Structural imaging biomarkers of sudden unexpected death in epilepsy.

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

Cognitive phenotype of juvenile absence epilepsy: An investigation of patients and unaffected siblings

Objective: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE-associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. Methods: We 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, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. Results: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. Significance: JAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share 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

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is 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 functional magnetic resonance imaging (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 anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the 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)

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

BACKGROUND In 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. METHODS Here, 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. RESULTS In 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. CONCLUSION Our 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

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

Background: In 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. Methods: Here, 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. Results: In 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. Conclusion: Our 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

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While its neural substrates have been extensively investigated 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 devise 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, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE were broadly similar to those in TLE, but some patterns 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. Functional abnormalities in FLE and TLE appeared 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 behavior that may be amenable to future remediation strategies

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.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 individualized prognostics and targeted therapeutics

A neuropsychological study in patients with juvenile myoclonic epilepsy and their healthy siblings

In dieser Fall-Kontroll-Studie wurde erstmalig das prospektive Gedächtnis bei 19 Patienten mit juveniler myoklonischer Epilepsie (JME) und 21 ihrer nicht erkrankten, neurologisch gesunden Geschwister im Vergleich zu 21 gesunden Kontrollprobanden untersucht. Das prospektive Gedächtnis umfasst die Fähigkeit, Handlungsintentionen zu bilden und zu einem späteren Zeitpunkt durchzuführen. Ihm wird eine hohe Bedeutung im Management alltagsrelevanter Tätigkeiten, wie beispielsweise der Termineinhaltung, zugeschrieben. Die einzelnen Phasen des prospektiven Erinnerns umfassen die Handlungsplanung und Intentionsbildung, ein Behaltensintervall, die Handlungsinitiierung nach Erkennen eines dafür bestimmten Stimulus, die plangetreue Handlungsdurchführung und abschließende Bewertung. Wahrscheinlich sind höhere kognitive Funktionen, in erster Linie Exekutivfunktionen, maßgeblich am reibungslosen Ablauf prospektiver Gedächtnisleistungen beteiligt. Bisherige neuropsychologische Untersuchungen an JME-Patienten und ihren Geschwistern haben Funktionsstörungen des präfrontalen Kortex, insbesondere der Exekutivfunktionen und des Arbeitsgedächtnisses, nachgewiesen. Möglicherweise bilden subtile strukturelle und funktionelle Veränderungen der thalamo- frontokortikalen Schleife in neuropathologischen Untersuchungen und funktionellen Bildgebungsstudien das strukturelle Korrelat der geschilderten kognitiven Funktionsstörungen. Die JME geht mit einer hohen genetischen Prädisposition einher. Unter der Annahme, dass es sich bei der JME um eine genetisch determinierte Störung des Gehirnreifungsprozesses handelt, die sich mit einer altersgebundenen thalamo-kortikalen Netzwerkdysfunktion manifestiert, wurden in dieser Studie sowohl das prospektive Erinnern als auch weitere kognitive Funktionen bei Patienten und Geschwistern untersucht. Die Geschwister wurden in Hinblick auf Alter, Geschlecht und Schulbildung mit gesunden Kontrollprobanden parallelisiert. Die neuropsychologische Untersuchung erfolgte mit standardisierten Testverfahren zur basalen Aufmerksamkeit, zu den retrospektiven Gedächtnisfunktionen, dem Arbeitsgedächtnis und den Exekutivfunktionen, sowie mit einem experimentellen Testverfahren, der komplexen prospektiven Mehrfachaufgabe, zur Prüfung des prospektiven Gedächtnisses. Dabei kann jede Phase des prospektiven Erinnerns einzeln bewertet werden. Mit Hilfe der Korrelationsanalyse wurden unter den kognitiven Einzelfunktionen die Einflussfaktoren auf die prospektive Gedächtnisleistung ermittelt. Patienten und Geschwister erhielten zusätzlich eine EEG- Untersuchung. Patienten und Geschwister boten spezifische Defizite in der Bewältigung der komplexen prospektiven Mehrfachaufgabe. Zusammenfassend war bei Patienten und Geschwistern die Phase der Plankomplexität während der Intentionsbildung beeinträchtigt. Außerdem kam es während der Planausführung signifikant häufiger zu Regelverstößen. Zusätzlich führten die Patienten signifikant weniger Aufgaben durch und arbeiteten tendenziell nicht plangetreu. Insgesamt fielen die Ergebnisse der Geschwister zwischen die der Patienten und der Kontrollen. In Hinblick auf die kognitiven Kontrollvariablen waren die Patienten zusätzlich in den figuralen Kurzzeitgedächtnisleistungen, sowie den Exekutivfunktionen semantische Wortflüssigkeit und Interferenzfähigkeit beeinträchtigt. Sonst ergaben sich keine signifikanten Gruppenunterschiede. Unter Berücksichtigung der Korrelationsanalyse sind die Defizite der Patienten und Geschwister in der prospektiven Gedächtnisaufgabe wahrscheinlich Ausdruck eines Planungsdefizits und mangelnder Interferenzfähigkeit. Das höhere Maß an Impulsivität bei der Aufgabenbearbeitung mit häufigen Regelverstößen könnte das Korrelat der von einigen Autoren geschilderten Persönlichkeitscharakteristika bei JME-Patienten mit Impulsivität und Unbeständigkeit sein. Möglicherweise tragen Medikamenteneffekte und subklinische EEG- Aktivität zu den im Vergleich zu den Geschwistern etwas schlechteren Ergebnissen der Patienten bei. Grundsätzlich untermauern die vorliegenden Ergebnisse die Hypothese, dass kognitive Defizite als Teil des Syndroms und nicht als Folge epileptischer Anfälle zu interpretieren sind. Somit ist eine genetische Vermittlung Syndrom- spezifischer kognitiver Defizite wahrscheinlich.Objective. Prospective memory (PM) describes the ability to fulfil 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 JME patients, their siblings and healthy controls. Methods. Nineteen JME patients, 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. JME patients and siblings showed specific deficits during intention formation and intention execution of PM. JME patients were more impaired than both siblings and healthy controls. Correlation analysis revealed an influence of several executive functions on both siblings and JME patients’ prospective memory abilities. 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 JME patients’ 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 patients’ performance

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

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