Publications by authors named "Britta Wandschneider"

21 Publications

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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

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

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

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy.

Epilepsia 2019 04 14;60(4):718-729. Epub 2019 Mar 14.

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

Objective: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Methods: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.

Results: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.

Significance: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.
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http://dx.doi.org/10.1111/epi.14689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479118PMC
April 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

The impact of brain-derived neurotrophic factor Val66Met polymorphism on cognition and functional brain networks in patients with intractable partial epilepsy.

CNS Neurosci Ther 2019 02 27;25(2):223-232. Epub 2018 Jun 27.

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

Introduction: Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups.

Aims: We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE.

Methods: In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n = 276), postoperative cognitive change (n = 126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n = 37 and 34).

Results: mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients.

Conclusions: Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE.
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http://dx.doi.org/10.1111/cns.13003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488925PMC
February 2019

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

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

Effect of topiramate and zonisamide on fMRI cognitive networks.

Neurology 2017 Mar 17;88(12):1165-1171. Epub 2017 Feb 17.

From the Department of Clinical and Experimental Epilepsy (B.W., J.B., A.H., P.J.T., J.S.D., M.J.K.), UCL Institute of Neurology, London; and MRI Unit (B.W., J.B., L.T., A.H., P.J.T., J.S.D., M.J.K.), Epilepsy Society, Chalfont St. Peter, UK.

Objective: To investigate the effects of topiramate (TPM), zonisamide (ZNS), and levetiracetam (LEV) on cognitive network activations in patients with focal epilepsy using an fMRI language task.

Methods: In a retrospective, cross-sectional study, we identified patients from our clinical database of verbal fluency fMRI studies who were treated with either TPM (n = 32) or ZNS (n = 51). We matched 62 patients for clinical measures who took LEV but not TPM or ZNS. We entered antiepileptic comedications as nuisance variables and compared out-of-scanner psychometric measures for verbal fluency and working memory between groups.

Results: Out-of-scanner psychometric data showed overall poorer performance for TPM compared to ZNS and LEV and poorer working memory performance in ZNS-treated patients compared to LEV-treated patients. We found common fMRI effects in patients taking ZNS and TPM, with decreased activations in cognitive frontal and parietal lobe networks compared to those taking LEV. Impaired deactivation was seen only with TPM.

Conclusions: Our findings suggest that TPM and ZNS are associated with similar dysfunctions of frontal and parietal cognitive networks, which are associated with impaired performance. TPM is also associated with impaired attenuation of language-associated deactivation. These studies imply medication-specific effects on the functional neuroanatomy of language and working memory networks.

Classification Of Evidence: This study provides Class III evidence that in patients with focal epilepsy, TPM and ZNS compared to LEV lead to disruption of language and working memory networks.
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http://dx.doi.org/10.1212/WNL.0000000000003736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373787PMC
March 2017

Pharmaco fMRI: Determining the functional anatomy of the effects of medication.

Neuroimage Clin 2016 4;12:691-697. Epub 2016 Oct 4.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK; MRI Unit, Epilepsy Society, Chalfont St Peter, UK.

Functional MRI studies have helped to elucidate underlying mechanisms in complex neurological and neuropsychiatric disorders. Disease processes often involve complex large-scale network interactions, extending beyond the presumed main disease focus. Given both the complexity of the clinical phenotype and the underlying dysfunctional brain circuits, so called pharmaco-fMRI (ph-MRI) studies probe pharmacological effects on functional neuro-anatomy, and can help to determine early treatment response, mechanisms of drug efficacy and side effects, and potentially advance CNS drug development. In this review, we discuss recent ph-MRI research in three major neuropsychiatric and neurological disorders and associated network alterations, namely selective serotonin and noradrenergic reuptake inhibitors in affective disorders and emotional processing circuits; antiepileptic drugs in epilepsy and cognitive networks; and stimulants in attention-deficit/hyperactivity disorder and networks of attention control. We conclude that ph-MRI studies show consistent and reproducible changes on disease relevant networks, and prove sensitive to early pharmacological effects on functional anatomy associated with disease. Further CNS drug research and development would benefit greatly from improved disease phenotyping, or biomarkers, using advanced imaging techniques.
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http://dx.doi.org/10.1016/j.nicl.2016.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067101PMC
November 2017

Structural imaging biomarkers of sudden unexpected death in epilepsy.

Brain 2015 Oct 10;138(Pt 10):2907-19. Epub 2015 Aug 10.

1 NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK 2 Epilepsy Society, Chalfont St Peter SL9 0RJ, UK 4 The Centre for SUDEP Research, National Institute of Neurological Disorders and Stroke, USA

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies.
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http://dx.doi.org/10.1093/brain/awv233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671481PMC
October 2015

Juvenile myoclonic epilepsy: A system disorder of the brain.

Epilepsy Res 2015 Aug 27;114:2-12. Epub 2015 Apr 27.

UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Electronic address:

The prevailing understanding of generalized epilepsy is shaped by the traditional definition that "the responsible neuronal discharge takes place, if not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides". This view is no longer tenable since concurrent findings using multiple methods have accumulated to reveal the role of bilateral networks of distributed and selective cortical and subcortical structures in so-called generalized ictogenesis. Most of this research has been focused on juvenile myoclonic epilepsy (JME), which today is commonly considered the archetypical syndrome of the idiopathic generalized epilepsies. Based upon recent research in the fields of clinical epileptology, neuropsychology and psychiatry, clinical neurophysiology, neuroimaging and epilepsy genetics this article, for the first time, unites these new findings into a comprehensive nosological view. Genetically determined dysfunctions of important cognitive systems like visuomotor coordination and linguistic communication appear now as key mechanisms of seizure generation in JME. This review suggests a new paradigm to consider JME as a system disorder of the brain analogous to other neurological system disorders.
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http://dx.doi.org/10.1016/j.eplepsyres.2015.04.008DOI Listing
August 2015

Retinal nerve fibre layer thinning is associated with drug resistance in epilepsy.

J Neurol Neurosurg Psychiatry 2016 Apr 17;87(4):396-401. Epub 2015 Apr 17.

Department of Clinical and Experimental Epilepsy, NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK.

Objective: Retinal nerve fibre layer (RNFL) thickness is related to the axonal anterior visual pathway and is considered a marker of overall white matter 'integrity'. We hypothesised that RNFL changes would occur in people with epilepsy, independently of vigabatrin exposure, and be related to clinical characteristics of epilepsy.

Methods: Three hundred people with epilepsy attending specialist clinics and 90 healthy controls were included in this cross-sectional cohort study. RNFL imaging was performed using spectral-domain optical coherence tomography (OCT). Drug resistance was defined as failure of adequate trials of two antiepileptic drugs to achieve sustained seizure freedom.

Results: The average RNFL thickness and the thickness of each of the 90° quadrants were significantly thinner in people with epilepsy than healthy controls (p<0.001, t test). In a multivariate logistic regression model, drug resistance was the only significant predictor of abnormal RNFL thinning (OR=2.09, 95% CI 1.09 to 4.01, p=0.03). Duration of epilepsy (coefficient -0.16, p=0.004) and presence of intellectual disability (coefficient -4.0, p=0.044) also showed a significant relationship with RNFL thinning in a multivariate linear regression model.

Conclusions: Our results suggest that people with epilepsy with no previous exposure to vigabatrin have a significantly thinner RNFL than healthy participants. Drug resistance emerged as a significant independent predictor of RNFL borderline attenuation or abnormal thinning in a logistic regression model. As this is easily assessed by OCT, RNFL thickness might be used to better understand the mechanisms underlying drug resistance, and possibly severity. Longitudinal studies are needed to confirm our findings.
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http://dx.doi.org/10.1136/jnnp-2015-310521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819648PMC
April 2016

Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.

Neurology 2014 Oct 24;83(17):1508-12. Epub 2014 Sep 24.

From the Department of Clinical and Experimental Epilepsy (B.W., J.S., M.S., M.C., M.S., P.J.T., J.S.D., M.J.K.), UCL Institute of Neurology, London; the MRC Cognition and Brain Science Unit (J.S.), University of Cambridge; the Imaging and Biophysics Department (M.C.), UCL Institute of Child Health, Great Ormond Street Hospital, London, UK; and the MR Research Center (L.R.K.), Semmelweis University, Budapest, Hungary.

Objective: We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE).

Methods: In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose.

Results: We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left.

Conclusions: Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response.

Classification Of Evidence: This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures.
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http://dx.doi.org/10.1212/WNL.0000000000000910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222853PMC
October 2014

Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype?

Brain 2014 Sep 7;137(Pt 9):2469-79. Epub 2014 Jul 7.

1 Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

Juvenile myoclonic epilepsy is a heritable idiopathic generalized epilepsy syndrome, characterized by myoclonic jerks and frequently triggered by cognitive effort. Impairment of frontal lobe cognitive functions has been reported in patients with juvenile myoclonic epilepsy and their unaffected siblings. In a recent functional magnetic resonance imaging study we reported abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm, providing an underlying mechanism for cognitively triggered jerks. In this study, we used the same task in 15 unaffected siblings (10 female; age range 18-65 years, median 40) of 11 of those patients with juvenile myoclonic epilepsy (six female; age range 22-54 years, median 35) and compared functional magnetic resonance imaging activations with 20 age- and gender-matched healthy control subjects (12 female; age range 23-46 years, median 30.5). Unaffected siblings showed abnormal primary motor cortex and supplementary motor area co-activation with increasing cognitive load, as well as increased task-related functional connectivity between motor and prefrontal cognitive networks, with a similar pattern to patients (P < 0.001 uncorrected; 20-voxel threshold extent). This finding in unaffected siblings suggests that altered motor system activation and functional connectivity is not medication- or seizure-related, but represents a potential underlying mechanism for impairment of frontal lobe functions in both patients and siblings, and so constitutes an endophenotype of juvenile myoclonic epilepsy.
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http://dx.doi.org/10.1093/brain/awu175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132647PMC
September 2014

Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy.

Expert Rev Neurother 2014 Jul 14;14(7):819-31. Epub 2014 Jun 14.

Department of Clinical and Experimental Epilepsy, University College London - Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK.

Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways; advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome; clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous; many JME patients have psycho-social issues, even though their intelligence is normal; antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME.
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http://dx.doi.org/10.1586/14737175.2014.928203DOI Listing
July 2014

Risk-taking behavior in juvenile myoclonic epilepsy.

Epilepsia 2013 Dec 18;54(12):2158-65. Epub 2013 Oct 18.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom; Epilepsy Society MRI Unit, Epilepsy Society, Chalfont St Peter, United Kingdom.

Objective: Patients with juvenile myoclonic epilepsy (JME) often present with risk-taking behavior, suggestive of frontal lobe dysfunction. Recent studies confirm functional and microstructural changes within the frontal lobes in JME. This study aimed at characterizing decision-making behavior in JME and its neuronal correlates using functional magnetic resonance imaging (fMRI).

Methods: We investigated impulsivity in 21 JME patients and 11 controls using the Iowa Gambling Task (IGT), which measures decision making under ambiguity. Performance on the IGT was correlated with activation patterns during an fMRI working memory task.

Results: Both patients and controls learned throughout the task. Post hoc analysis revealed a greater proportion of patients with seizures than seizure-free patients having difficulties in advantageous decision making, but no difference in performance between seizure-free patients and controls. Functional imaging of working memory networks showed that overall poor IGT performance was associated with an increased activation in the dorsolateral prefrontal cortex (DLPFC) in JME patients. Impaired learning during the task and ongoing seizures were associated with bilateral medial prefrontal cortex (PFC) and presupplementary motor area, right superior frontal gyrus, and left DLPFC activation.

Significance: Our study provides evidence that patients with JME and ongoing seizures learn significantly less from previous experience. Interictal dysfunction within "normal" working memory networks, specifically, within the DLPFC and medial PFC structures, may affect their ability to learn.
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http://dx.doi.org/10.1111/epi.12413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209120PMC
December 2013

Consensus on diagnosis and management of JME: From founder's observations to current trends.

Epilepsy Behav 2013 Jul;28 Suppl 1:S87-90

University of Rome Sapienza II, Rome, Italy.

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?
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http://dx.doi.org/10.1016/j.yebeh.2012.11.051DOI Listing
July 2013

Juvenile myoclonic epilepsy--neuroimaging findings.

Epilepsy Behav 2013 Jul;28 Suppl 1:S40-4

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

Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychological studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. Positron emission tomography demonstrated metabolic and neurotransmitter changes in the dorsolateral prefrontal cortex reflecting the particular cognitive and behavioral profile of JME patients. (1)H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome. Quantitative MRI revealed significant abnormalities of cortical gray matter in medial frontal areas close to the supplementary motor area and diffusion abnormalities with increased functional coupling between the motor and prefrontal cognitive systems. This altered structural connectivity of the supplementary motor area provides an explanatory framework for the particular imaging findings, seizure type, and seizure-provoking mechanisms in JME.
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http://dx.doi.org/10.1016/j.yebeh.2012.06.035DOI Listing
July 2013

Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data.

Epilepsia 2012 Dec 25;53(12):2091-8. Epub 2012 Oct 25.

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

Juvenile myoclonic epilepsy is the most common idiopathic epilepsy syndrome and is considered a benign seizure disorder that responds well to antiepileptic drug treatment, in particular sodium valproate. By definition, routine brain imaging shows no abnormalities, but advanced imaging studies have identified functional and structural abnormalities in the frontal cortex and thalamus. Neuropsychological studies revealed subtle cognitive deficits in patients with JME, mainly implicating the frontal lobes. These findings are in keeping with anecdotal reports of behavioral problems in JME. Cognitive dysfunction in otherwise healthy siblings of patients with JME and a high heritability support the concept of a genetically determined thalamo-frontocortical network dysfunction, accounting for the cognitive impairment and cognitively triggered "motor seizures."
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http://dx.doi.org/10.1111/epi.12003DOI Listing
December 2012