerated one-pot/two-step method for ‘click’ labeling of small molecule tracers with [18F]FEA. The method exploits the ability of the copper(I) ligand bathophenanthrolinedisulfonate to accelerate the rate of the cycloaddition reaction. As a result, alkynes can be added directly to the crude reaction mixture containing [18F]FEA, and as cyclisation occurs almost immediately at room temperature, the reaction is tolerant to labile functional groups. The method was demonstrated by reacting [18F]FEA with a series of alkyne-functionalized 6-halopurines to give the corresponding triazoles in 55–76% analytical radiochemical yield.

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Objective: To define the ictal cortical/subcortical network of reading-induced seizures. Methods: We analyzed ictal magnetoencephalography (MEG) and EEG-correlated fMRI (EEG-fMRI) data in a unique patient with reading epilepsy (RE) affected by frequent perioral reflex myocloni triggered by reading silently. Results: Ictal MEG corroborated EEG localization and revealed activity extending precentrally into Brodmann area (BA) 6. fMRI blood oxygen level−dependent (BOLD) signal changes in the left deep piriform cortex (PFC) and left BA6 preceded seizures and occurred before BOLD changes were observed in thalamus and right inferior frontal gyrus (BA44). Dynamic causal modeling provided evidence of a causal link between hemodynamic changes in the left PFC and reading-evoked seizures. Conclusion: Our findings support the important role of deep cortical and subcortical structures, in particular the frontal PFC, as key regions in initiating and modulating seizure activity. In our patient with RE, BA6 appeared to be the area linking cognitive activation and seizure activity.

Summary Purpose In patients with left temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) decreased naming ability is common, suggesting a critical role for the medial left temporal lobe in this task. We investigated the integrity of language networks with functional MRI (fMRI) in controls and TLE patients. Experimental design We performed an fMRI verbal fluency paradigm in 22 controls and 66 patients with unilateral mesial TLE (37 left HS, 29 right HS). Verbal fluency and naming ability were investigated as part of the standard presurgical neuropsychological assessment. Naming ability was assessed using a visual confrontation naming test. Results Left TLE patients had significantly lower naming scores than controls and those with right TLE. Right TLE patients performed less well than controls, but better than those with left TLE. Left TLE had significantly lower scores for verbal fluency than controls. In controls and right TLE, left hippocampal activation during the verbal fluency task was significantly correlated with naming, characterised by higher scores in subjects with greater hippocampal fMRI activation. In left TLE no correlation with naming scores was seen in the left hippocampus, but there was a significant correlation in the left middle and inferior frontal gyri, not observed in controls and right TLE. In left and right TLE, out of scanner verbal fluency scores significantly correlated with fMRI activation for verbal fluency in the left middle and inferior frontal gyri. Conclusion Good confrontation naming ability depends on the integrity of the hippocampus and the connecting fronto-temporal networks. Functional MRI activation in the left hippocampus during verbal fluency is associated with naming function in healthy controls and patients with right TLE. In left TLE, there was evidence of involvement of the left frontal lobe when naming was more proficient, most likely reflecting a compensatory response due to the ongoing epileptic activity and/or underlying pathology.

Juvenile myoclonic epilepsy is the most frequent idiopathic generalized epilepsy syndrome. It is characterized by predominant myoclonic jerks of upper limbs, often provoked by cognitive activities, and typically responsive to treatment with sodium valproate. Neurophysiological, neuropsychological and imaging studies in juvenile myoclonic epilepsy have consistently pointed towards subtle abnormalities in the medial frontal lobes. Using functional magnetic resonance imaging with an executive frontal lobe paradigm, we investigated cortical activation patterns and interaction between cortical regions in 30 patients with juvenile myoclonic epilepsy and 26 healthy controls. With increasing cognitive demand, patients showed increasing coactivation of the primary motor cortex and supplementary motor area. This effect was stronger in patients still suffering from seizures, and was not seen in healthy controls. Patients with juvenile myoclonic epilepsy showed increased functional connectivity between the motor system and frontoparietal cognitive networks. Furthermore, we found impaired deactivation of the default mode network during cognitive tasks with persistent activation in medial frontal and central regions in patients. Coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks provide an explanation how cognitive effort can cause myoclonic jerks in juvenile myoclonic epilepsy. The supplementary motor area represents the anatomical link between these two functional systems, and our findings may be the functional correlate of previously described structural abnormalities in the medial frontal lobe in juvenile myoclonic epilepsy. © 2011 The Author. Wellcome Trust (Project Grant No 079474); The Big Lottery Fund, Wolfson Trust and the Epilepsy Society (ES MRI scanner). Part of this work was undertaken at University College London Hospitals who received a proportion of funding from the NIHR, Biomedical Research Centres funding scheme.

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T(1)-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24-43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24-47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection. peerReviewed

Probabilistic atlases of neuroanatomy are more representative of population anatomy than single brain atlases. They allow anatomical labeling of the results of group studies in stereotaxic space, automated anatomical labeling of individual brain imaging datasets, and the statistical assessment of normal ranges for structure volumes and extents. No such manually constructed atlas is currently available for the frequently studied group of young adults. We studied 20 normal subjects (10 women, median age 31 years) with high‐resolution magnetic resonance imaging (MRI) scanning. Images were nonuniformity corrected and reoriented along both the anterior‐posterior commissure (AC–PC) line horizontally and the midsagittal plane sagittally. Building on our previous work, we have expanded and refined existing algorithms for the subdivision of MRI datasets into anatomical structures. The resulting algorithm is presented in the Appendix. Forty‐nine structures were interactively defined as three‐dimensional volumes‐of‐interest (VOIs). The resulting 20 individual atlases were spatially transformed (normalized) into standard stereotaxic space, using SPM99 software and the MNI/ICBM 152 template. We evaluated volume data for all structures both in native space and after spatial normalization, and used the normalized superimposed atlases to create a maximum probability map in stereotaxic space, which retains quantitative information regarding inter‐subject variability. Its potential applications range from the automatic labeling of new scans to the detection of anatomical abnormalities in patients. Further data can be extracted from the atlas for the detailed analysis of individual structures. Hum. Brain Mapping 19:224–247,2003. ©2003 Wiley‐Liss,Inc.

The connectivity information contained in diffusion tensor imaging (DTI) has previously been used to parcellate cortical and subcortical regions based on their connectivity profiles. The aim of the current study is to investigate the utility of a novel approach to connectivity based parcellation of the thalamus using probabilistic tractography and independent component analysis (ICA). We use ICA to identify spatially coherent tractograms as well as their underlying seed regions, in a single step. We compare this to seed-based tractography results and to an established and reliable approach to parcellating the thalamus based on the dominant cortical connection from each thalamic voxel (Behrens et al., 2003a,b). The ICA approach identifies thalamo-cortical pathways that correspond to known anatomical connections, as well as parcellating the underlying thalamus in a spatially similar way to the connectivity based parcellation. We believe that the use of such a multivariate method to interpret the complex datasets created by probabilistic tractography may be better suited than other approaches to parcellating brain regions., Research Highlights ► Independent component analysis used to segment the thalamus ► Promising technique to parcel out consistent fibre tracts ► Independent components consistent with tractography from the same region ► Independent components consistent with other clustering methods ► Multivariate method applied to segment probabilistic tractography

Summary Purpose Topiramate (TPM) is known to cause language impairment in healthy volunteers and patients with epilepsy. We assessed the effects of TPM on functional language networks in both patients with focal epilepsies and healthy controls using functional magnetic resonance imaging (fMRI). Methods We obtained fMRI data in 24 controls and 35 patients with frontal lobe epilepsy using a simple verbal fluency (VF) paradigm. Eight of the 35 patients were treated with TPM in polytherapy. We compared cognitive task related activations and de-activations in patients taking TPM with patients taking other AEDs and healthy controls. In a longitudinal pilot study with VF-fMRI paradigm, we studied two patients with focal epilepsies twice, prior to starting and on stable doses of TPM, two patients twice, before and after tapering TPM completely and two healthy controls twice, before and after single doses of 200 mg TPM. Key findings Cross sectional analyses of VF-fMRI showed a reduction in the task-related deactivation of the default mode network (DMN) in patients taking TPM. The longitudinal study corroborated these findings as both chronic administration and a single dose of TPM were associated with impaired categorical verbal fluency and disruption of task-related deactivations. Significance Similar neuropsychological and fMRI findings in patients and healthy controls indicate a specific effect of TPM in default mode network areas that may be essential components of the language network. Our preliminary data suggest a mechanism by which TPM impairs cognitive processing during language function and highlights the sensitivity of fMRI to detect the effects of AEDs on cognitive brain networks.

IntroductionTemporal lobe epilepsy (TLE) is associated with disrupted memory function. The structural changes underlying this memory impairment have not been demonstrated previously with tractography.MethodsWe performed a tractography analysis of diffusion magnetic resonance imaging scans in 18 patients with unilateral TLE undergoing presurgical evaluation, and in 10 healthy controls. A seed region in the anterior parahippocampal gyrus was selected from which to trace the white matter connections of the medial temporal lobe. A correlation analysis was carried out between volume and mean fractional anisotropy (FA) of the connections, and pre-operative material specific memory performance.ResultsThere was no significant difference between the left and right sided connections in controls. In the left TLE patients, the connected regions ipsilateral to the epileptogenic region were found to be significantly reduced in volume and mean FA compared with the contralateral region, and left-sided connections in control subjects. Significant correlations were found in left TLE patients between left and right FA, and verbal and non-verbal memory respectively.ConclusionTractography demonstrated the alteration of white matter pathways that may underlie impaired memory function in TLE. A detailed knowledge of the integrity of these connections may be useful in predicting memory decline in chronic temporal lobe epilepsy.

Background Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand [11C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo. Methods Fifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [11C]MePPEP of 364 MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~ 30–60 min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity. Results Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (> 0.75) or excellent (> 0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions ± standard deviation 0.83 ± 0.03), rank shaping regularised spectral analysis (0.82 ± 0.05), and the 2kbv model (0.82 ± 0.09), but mSUVs were also reliable for most regions (0.79 ± 0.13). Mean test–retest changes among the five well-performing methods ranged from 12 ± 10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32 ± 13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6). Conclusion Quantification of CB1 receptor availability using [11C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [11C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease., Graphical abstract Cannabinoid receptor concentrations assessed with [11C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric VT map., Highlights • [11C]MePPEP is a PET tracer for cannabinoid receptors (CB1R). • Extensive evaluation of [11C]MePPEP data quantification strategies in large sample • We highlight successful methods to quantify CB1R in regions of interest. • Highly reliable parametric maps (ICC 0.83 ± 0.03) allow whole-brain surveys. • Modified standard uptake values also reliable, without arterial input functions

SummaryBone mineral density (BMD) and content (BMC) were measured in 208 institutionalised patients with refractory epilepsy. BMD was in the osteoporotic range in 43% of males and 21% of females. BMC was reduced only in male patients. Apart from age and gender, no other factor or specific AED was particularly associated with reduced BMD or BMC. This study indicates the magnitude of the problem of bone disease in refractory epilepsy, in particular affecting young and male patients with chronic epilepsy.

Positron emission tomography (PET) is a neuroimaging method that offers insights into the molecular functioning of a human brain. It has been widely used to study metabolic and neurotransmitter abnormalities in people with epilepsy. This article reviews the development of several PET radioligands and their application in studying the molecular mechanisms of epilepsy. Over the last decade, tracers binding to serotonin and γ-aminobutyric acid (GABA) receptors have been used to delineate the location of the epileptic focus. PET studies have examined the role of opioids, cannabinoids, acetylcholine, and dopamine in modulating neuronal hyperexcitability and seizure termination. In vivo analyses of drug transporters, e.g., P-glycoprotein, have increased our understanding of pharmacoresistance that could inform new therapeutic strategies. Finally, PET experiments targeting neuroinflammation and glutamate receptors might guide the development of novel biomarkers of epileptogenesis.