Publications by authors named "Matthias J Koepp"

109 Publications

Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management.

Drugs Aging 2021 Apr 23;38(4):285-299. Epub 2021 Feb 23.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Stroke is the leading cause of seizures and epilepsy in older adults. Patients who have larger and more severe strokes involving the cortex, are younger, and have acute symptomatic seizures and intracerebral haemorrhage are at highest risk of developing post-stroke epilepsy. Prognostic models, including the SeLECT and CAVE scores, help gauge the risk of epileptogenesis. Early electroencephalogram and blood-based biomarkers can provide information additional to the clinical risk factors of post-stroke epilepsy. The management of acute versus remote symptomatic seizures after stroke is markedly different. The choice of an ideal antiseizure medication should not only rely on efficacy but also consider adverse effects, altered pharmacodynamics in older adults, and the influence on the underlying vascular co-morbidity. Drug-drug interactions, particularly those between antiseizure medications and anticoagulants or antiplatelets, also influence treatment decisions. In this review, we describe the epidemiology, risk factors, biomarkers, and management of seizures after an ischaemic or haemorrhagic stroke. We discuss the special considerations required for the treatment of post-stroke epilepsy due to the age, co-morbidities, co-medication, and vulnerability of stroke survivors.
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http://dx.doi.org/10.1007/s40266-021-00837-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007525PMC
April 2021

Αlpha 5 subunit-containing GABA receptors in temporal lobe epilepsy with normal MRI.

Brain Commun 2021 7;3(1):fcaa190. Epub 2021 Jan 7.

Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK.

GABA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [C]flumazenil has revealed reductions in GABA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of and measures from a single bolus injection of [C]Ro15-4513. The epilepsy group had higher in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas ( < 0.004). This was associated with reduced : ratios within the same areas ( < 0.009). Comparisons of for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation -0.4 ± 1.0 versus 0.7 ± 0.3;  = 0.02). In individuals with epilepsy, hippocampal did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced in the hippocampal area, which was significant ipsilaterally ( = 0.03), as expected from [C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.
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http://dx.doi.org/10.1093/braincomms/fcaa190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811756PMC
January 2021

Clinical outcomes of COVID-19 in long-term care facilities for people with epilepsy.

Epilepsy Behav 2021 02 5;115:107602. Epub 2020 Nov 5.

Department of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy (CCE), Chalfont St Peter, Bucks SL9 0RJ, UK.

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.
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http://dx.doi.org/10.1016/j.yebeh.2020.107602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643621PMC
February 2021

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development.

Epilepsia 2020 11 14;61(11):2340-2364. Epub 2020 Nov 14.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
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http://dx.doi.org/10.1111/epi.16725DOI Listing
November 2020

Resective surgery prevents progressive cortical thinning in temporal lobe epilepsy.

Brain 2020 12;143(11):3262-3272

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal ageing. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case-control neuroimaging study, we included subjects with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural MRI scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to ageing-related cortical thinning in healthy subjects, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 versus healthy volunteers 0.0032 ± 0.0013 mm/year, P < 0.0001) and right (right TLE 0.0198 ± 0.0016 versus healthy volunteers 0.0037 ± 0.0016 mm/year, P < 0.0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = 0.0006) or right (0.0052 ± 0.0020 mm/year, P = 0.0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal ageing. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal ageing. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.
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http://dx.doi.org/10.1093/brain/awaa284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719024PMC
December 2020

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development.

Epilepsia 2020 11 9;61(11):2365-2385. Epub 2020 Nov 9.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.
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http://dx.doi.org/10.1111/epi.16726DOI Listing
November 2020

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

Neurology 2020 10 26;95(17):e2427-e2441. Epub 2020 Aug 26.

From the Department of Clinical and Experimental Epilepsy (L.C., L.A.A., K.T., S.B.V., M.C., M.G., M.K.S., P.J.T., G.P.W., J.S.D., M.J.K.) and Neuroradiological Academic Unit (S.B.V.), UCL Queen Square Institute of Neurology, London; MRI Unit (L.C., L.A.A., K.T., S.B.V., M.C., M.G., M.K.S., P.J.T., G.P.W., J.S.D., M.J.K.), Epilepsy Society, Chalfont St Peter, Buckinghamshire, UK; Departments of Bioengineering (L.C., X.H., D.S.B.), Physics and Astronomy (D.S.B.), Electrical and Systems Engineering (D.S.B.), Neurology (D.S.B.), and Psychiatry (D.S.B.), University of Pennsylvania, Philadelphia; Department of Neurology (K.T.), Medical University of Vienna, Austria; Centre for Medical Image Computing (S.B.V.), University College London, UK; Department of Neurology (M.G.), University Hospital Zurich, Switzerland; Santa Fe Institute (D.S.B.), NM; Department of Medicine, Division of Neurology (G.P.W.), Queen's University, Kingston, Canada; and Department of Neurology (M.R.S.), Thomas Jefferson University, Philadelphia, PA.

Objective: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality.

Methods: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality.

Results: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS.

Conclusions: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.
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http://dx.doi.org/10.1212/WNL.0000000000010645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682917PMC
October 2020

Impaired naming performance in temporal lobe epilepsy: language fMRI responses are modulated by disease characteristics.

J Neurol 2021 Jan 3;268(1):147-160. Epub 2020 Aug 3.

Epilepsy Society MRI Unit, Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0LR, UK.

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.
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http://dx.doi.org/10.1007/s00415-020-10116-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815622PMC
January 2021

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

Epilepsia 2020 07 25;61(7):1438-1452. Epub 2020 Jun 25.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME.

Methods: This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks.

Results: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005).

Significance: Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.
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http://dx.doi.org/10.1111/epi.16575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681252PMC
July 2020

Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy.

Ann Neurol 2020 07 28;88(1):170-182. Epub 2020 May 28.

Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom.

Objective: 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 analyzed hippocampal surface shapes on high-resolution magnetic resonance 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 TLE (LTLE) and right TLE (RTLE) 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 < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline.

Interpretation: Memory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020 ANN NEUROL 2020;88:170-182.
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http://dx.doi.org/10.1002/ana.25762DOI Listing
July 2020

Cognitive Function in Genetic Generalized Epilepsies: Insights From Neuropsychology and Neuroimaging.

Front Neurol 2020 10;11:144. Epub 2020 Mar 10.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.

Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from pre-school years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication.
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http://dx.doi.org/10.3389/fneur.2020.00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076110PMC
March 2020

Pharmaco-fMRI: A Tool to Predict the Response to Antiepileptic Drugs in Epilepsy.

Front Neurol 2019 13;10:1203. Epub 2019 Nov 13.

Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.

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.
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http://dx.doi.org/10.3389/fneur.2019.01203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863979PMC
November 2019

Decreased GABA-A Receptor Binding in Association With β-Lactam Antibiotic Use.

Clin Nucl Med 2019 Dec;44(12):981-982

School of Biomedical Engineering & Imaging Sciences, King's College London, and Guy's and St Thomas' PET Centre, St Thomas' Hospital.

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.
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http://dx.doi.org/10.1097/RLU.0000000000002811DOI Listing
December 2019

Naming fMRI predicts the effect of temporal lobe resection on language decline.

Ann Clin Transl Neurol 2019 11 2;6(11):2186-2196. Epub 2019 Oct 2.

Epilepsy Society MRI Unit, Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0LR, United Kingdom.

Objective: To develop language functional MRI (fMRI) methods that accurately predict postsurgical naming decline in temporal lobe epilepsy (TLE).

Methods: Forty-six patients with TLE (25 left) and 19 controls underwent two overt fMRI paradigms (auditory naming and picture naming, both with active baseline conditions) and one covert task (verbal fluency). Clinical naming performance was assessed preoperatively and 4 months following anterior temporal lobe resection. Preoperative fMRI activations were correlated with postoperative naming decline. Individual laterality indices (LI) were calculated for temporal (auditory and picture naming) and frontal regions (verbal fluency) and were considered as predictors of naming decline in multiple regression models, along with other clinical variables (age at onset of seizures, preoperative naming scores, hippocampal volume, age).

Results: In left TLE patients, activation of the left posterior inferior temporal gyrus during auditory naming and activation of left fusiform gyrus during picture naming were related to greater postoperative naming decline. Activation LI were the best individual predictors of naming decline in a multivariate regression model. For picture naming, an LI of higher than 0.34 gave 100% sensitivity and 92% specificity (positive predictive value (PPV) 91.6%). For auditory naming, a temporal lobe LI higher than 0.18 identified all patients with a clinically significant naming decline with 100% sensitivity and 58% specificity (PPV: 58.3%). No effect was seen for verbal fluency.

Interpretation: Auditory and picture naming fMRI are clinically applicable to predict postoperative naming decline after left temporal lobe resection in individual patients, with picture naming being more specific.
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http://dx.doi.org/10.1002/acn3.50911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856622PMC
November 2019

Developmental MRI markers cosegregate juvenile patients with myoclonic epilepsy and their healthy siblings.

Neurology 2019 09 29;93(13):e1272-e1280. Epub 2019 Aug 29.

From the Neuroimaging of Epilepsy Laboratory (B.W., S.-J.H., B.C.B., F.F., N.B., A.B.), McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal; Department of Clinical and Experimental Epilepsy (B.W., C.V., M.J.K.), UCL Institute of Neurology, London, UK; Epilepsy Center, Department of Neurology (C.V.), Klinikum Großhadern, University of Munich, Germany; and Multimodal Imaging and Connectome Analysis Lab (B.C.B.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.

Objective: MRI studies of genetic generalized epilepsies have mainly described group-level changes between patients and healthy controls. To determine the endophenotypic potential of structural MRI in juvenile myoclonic epilepsy (JME), we examined MRI-based cortical morphologic markers in patients and their healthy siblings.

Methods: In this prospective, cross-sectional study, we obtained 3T MRI in patients with JME, siblings, and controls. We mapped sulco-gyral complexity and surface area, morphologic markers of brain development, and cortical thickness. Furthermore, we calculated mean geodesic distance, a surrogate marker of cortico-cortical connectivity.

Results: Compared to controls, patients and siblings showed increased folding complexity and surface area in prefrontal and cingulate cortices. In these regions, they also displayed abnormally increased geodesic distance, suggesting network isolation and decreased efficiency, with strongest effects for limbic, fronto-parietal, and dorsal-attention networks. In areas of findings overlap, we observed strong patient-sibling correlations. Conversely, neocortical thinning was present in patients only and related to disease duration. Patients showed subtle impairment in mental flexibility, a frontal lobe function test, as well as deficits in naming and design learning. Siblings' performance fell between patients and controls.

Conclusion: MRI markers of brain development and connectivity are likely heritable and may thus serve as endophenotypes. The topography of morphologic anomalies and their abnormal structural network integration likely explains cognitive impairments in patients with JME and their siblings. By contrast, cortical atrophy likely represents a marker of disease.
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http://dx.doi.org/10.1212/WNL.0000000000008173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011863PMC
September 2019

Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.

Brain 2019 09;142(9):2670-2687

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, UK.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.
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http://dx.doi.org/10.1093/brain/awz215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776114PMC
September 2019

Progressive Cortical Thinning in Patients With Focal Epilepsy.

JAMA Neurol 2019 Oct;76(10):1230-1239

Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom.

Importance: It is controversial whether epilepsy is a static or progressive disease. Evidence of progressive gray matter loss in epilepsy would support early diagnosis, rapid treatment, and early referral for surgical interventions.

Objective: To demonstrate progressive cortical thinning in patients with focal epilepsy distinct from cortical thinning associated with normal aging.

Design, Setting, And Participants: A case-control neuroimaging study was conducted from August 3, 2004, to January 26, 2016, among 190 patients with focal epilepsy at a tertiary epilepsy referral center (epilepsy data) and 3 independent comparison cohorts matched for age and sex (healthy volunteer data; n = 141).

Exposures: Two or more high-resolution T1-weighted magnetic resonance imaging scans at least 6 months apart (mean [SD] interval, 2.5 [1.6] years).

Main Outcomes And Measures: Global and vertexwise rate of progressive cortical thinning.

Results: A total of 190 people with focal epilepsy (99 women and 91 men; mean [SD] age, 36 [11] years; 396 magnetic resonance imaging scans) were compared with 141 healthy volunteers (76 women and 65 men; mean [SD] age, 35 [17] years; 282 magnetic resonance imaging scans). Widespread highly significant progressive cortical thinning exceeding normal aging effects, mainly involving the bilateral temporal lobes, medial parietal and occipital cortices, pericentral gyri, and opercula, was seen in 146 individuals with epilepsy (76.8%; 95% CI, 58%-95%). The mean (SD) annualized rate of global cortical thinning in patients with epilepsy was twice the rate of age-associated thinning observed in healthy volunteers (0.024 [0.061] vs 0.011 [0.029] mm/y; P = .01). Progression was most pronounced in adults older than 55 years and during the first 5 years after the onset of seizures. Areas of accelerated cortical thinning were detected in patients with early onset of epilepsy and in patients with hippocampal sclerosis. Accelerated thinning was not associated with seizure frequency, history of generalized seizures, or antiepileptic drug load and did not differ between patients with or without ongoing seizures. Progressive atrophy in temporal (n = 101) and frontal (n = 28) lobe epilepsy was most pronounced ipsilaterally to the epileptic focus but also affected a widespread area extending beyond the focus and commonly affected the contralateral hemisphere. For patients with temporal lobe epilepsy, accelerated cortical thinning was observed within areas structurally connected with the ipsilateral hippocampus.

Conclusions And Relevance: Widespread progressive cortical thinning exceeding that seen with normal aging may occur in patients with focal epilepsy. These findings appear to highlight the need to develop epilepsy disease-modifying treatments to disrupt or slow ongoing atrophy. Longitudinal cortical thickness measurements may have the potential to serve as biomarkers for such studies.
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http://dx.doi.org/10.1001/jamaneurol.2019.1708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604082PMC
October 2019

Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force.

Epilepsia 2019 06 28;60(6):1054-1068. Epub 2019 May 28.

Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1111/epi.15612DOI Listing
June 2019

A summary of data presented at the XIV conference on new antiepileptic drug and devices (EILAT XIV).

Epilepsy Res 2019 07 11;153:66-67. Epub 2019 Mar 11.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain from May 13th to 16th 2018. Again, presentations on new medical devices and neuromodulation and discussions on device-related regulatory aspects were included in the programme. The virtual special issue on "neuromodulation" summarises the presentations focusing firstly, on the pre-clinical developments and the difficulties of clinical trial designs for neuromodulatory therapies, including vagus nerve stimulation (VNS) and Brain-Responsive Neurostimulation (RNS), and the use of transcutaneous vagus nerve stimulation (tVNS) as a potential screening tool for determining the efficacy of neuromodulatory treatments in individual patients; secondly, on wearable devices for seizure monitoring through indices of peripheral sympathetic nervous activity, the use of such devices in combination with biofeedback for the treatment of epilepsy, and its potential for improving epilepsy specialist services, particularly in remote areas.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.002DOI Listing
July 2019

Association of Piriform Cortex Resection With Surgical Outcomes in Patients With Temporal Lobe Epilepsy.

JAMA Neurol 2019 06;76(6):690-700

UK National Institute for Health Research, University College London (UCL) Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.

Importance: A functional area associated with the piriform cortex, termed area tempestas, has been implicated in animal studies as having a crucial role in modulating seizures, but similar evidence is limited in humans.

Objective: To assess whether removal of the piriform cortex is associated with postoperative seizure freedom in patients with temporal lobe epilepsy (TLE) as a proof-of-concept for the relevance of this area in human TLE.

Design, Setting, And Participants: This cohort study used voxel-based morphometry and volumetry to assess differences in structural magnetic resonance imaging (MRI) scans in consecutive patients with TLE who underwent epilepsy surgery in a single center from January 1, 2005, through December 31, 2013. Participants underwent presurgical and postsurgical structural MRI and had at least 2 years of postoperative follow-up (median, 5 years; range, 2-11 years). Patients with MRI of insufficient quality were excluded. Findings were validated in 2 independent cohorts from tertiary epilepsy surgery centers. Study follow-up was completed on September 23, 2016, and data were analyzed from September 24, 2016, through April 24, 2018.

Exposures: Standard anterior temporal lobe resection.

Main Outcomes And Measures: Long-term postoperative seizure freedom.

Results: In total, 107 patients with unilateral TLE (left-sided in 68; 63.6% women; median age, 37 years [interquartile range {IQR}, 30-45 years]) were included in the derivation cohort. Reduced postsurgical gray matter volumes were found in the ipsilateral piriform cortex in the postoperative seizure-free group (n = 46) compared with the non-seizure-free group (n = 61). A larger proportion of the piriform cortex was resected in the seizure-free compared with the non-seizure-free groups (median, 83% [IQR, 64%-91%] vs 52% [IQR, 32%-70%]; P < .001). The results were seen in left- and right-sided TLE and after adjusting for clinical variables, presurgical gray matter alterations, presurgical hippocampal volumes, and the proportion of white matter tract disconnection. Findings were externally validated in 2 independent cohorts (31 patients; left-sided TLE in 14; 54.8% women; median age, 41 years [IQR, 31-46 years]). The resected proportion of the piriform cortex was individually associated with seizure outcome after surgery (derivation cohort area under the curve, 0.80 [P < .001]; external validation cohorts area under the curve, 0.89 [P < .001]). Removal of at least half of the piriform cortex increased the odds of becoming seizure free by a factor of 16 (95% CI, 5-47; P < .001). Other mesiotemporal structures (ie, hippocampus, amygdala, and entorhinal cortex) and the overall resection volume were not associated with outcomes.

Conclusions And Relevance: These results support the importance of resecting the piriform cortex in neurosurgical treatment of TLE and suggest that this area has a key role in seizure generation.
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http://dx.doi.org/10.1001/jamaneurol.2019.0204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490233PMC
June 2019

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development.

Epilepsia 2018 10;59(10):1811-1841

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington.

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS-001 (huperzine A), 2-deoxy-d-glucose, FV-082, FV-137, JNJ-40411813, JNJ-55511118 and analogs, ketone-enhanced antiepileptic drugs, oxynytones, OV329, TAK-935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease-modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.
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http://dx.doi.org/10.1111/epi.14557DOI Listing
October 2018

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development.

Epilepsia 2018 10;59(10):1842-1866

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington.

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium-chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec-butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo-controlled randomized controlled trials, with promising efficacy and safety results.
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http://dx.doi.org/10.1111/epi.14555DOI Listing
October 2018

Comment on " In Vivo [F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates".

ACS Chem Neurosci 2019 01 11;10(1):768-772. Epub 2018 Oct 11.

School of Biomedical Engineering and Imaging Sciences , King's College London , London SE1 7EH , United Kingdom.

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, [F]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 [F]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 [F]GE-179 in animals via traditional blocking, due to its low availability of target sites ( B). 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 B. 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.
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http://dx.doi.org/10.1021/acschemneuro.8b00246DOI Listing
January 2019

Left temporal lobe language network connectivity in temporal lobe epilepsy.

Brain 2018 08;141(8):2406-2418

Epilepsy Society MRI Unit, Epilepsy Society, Chalfont St Peter, SL9 0LR, UK.

Impairment of naming function is a critical problem for temporal lobe epilepsy patients, yet the neural correlates of the disruption of temporal lobe language networks are poorly understood. Using functional MRI, we investigated the activation and task-related functional connectivity of left temporal lobe language networks and their relation to clinical naming performance and disease characteristics. We studied 59 adult patients with temporal lobe epilepsy (35 left temporal lobe epilepsy) and 32 healthy controls with auditory and visual naming functional MRI tasks. Time series of activation maxima in the left posterior inferior temporal lobe were extracted to create a psychophysiological interaction regressor for subsequent seed-based whole-brain task-related functional connectivity analyses. Correlational analyses were performed to assess the association of functional MRI activation and functional connectivity with clinical naming scores, age of onset of epilepsy, and duration of epilepsy. Auditory naming elicited activation in the left posterior inferior temporal gyrus and visual naming in the left fusiform gyrus across all groups. Activations in the left inferior temporal gyrus, left thalamus and left supplementary motor region during auditory naming as well as left fusiform activations during picture naming correlated with better clinical naming performance. Functional connectivity analyses indicated coupling of left posterior inferior temporal regions to bilateral anterior and posterior temporal lobe regions and the bilateral inferior precentral gyrus as well as contralateral occipital cortex. Stronger functional connectivity was associated with better clinical naming performance in all groups. In patients with left temporal lobe epilepsy only, functional connectivity increased with later age of onset of epilepsy and shorter disease duration. This suggests that onset of seizures early in life and prolonged disease duration lead to disrupted recruitment of temporal lobe networks ipsilateral to the seizure focus, which might account for naming deficits in temporal lobe epilepsy.
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http://dx.doi.org/10.1093/brain/awy164DOI Listing
August 2018

Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.

Epilepsia 2018 07 13;59(7):1362-1371. Epub 2018 Jun 13.

Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.

Objective: To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy.

Methods: In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency.

Results: Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation.

Significance: Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.
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http://dx.doi.org/10.1111/epi.14448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216427PMC
July 2018

Simplifying [F]GE-179 PET: are both arterial blood sampling and 90-min acquisitions essential?

EJNMMI Res 2018 Jun 11;8(1):46. Epub 2018 Jun 11.

Division of Brain Sciences, Imperial College London, London, UK.

Introduction: The NMDA receptor radiotracer [F]GE-179 has been used with 90-min scans and arterial plasma input functions. We explored whether (1) arterial blood sampling is avoidable and (2) shorter scans are feasible.

Methods: For 20 existing [F]GE-179 datasets, we generated (1) standardised uptake values (SUVs) over eight intervals; (2) volume of distribution (V) images using population-based input functions (PBIFs), scaled using one parent plasma sample; and (3) V images using three shortened datasets, using the original parent plasma input functions (ppIFs).

Results: Correlations with the original ppIF-derived 90-min Vs increased for later interval SUVs (maximal ρ = 0.78; 80-90 min). They were strong for PBIF-derived Vs (ρ = 0.90), but between-subject coefficient of variation increased. Correlations were very strong for the 60/70/80-min original ppIF-derived Vs (ρ = 0.97-1.00), which suffered regionally variant negative bias.

Conclusions: Where arterial blood sampling is available, reduction of scan duration to 60 min is feasible, but with negative bias. The performance of SUVs was more consistent across participants than PBIF-derived Vs.
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http://dx.doi.org/10.1186/s13550-018-0396-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995767PMC
June 2018

The SeLECT score is useful to predict post-stroke epilepsy.

Lancet Neurol 2018 05 16;17(5):395-396. Epub 2018 Feb 16.

Department of Neurology, Kantonsspital St Gallen, St Gallen CH-9007, Switzerland.

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http://dx.doi.org/10.1016/S1474-4422(18)30075-9DOI Listing
May 2018

Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): a multivariable prediction model development and validation study.

Lancet Neurol 2018 02;17(2):143-152

Department of Neurology, Kantonsspital St Gallen, St Gallen, Switzerland. Electronic address:

Background: Stroke is one of the leading causes of acquired epilepsy in adults. An instrument to predict whether people are at high risk of developing post-stroke seizures is not available. We aimed to develop and validate a prognostic model of late (>7 days) seizures after ischaemic stroke.

Methods: In this multivariable prediction model development and validation study, we developed the SeLECT score based on five clinical predictors in 1200 participants who had an ischaemic stroke in Switzerland using backward elimination of a multivariable Cox proportional hazards model. We externally validated this score in 1169 participants from three independent international cohorts in Austria, Germany, and Italy, and assessed its performance with the concordance statistic and calibration plots.

Findings: Data were complete for 99·2% of the predictors (99·2% for Switzerland, 100% for Austria, 97% for Germany, and 99·7% for Italy) and 100% of the outcome parameters. Overall, the risk of late seizures was 4% (95% CI 4-5) 1 year after stroke and 8% (6-9) 5 years after stroke. The final model included five variables and was named SeLECT on the basis of the first letters of the included parameters (severity of stroke, large-artery atherosclerotic aetiology, early seizures, cortical involvement, and territory of middle cerebral artery involvement). The lowest SeLECT value (0 points) was associated with a 0·7% (95% CI 0·4-1·0) risk of late seizures within 1 year after stroke (1·3% [95% CI 0·7-1·8] within 5 years), whereas the highest value (9 points) predicted a 63% (42-77) risk of late seizures within 1 year (83% [62-93] within 5 years). The model had an overall concordance statistic of 0·77 (95% CI 0·71-0·82) in the validation cohorts. Calibration plots indicated high agreement of predicted and observed outcomes.

Interpretation: This easily applied instrument was shown to be a good predictor of the risk of late seizures after stroke in three external validation cohorts and is freely available as a smartphone app. The SeLECT score has the potential to identify individuals at high risk of seizures and is a step towards more personalised medicine. It can inform the selection of an enriched population for antiepileptogenic treatment trials and will guide the recruitment for biomarker studies of epileptogenesis.

Funding: None.
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http://dx.doi.org/10.1016/S1474-4422(17)30404-0DOI Listing
February 2018

Imaging Biomarkers of Anti-Epileptic Drug Action: Insights from Magnetic Resonance Imaging.

Curr Pharm Des 2017 ;23(37):5727-5739

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, United Kingdom.

Background: Approximately one third of patients with epilepsy are refractory to medical treatment. Adverse effects associated with Anti-Epileptic Drugs (AEDs) are considered to affect quality of life often more than seizures themselves. Neuroimaging techniques, particularly Magnetic Resonance Imaging (MRI), have proven instrumental in clinical decision making in relation to epilepsy surgery, but may also provide further insights into the mechanisms underlying treatment response and side effects associated with AEDs.

Objective And Method: We searched PubMed and Scopus databases for original articles and reviews published in the last two decades, which addressed the effects of AEDs on structural MRI, functional MRI and Magnetic Resonance Spectroscopy (MRS) measures.

Results: The majority of investigations implemented task-based fMRI, and probed the influence of widely used anti-epileptic drugs on tasks assessing language, executive functions and emotion recognition. Collectively, MRI allows detecting reproducible AED-related effects on regions and networks relevant to disease pathomechanisms, thus elucidating the anatomo-functional substrates of cognitive side effects. MRS analyses shed light on the molecular correlates of AED action, and may provide indicators of treatment response.

Conclusion: MRI techniques have considerably improved our understanding of the effects of AEDs at a regional and network level, and provide biomarkers with potential to improve routine clinical decision making in epilepsy.
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http://dx.doi.org/10.2174/1381612823666170809113636DOI Listing
July 2019

A meta-analysis on progressive atrophy in intractable temporal lobe epilepsy: Time is brain?

Neurology 2017 Aug 7;89(5):506-516. Epub 2017 Jul 7.

From the Neuroimaging of Epilepsy Laboratory (L.C., A.B., N.B., B.C.B.) and Multimodal Imaging and Connectome Analysis Laboratory (B.C.B.), Montreal Neurological Institute and Hospital, McGill University; Department of Clinical Neurosciences (S.W.), University of Calgary, Canada; and Department of Clinical and Experimental Epilepsy (L.C., M.J.K.), UCL Institute of Neurology, London, UK.

Objective: It remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence.

Methods: We conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE.

Results: We screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of = -0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] -0.51 to -0.32; < 0.0001; = 65.22%) and = -0.35 related to seizure frequency (95% CI -0.47 to -0.22; < 0.0001; = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures.

Conclusions: While the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease progression.
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http://dx.doi.org/10.1212/WNL.0000000000004176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539734PMC
August 2017