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Genetic generalized epilepsy (GGE) syndromes start during childhood or adolescence, and four commonly persist into adulthood, making up 15–20% of all cases of epilepsy in adults. These four GGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic–clonic seizures alone. However, in ~20% of patients with GGE, characteristics of more than one syndrome are present. Novel insights into the genetic aetiology, comorbidities and prognosis of the GGE syndromes have emerged and challenge traditional concepts about these conditions. Evidence has shown that the mode of inheritance in GGE is mostly polygenic. Neuropsychological and imaging studies indicate similar abnormalities in unaffected relatives of patients with GGE, supporting the concept that underlying alterations in bilateral frontothalamocortical networks are genetically determined. Contrary to popular belief, first-line anti-seizure medication often fails to provide seizure freedom in combination with good tolerability. Nevertheless, long-term follow-up studies have shown that with advancing age, many patients can discontinue their anti-seizure medication without seizure relapses. Several outcome predictors have been identified, but prognosis across the syndromes is more homogeneous than previously assumed. Overall, overlap in pathophysiology, seizure types, treatment responses and outcomes support the idea that GGEs are not separate nosological entities but represent a neurobiological continuum. In this Review, the authors consider how current understanding of four genetic generalized epilepsy syndromes that commonly occur in adults challenges traditional concepts about these conditions and suggests that they are not distinct but sit on a neurobiological continuum.

Perampanel, a non-competitive antagonist of the post-synaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency fMRI twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in ASM regime in-between. After commencing perampanel, individuals had higher task-related activations in left orbito-frontal cortex (OFC), less task-related activations in subcortical regions including left thalamus and left caudate, and lower task-related thalamo-caudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. We capitalise on a large-scale, cross-sectional structural MRI dataset of 814 people with epilepsy. We use a recently developed machine-learning algorithm, Subtype and Stage Inference (SuStaIn), to develop a novel data-driven disease taxonomy based on distinct patterns of spatiotemporal progression of brain atrophy. We identify two subtypes common to focal and idiopathic generalised epilepsies, characterised by neocortical-driven or basal ganglia-driven progression, and a third subtype, only detected in focal epilepsies, characterised by hippocampus-driven progression. We corroborate external validity via an independent cohort of 254 people and decode associations between progression subtypes and clinical measures of epilepsy severity. Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualised prognostics and targeted therapeutics.

ObjectiveThe cognitive profile of juvenile absence epilepsy (JAE) remains uncharacterized. This study aimed to: (i) elucidate the neuropsychological profile of JAE; (ii) identify familial cognitive traits, by investigating unaffected JAE siblings; (iii) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to JME; and (iv) identify associations between cognitive abilities and clinical characteristics.MethodsWe investigated 123 participants: 23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME, who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, learning, and executive function. We also correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy.ResultsPatients with JAE performed worse than controls across tests of psychomotor speed, language, learning and executive function. Patients and siblings were similarly impaired on language measures of verbal comprehension, phonemic fluency, and semantic fluency compared to controls. Receiver operating characteristic curves indicated successful discrimination of patients with JAE and siblings from controls via linguistic measures. Individuals with JME also presented with multidomain cognitive impairment and had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better performance on psychomotor speed and executive function tests.SignificanceJAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings demonstrate shared impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset.KEY POINTSJAE presents with multidomain cognitive impairment involving language, attention/ psychomotor speed, executive function, and learning.Impaired language is common to people with JAE and their unaffected siblings, suggestive of a familial trait (endophenotype).Response inhibition is worse in JME than JAE, indicating distinct cognitive profiles across the IGE spectrum.Early age at epilepsy onset is associated with worse cognitive performance in JAE and JME.

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.

Die Bildgebung hat in den letzten 25 Jahren wesentliche neue Hinweise zum Verstandnis der Pathophysiologie der juvenilen myoklonischen Epilepsie (JME) geliefert. In diesem Artikel werden die Kernpunkte dieser Arbeiten zusammengefasst, und ihre Bedeutung im Zusammenhang mit genetischen Veranderungen und der Hirnentwicklung bei JME wird diskutiert. Zusammenfassend liegt bei der JME eine komplexe, multifaktorielle Entwicklungsstorung vor, die zu verschiedenen strukturellen und funktionellen Veranderungen kortikaler und subkortikaler Strukturen fuhrt. Dies fuhrt letztendlich zu einer pathologisch erhohten kortikokortikalen Konnektivitat, gestorter kortikaler Inhibition und gestorter thalamokortikaler Ruckkopplung. Ein Schwerpunkt dieser Veranderungen betrifft das frontozentrale motorische System, neuere Arbeiten zeigen aber auch daruber hinaus signifikante Veranderungen in anderen Hirnregionen

Objectives/AimsCognitive impairment is a common comorbidity of epilepsy, and can be more burdensome than seizures themselves. Temporal and frontal lobe epilepsy (TLE, FLE) are accompanied by multi-domain cognitive impairment. While the underlying neural substrates have been extensively investigated in TLE, functional imaging studies in FLE are scarce. Here, we aimed to: (i) investigate systems-level neural processes accounting for cognitive dysfunction in FLE; (ii) directly compare FLE and TLE patients, establishing commonalities and differences; and (iii) decode the potential influence of clinical characteristics on cognitive network architecture.MethodsWe capitalized on a large, single-centre sample of 172 adult participants (56 with FLE, 64 with TLE, 52 with controls) who were investigated via: (i) an extensive neuropsychological test battery that included attention, psychomotor speed, language, working memory, executive function, and episodic memory tests; and (ii) four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in age of epilepsy onset, disease duration, and antiseizure medication load. We mapped task-related brain activation and deactivation using a novel multiscale approach, and tracked reorganization in FLE and TLE. We complemented voxel-based maps with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional networks, and (ii) the principal functional connectivity gradient, that encodes a continuous transition from lower-level (sensory) to higher-order (transmodal) brain areas.ResultsWe find that cognitive impairment in FLE is accompanied by broadly reduced activation across frontoparietal attentional and executive networks, and reduced default-mode network deactivation, indicating large-scale disorganization of task-related recruitment, particularly during working memory. Patterns of dysfunction in FLE and TLE are broadly similar, but some traits are syndrome-specific: impaired task-related deactivation of the default-mode network is more prominent in FLE, while impaired recruitment of posterior language areas is more marked in TLE. More severe epilepsy, as tracked by age at onset, epilepsy duration, seizure frequency, time since last seizure, and propensity for focal-to-bilateral tonic-clonic seizures, relates to more marked cognitive network disorganization both in FLE and TLE.ConclusionsOur study elucidates neural processes underlying cognitive impairment in the most common focal epilepsies, identifies frontoparietal executive alterations as a shared biological signature, irrespective of seizure focus localization, and shows that temporal lobe language alterations are TLE-specific. The highlighted systems-level behaviour may be amenable to future remediation strategies, including neurostimulation.

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While the underlying neural substrates in TLE have been extensively investigated, functional imaging studies in FLE are scarce. In this study, we profiled cognitive dysfunction in FLE, and directly compared FLE and TLE patients to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls), using neuropsychological tests and four functional MRI tasks probing the neural correlates of expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-epileptic drug load. We devised a multiscale approach to map the landscape of brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects (i) across intrinsic functional systems, and (ii) along the principal functional connectivity gradient, which encodes a continuous transition from lower-level sensory to higher-order transmodal brain areas. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. Functional abnormalities in FLE were modulated by disease load. Patterns of dysfunction in FLE were broadly similar to those in TLE, but some traits were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies.

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.

BackgroundIn epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined.MethodsHere, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). “Drug load” was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication.ResultsIn people taking “moderate” ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking “severe” ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with “moderate” ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex.ConclusionOur study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.

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.

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.

Konventionelle bildgebende Verfahren sind bei Patienten mit idiopathischen generalisierten Epilepsien per definitionem unauffallig. MRT-basierte (Magnetresonanztomographie), morphometrische Verfahren konnten jedoch in Gruppenanalysen subtile strukturelle Veranderungen insbesondere im mesialen Frontallappen, supplementar motorischen Areal und Thalamus nachweisen. Erganzende funktionelle MRT- und Diffusions-Tensor-Bildgebungs(DTI)-Untersuchungen bei Patienten mit juveniler myoklonischer Epilepsie (JME) zeigen eine erhohte funktionelle und strukturelle Konnektivitat zwischen prafrontalen kognitiven und motorischen Kortexarealen, die Erklarungen fur krankheitstypische Anfallsreflexmechanismen bieten. Studien an neu diagnostizierten Patienten, longitudinale Studien sowie Untersuchungen an gesunden Geschwistern von JME-Patienten weisen darauf hin, dass diese Veranderungen am ehesten Ursache im Sinne einer genetisch determinierten Entwicklungsstorung sind und nicht eine sekundare Folge der chronischen Epilepsie.

Author(s): Allen, Luke A; Vos, Sjoerd B; Kumar, Rajesh; Ogren, Jennifer A; Harper, Rebecca K; Winston, Gavin P; Balestrini, Simona; Wandschneider, Britta; Scott, Catherine A; Ourselin, Sebsatien; Duncan, John S; Lhatoo, Samden D; Harper, Ronald M; Diehl, Beate | Abstract: ObjectiveThe 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.MethodsWe 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.ResultsSubstantial 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.SignificanceSUDEP 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.

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.

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.

Using multi-modal MRI, Caciagli et al. document abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their unaffected siblings, which are associated with altered memory-associated functional activations. These findings represent novel genetic imaging phenotypes, and imply a neurodevelopmental mechanism with expression during the prenatal stage., 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.

Summary 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.

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.

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.

The prevalence and incidence of epilepsies in elderly is high. Due to demographic development, the portion of elderly patients with epilepsy will continue to rise over the next decades. In this study, we aimed to investigate seizure semiology, etiology, comorbidity, and therapy in elderly patients dependent on onset of epilepsy and in comparison with younger patients. In a prospective multicentre study, 202 epilepsy patients were included in a consecutive manner and subdivided into three groups (group A1: >65 years, onset of epilepsy after the age of 65 years; group A2: >65 years with early onset epilepsy, seizure onset before the age of 50 years; and group B

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.

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."

Moderne bildgebende Verfahren bieten neue Moglichkeiten, die Pathomechanismen idopathisch generalisierter Epilepsien (IGE) zu ergrunden. Dieser Beitrag fasst aktuelle Studien mit strukturellen und funktionellen MRT-, MR-Spektroskopie und PET-Untersuchungen zusammen und verdeutlicht sie exemplarisch an einigen Studien. In den meisten Studien werden strukturelle und/oder funktionelle Veranderungen des Thalamus und frontaler Kortexegionen berichtet. Zusatzlich werden syndromspezifische Unterschiede beschrieben. Die Befunde lassen eine zugrunde liegende thalamofrontokortikale Netzwerkstorung bei IGE vermuten und sprechen gegen die traditionelle syndromatische Trennung in fokale und generalisierte Epilepsien.

Objective: Prospective memory (PM) describes the ability to fulfill previously planned intentions and is highly dependent on executive functions. Previous studies have shown deficits in executive functions in patients with juvenile myoclonic epilepsy (JME) and in their unaffected siblings. JME has a strong genetic predisposition and it is hypothesized that cognitive deficits are also genetically determined. The present study aimed at investigating potential differences in PM between patients with JME, their siblings, and healthy controls. Methods: Nineteen patients with JME, 21 siblings, and 21 healthy controls were examined with a complex PM paradigm allowing us to evaluate the different phases of PM (i.e., intention formation, intention retention, intention initiation, intention execution). Results: Patients with JME and siblings showed specific deficits during intention formation and intention execution of PM. Patients with JME were more impaired than both siblings and healthy controls. Correlation analysis revealed an influence of planning on prospective memory abilities in patients with JME. Conclusion: The results of this study support the hypothesis of frontal dysfunctions being part of the epileptic syndrome and therefore genetically determined. As in this study patients with JME are more severely cognitively impaired than their siblings, additional influencing factors, such as side effects of anticonvulsants or cognitive effects of subclinical epileptic discharges, might contribute to patients9 performance.

ZusammenfassungObwohl die meisten Schwangerschaften unter Antiepileptika komplikationslos verlaufen, ist eine In-utero-Exposition mit Antikonvulsiva mit einem erhöhten Fehlbildungsrisiko assoziiert. Um eine sinnvolle Abwägung des Fehlbildungsrisikos im Vergleich zu möglichen Anfallsrezidiven bei Umstellung oder Reduktion der Antiepileptika treffen zu können, sind in den letzten Jahren mehrere prospektive Schwangerschaftsregister geschaffen worden, die eine systematische und statistisch aussagekräftige Untersuchung des Fehlbildungsrisikos erlauben. Als Risikofaktoren erhöhter Teratogenität gelten in erster Linie die Polytherapie und die Therapie mit Valproat. Dabei ist der Valproateffekt dosisabhängig. Lamotrigin und Carbamazepin scheinen zu den günstigeren Präparaten zu zählen. Bezüglich eines spezifischen Fehlbildungsprofils der neuen Antiepileptika können bei kleinen Fallzahlen keine verlässlichen Aussagen getroffen werden. Zusätzlich wurde in den letzten Jahren der Verdacht einer negativen Auswirkung auf die neurokognitive Entwicklung insbesondere bei In-utero-Exposition mit Valproat diskutiert.

The mechanisms underlying sudden unexpected death in epilepsy (SUDEP) remain unclear. Wandschneider et al. reveal increased amygdalo-hippocampal volume in cases of SUDEP and in individuals at high risk, compared to individuals at low risk and people without epilepsy. Findings are consistent with histopathological reports in sudden infant death syndrome., 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.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Due to demographic change and high incidence of epilepsy in elderly, the number of elderly with epilepsies is increasing. However, only few studies investigated the impact of epilepsy on quality of life (QoL). We investigated how epilepsy affects different aspects of QoL dependent on the age of the patients and the age of onset of epilepsy. Materials and methods: In a multicenter, cross-sectional study, three patient groups were recruited from five centers: Group A1: 45 elderly (≥65 years.) with late onset of epilepsy (≥65 years), group A2: 51 elderly (≥65 years.) with early-onset, long-lasting epilepsy (≤50 years), group B: 41 young adults (≤50 years) with epilepsy. Statistical analysis of differences between groups was performed using generalized linear models. Results: Elderly with late-onset epilepsy (group A1) had a significantly lower seizure frequency, were treated with less anti-epileptic drugs (AEDs), and reported a better tolerability of AED treatment, but had more comorbidities compared with groups A2 and B. After adjusting for seizure frequency, tolerability of AEDs and comorbidity, young adults (group B) reported the highest overall QoL, whereas patients of group A1 and A2 did not differ significantly. Epilepsy-related fears, especially fears of stigmatization, were significantly higher in elderly with long-lasting epilepsy compared with groups A1 and B. Conclusion: Seizure-related variables, tolerability of AEDs and comorbidity have a stronger impact on QoL and on restrictions due to epilepsy than age, age at onset of epilepsy or duration of epilepsy. However, some results indicate group-specific patterns of impairment and epilepsy-related fears.

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?

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."