Search

Temporal lobe epilepsy (TLE) affects brain networks and is associated with impairment of episodic memory. Temporal and extratemporal reorganization of memory functions is described in functional magnetic resonance imaging (fMRI) studies. Functional reorganizations have been shown at the local activation level, but network-level alterations have been underinvestigated. We aim to investigate the functional anatomy of memory networks using memory fMRI and determine how this relates to memory function in TLE.Ninety patients with unilateral TLE (43 left) and 29 controls performed a memory-encoding fMRI paradigm of faces and words with subsequent out-of-scanner recognition test. Subsequent memory event-related contrasts of words and faces remembered were generated. Psychophysiological interaction analysis investigated task-associated changes in functional connectivity seeding from the mesial temporal lobes (MTLs). Correlations between changes in functional connectivity and clinical memory scores, epilepsy duration, age at epilepsy onset, and seizure frequency were investigated, and between connectivity supportive of better memory and disease burden. Connectivity differences between controls and TLE, and between TLE with and without hippocampal sclerosis, were explored using these confounds as regressors of no interest.Compared to controls, TLE patients showed widespread decreased connectivity between bilateral MTLs and frontal lobes, and increased local connectivity between the anterior MTLs bilaterally. Increased intrinsic connectivity within the bilateral MTLs correlated with better out-of-scanner memory performance in both left and right TLE. Longer epilepsy duration and higher seizure frequency were associated with decreased connectivity between bilateral MTLs and left/right orbitofrontal cortex (OFC) and insula, connections supportive of memory functions. TLE due to hippocampal sclerosis was associated with greater connectivity disruption within the MTL and extratemporally.Connectivity analyses showed that TLE is associated with temporal and extratemporal memory network reorganization. Increased bilateral functional connectivity within the MTL and connectivity to OFC and insula are efficient, and are disrupted by greater disease burden.

We describe real-world experience with cannabidiol (CBD) in adults with Dravet Syndrome (DS) via GW Pharma early access programme at two UK neurology centres. Adults with genetically-confirmed DS had CBD added to existing therapy, titrated up to 20 mg/kg, as tolerated. The primary outcome measure was percentage reduction in convulsive seizures. Secondary outcome measures included changes in myoclonic seizures, and in cognition and quality of life as assessed by the Caregiver Global Impression of Change (CGIC), and incidence of adverse events (AEs). 18 adults (7 female; median age 27.5 years; range 20–51) were included. Median follow-up was 176 days. In one, another antiseizure drug, clobazam, was introduced during the programme. 3/17 (17.6%) had >30% reduction in convulsive seizures (range: 87.5–100%). AEs occurred in all, the most common being transaminitis (52.9%). Behavioural AEs led to discontinuation in 3/18 (16.7%), including a seizure-free responder. In 7/18, CBD was stopped due to lack of effect. 8/18 continue on treatment. Improvements in CGIC were reported in 41.2% and 47.1% by physicians and families, respectively. 17.6% achieved sufficient reduction in convulsive seizure frequency to qualify for NHS funding. AEs led to withdrawal in only 16.7%. Close monitoring and dose adjustments of other antiseizure drugs were necessary.

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow‐up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole‐genome sequencing through the 100 000 Genomes Project. Virtual gene panels were applied to frequency‐filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were as follows: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28‐52 years). Tonic‐clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome‐specific treatment options, avoidance of harmful drugs, and monitoring for common complications.

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.

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.

BackgroundCannabidiol is a newly-available treatment option for seizures in Dravet syndrome (DS).MethodsAdults in a cannabidiol early access programme at two epilepsy centres were included. Can- nabidiol was titrated up to 20mg/kg, as tolerated. The primary outcome measure was >30% reduction in convulsive seizures assessed at three months of treatment. Secondary outcome measures included later reduction in seizures and incidence of adverse drug reactions (ADRs).ResultsEighteen individuals (seven female; median age 27.5 years) with SCN1A mutation-positive DS took part. Median follow-up was 166 days; nine individuals continued on maintenance treatment. Median maximum dose was 18.6mg/kg/day. Four individuals (22.2%) had a >30% reduction in convulsive seizures by three months; in two, this became evident after three months. ADRs occurred in 14 (77.8%). Commonest ADRs were somnolence and derangement of LFTs (all 18 took concomitant valproate), occurring in eight and seven individuals, respectively. ADRs led to discontinuation in three, including a seizure-free individual. Twelve people (66.7%) required dosage changes to other antiepileptic drugs.ConclusionCannabidiol was effective in a fifth of patients. Two additional patients showed later reduction in seizure frequency, suggesting longer follow-up is warranted. Treatment was complicated by ADRs. Dose adjustments of other antiepileptic drugs may be needed.k.silvennoinen@ucl.ac.uk

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

Epilepsy neuroimaging is important for detecting the seizure onset zone, predicting and preventing deficits from surgery and illuminating mechanisms of epileptogenesis. An aspiration is to integrate imaging and genetic biomarkers to enable personalized epilepsy treatments.The ability to detect lesions, particularly focal cortical dysplasia and hippocampal sclerosis, is increased using ultra high-field imaging and postprocessing techniques such as automated volumetry, T2 relaxometry, voxel-based morphometry and surface-based techniques. Statistical analysis of PET and single photon emission computer tomography (STATISCOM) are superior to qualitative analysis alone in identifying focal abnormalities in MRI-negative patients. These methods have also been used to study mechanisms of epileptogenesis and pharmacoresistance.Recent language fMRI studies aim to localize, and also lateralize language functions. Memory fMRI has been recommended to lateralize mnemonic function and predict outcome after surgery in temporal lobe epilepsy.Combinations of structural, functional and post-processing methods have been used in multimodal and machine learning models to improve the identification of the seizure onset zone and increase understanding of mechanisms underlying structural and functional aberrations in epilepsy.

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.

Objective: To develop language functional MRI (fMRI) methods that accurately predict postsurgical naming decline in temporal lobe epilepsy (TLE). Methods: Forty‐six patients with TLE (25 left) and 19 controls underwent two overt fMRI paradigms (auditory naming and picture naming, both with active baseline conditions) and one covert task (verbal fluency). Clinical naming performance was assessed preoperatively and 4 months following anterior temporal lobe resection. Preoperative fMRI activations were correlated with postoperative naming decline. Individual laterality indices (LI) were calculated for temporal (auditory and picture naming) and frontal regions (verbal fluency) and were considered as predictors of naming decline in multiple regression models, along with other clinical variables (age at onset of seizures, preoperative naming scores, hippocampal volume, age). Results: In left TLE patients, activation of the left posterior inferior temporal gyrus during auditory naming and activation of left fusiform gyrus during picture naming were related to greater postoperative naming decline. Activation LI were the best individual predictors of naming decline in a multivariate regression model. For picture naming, an LI of higher than 0.34 gave 100% sensitivity and 92% specificity (positive predictive value (PPV) 91.6%). For auditory naming, a temporal lobe LI higher than 0.18 identified all patients with a clinically significant naming decline with 100% sensitivity and 58% specificity (PPV: 58.3%). No effect was seen for verbal fluency. Interpretation: Auditory and picture naming fMRI are clinically applicable to predict postoperative naming decline after left temporal lobe resection in individual patients, with picture naming being more specific.

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.

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.

BackgroundWe report a rare case of reflex epilepsy in a 36-year-old female who was initially diagnosed with juvenile myoclonic epilepsy (JME).Case PresentationAged 15, spontaneous left sided myoclonic jerks and rare generalised tonic clonic seizures (GTCS) began. JME was diagnosed then, based on generalised spike wave discharges.As GTCS occurred once a year, she opted against treatment. Aged 26, due to seizure exacerbation, levetiracetam was commenced with complete seizure cessation.Aged 34, ascending electric-shock-like sensations from her feet with myoclonic jerks occurred exclusively whilst performing or even thinking about specific tasks such as hair brushing and complex arithmetic. No spontaneous seizures occurred. She was diagnosed with anxiety and referred to the epilepsy clinic at NHNN.Borderline hypothyroidism was diagnosed 6 months prior to symptom onset and treated with levothyroxine. There was otherwise no change in behaviour or cognitive function.On video-telemetry habitual reflex events were preceded by brief bursts of predominantly left fronto-central spike-and-slow wave complexes. Inter-ictally there were independent left central spike-wave-complexes suggesting a left fronto-central focal reflex epilepsy syndrome.Levetiracetam was optimised and lamotrigine commenced with complete cessation of seizures.ConclusionIt is important to recognise reflex epilepsy syndromes, rare entities, as they are frequently misdiagnosed.

PurposeFunctional magnetic resonance imaging (fMRI) has previously demonstrated functional reorganisation of memory representations in people with Temporal Lobe Epilepsy (TLE). Less is known about the changes in functional connectivity within the memory network.MethodsWe studied 77 patients with unilateral TLE (37 left) and 27 controls. All participants performed a memory encoding fMRI paradigm of faces and words. Psychophysiological Interaction (PPI) analysis was conducted to examine brain regions that were time-correlated with activations in the left and right hippocampi.ResultsDuring word encoding, left TLE patients showed reduced connectivity from the left hippocampus to the prefrontal cortex, compared to controls. During face encoding, right TLE patients showed reduced connectivity from the right hippocampus to the ipsilateral lateral temporal lobe and bilateral fusiform gyri. However, left and right TLE patients showed greater connectivity to posterior hippocampi bilaterally during word and face encoding.ConclusionTLE is increasingly recognised as a network disease and correspondingly we demonstrate widespread memory network reorganisation in people with epilepsy. The reorganisation of eloquent functions has important implications in the planning of epilepsy surgery and a network approach may be helpful in the prediction of memory outcome after epilepsy surgery.

Summary Background Topical 5-aminolaevulinic acid photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown. Objectives To look for involvement of the proinflammatory mediators prostaglandin (PG)E2 and nitric oxide (NO) in topical PDT-induced erythema in human skin. Methods A series of studies was performed in healthy volunteers (n = 35). Following definition of the erythemal time course and dose response to 5-ALA-PDT, duplicate 5-ALA dose series were iontophoresed into the skin of each ventral forearm and exposed to 100 J cm−2 broadband red light. Within subject, arms were randomized to control, or treatment with the cyclooxygenase and NO synthase inhibitors indometacin and Nω-nitro-l-arginine methyl ester (l-NAME), respectively, and the impact on 5-ALA-PDT-induced erythema was quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT administration. Results A 5-ALA dose-related delayed erythema occurred by 3 h (r = 0·97, P

Summary Assessing the functional reserve of key memory structures in the medial temporal lobes (MTL) of pre-surgical patients with intractable temporal lobe epilepsy (TLE) remains a challenge. Conventional functional MRI (fMRI) memory paradigms have yet to fully convince of their ability to confidently assess the risk of a post-surgical amnesia. An alternative fMRI analysis method, multi-voxel pattern analysis (MVPA), focuses on the patterns of activity across voxels in specific brain regions that are associated with individual memory traces. This method makes it possible to investigate whether the hippocampus and related structures contralateral to any proposed surgery are capable of laying down and representing specific memories. Here we used MVPA-fMRI to assess the functional integrity of the hippocampi and MTL in patients with long-standing medically refractory TLE associated with unilateral hippocampal sclerosis (HS). Patients were exposed to movie clips of everyday events prior to scanning, which they subsequently recalled during high-resolution fMRI. MTL structures were delineated and pattern classifiers were trained to learn the patterns of brain activity across voxels associated with each memory. Predictable patterns of activity across voxels associated with specific memories could be detected in MTL structures, including the hippocampus, on the side contralateral to the HS, indicating their functional viability. By contrast, no discernible memory representations were apparent in the sclerotic hippocampus, but adjacent MTL regions contained detectable information about the memories. These findings suggest that MVPA in fMRI memory studies of TLE can indicate hippocampal functional reserve and may be useful to predict the effects of hippocampal resection in individual patients.

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

SUMMARY Purpose: Temporal lobe epilepsy (TLE) has been considered to impair long-term memory, whilst not affecting working memory, but recent evidence suggests that working memory is compromised. Functional MRI (fMRI) studies demonstrate that working memory involves a bilateral frontoparietal network the activation of which is disrupted in hippocampal sclerosis (HS). A specific role of the hippocampus to deactivate during working memory has been proposed with this mechanism faulty in patients with HS. Structural correlates of disrupted working memory in HS have not been explored. Methods: We studied 54 individuals with medically refractory TLE and unilateral HS (29 left) and 28 healthy controls. Subjects underwent 3T structural MRI, a visuospatial n-back fMRI paradigm and diffusion tensor imaging (DTI). Working memory capacity assessed by three span tasks (digit span backwards, gesture span, motor sequences) was combined with performance in the visuospatial paradigm to give a global working memory measure. Gray and white matter changes were investigated using voxel-based morphometry and voxel-based analysis of DTI, respectively. Key Findings: Individuals with left or right HS performed less well than healthy controls on all measures of working memory. fMRI demonstrated a bilateral frontoparietal network during the working memory task with reduced activation of the right parietal lobe in both patient groups. In left HS, gray matter loss was seen in the ipsilateral hippocampus and parietal lobe, with maintenance of the gray matter volume of the contralateral parietal lobe associated with better performance. White matter integrity within the frontoparietal network, in particular the superior longitudinal fasciculus and cingulum, and the contralateral temporal lobe, was associated with working memory performance. In right HS, gray matter loss was also seen in the ipsilateral hippocampus and parietal lobe. Working memory performance correlated with the gray matter volume of both frontal lobes and white matter integrity within the frontoparietal network and contralateral temporal lobe. Significance: Our data provide further evidence that working memory is disrupted in HS and impaired integrity of both gray and white matter is seen in functionally relevant areas. We suggest this forms the structural basis of the impairment of working memory, indicating widespread and functionally significant structural changes in patients with apparently isolated HS.

A 62-year-old right-handed woman was referred from ophthalmology in 2009, with a 5-year history of episodic and then more persistent balance difficulty. This was particularly noticeable during tasks requiring depth perception, such as walking down stairs, in the dark and when walking on uneven surfaces. She reported visual ‘bobbing’ when walking, with occasional vertigo, particularly following sudden head movements. As her unsteadiness progressed, she developed double vision on horizontal gaze, with the false image appearing askew (both horizontal and vertical separation). This was most noticeable during tasks requiring fast-tracking eye movements, such as scanning supermarket shelves. By early 2008, she had a ‘droopy’ left eyelid, worse in the evenings but with no limb weakness or difficulty with swallow or speech. Over the years, she developed left arm clumsiness and ‘slowing’ of movements. She now needed a walking stick for support. There was no weight loss, difficulty with hearing or tinnitus. She took treatment for hypertension and hypercholesterolaemia: her medications included bisoprolol, aspirin and atorvastatin. Eight years earlier, she had a melanoma removed from her left thigh. As a child, she had recurrent urinary tract infections complicated by pyelonephritis and requiring intravenous antibiotics; it was unclear as to whether she received aminoglycoside antibiotics. She did not smoke cigarettes and drank minimal alcohol. Her mother had died in her fifties from myocardial infarction and father had died in his fifties from complications of rheumatic heart disease. Her mother had suffered frequent debilitating headaches, diagnosed as migraines by a neurologist. She was one of twins, but her male co-twin died aged 36 h from unknown cause. A second brother, who also had migraine, died aged 54 years from myocardial infarction. She had two healthy children aged 38 and 36 years. On examination, there was no evidence of autonomic involvement. Her cognition was normal, with congruent mood. …

Working memory is a critical building block for almost all cognitive tasks, and impairment can cause significant disruption to daily life routines. We investigated the functional connectivity (FC) of the visuo-spatial working memory network in temporal lobe epilepsy and its relationship to the underlying white matter tracts emanating from the hippocampus. Fifty-two patients with unilateral hippocampal sclerosis (HS) (30 left) and 30 healthy controls underwent working memory functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). Six seed regions were identified for FC analysis; 4 within a task-positive network (left and right middle frontal gyri and superior parietal lobes), and 2 within a task-negative network (left and right hippocampi). FC maps were created by extracting the time-series of the fMRI signal in each region in each subject and were used as regressors of interest for additional GLM fMRI analyses. Structural connectivity (SC) corresponding to areas to which the left and right hippocampi were connected was determined using tractography, and a mean FA for each hippocampal SC map was calculated. Both left and right HS groups showed atypical FC between task-positive and task-negative networks compared to controls. This was characterised by co-activation of the task-positive superior parietal lobe ipsilateral to the typically task-negative sclerosed hippocampus. Correlational analysis revealed stronger FC between superior parietal lobe and ipsilateral hippocampus, was associated with worse performance in each patient group. The SC of the hippocampus was associated with the intra-hemispheric FC of the superior parietal lobe, in that greater SC was associated with weaker parieto-frontal FC. The findings suggest that the segregation of the task-positive and task-negative FC networks supporting working memory in TLE is disrupted, and is associated with abnormal structural connectivity of the sclerosed hippocampus. Co-activation of parieto-temporal regions was associated with poorer working memory and this may be associated with working memory dysfunction in TLE., Highlights ► Functional and structural connectivity of working memory in TLE ► Functionally segregated task-positive and -negative networks identified in controls ► Patients show integrated connectivity between positive and negative networks. ► Greater hippocampal structural connectivity related to greater functional disruption ► Poor working memory in TLE linked to disrupted segregation of working memory networks

SummaryObjective Assessment of language dominance using functional magnetic resonance imaging (fMRI) is a standard tool to estimate the risk of language function decline after epilepsy surgery. Although there has been considerable research in the characterization of language networks in bilingual individuals; little is known about the clinical usefulness of language mapping in a secondary language in patients with epilepsy, and how language lateralization assessed by fMRI may differ by the use of native or a secondary language paradigms. In this study we investigate language representation in a population of nonnative English speakers to assess differences in fMRI language lateralization between the first (native) and second language (English). Methods Sixteen nonnative English-speaking patients with focal drug-resistant epilepsy underwent language fMRI in their first (native) language (L1) and in English (L2). Differences between language maps using L1 and L2 paradigms were examined at the single subject level by comparing within-subject lateralization indexes obtained for each language. Differences at the group level were examined for each of the tasks and languages. Results Group maps for the second language (English) showed overlapping areas of activation with the native language, but with larger clusters, and more bilaterally distributed than for the first language. However, at the individual level, lateralization indexes were concordant between the two languages, except for one patient with bilateral hippocampal sclerosis who was left dominant in English and showed bilateral dominance for verb generation and right dominance for verbal fluency in his native tongue. Significance Language lateralization can generally be reliably derived from fMRI tasks in a second language provided that the subject can follow the task. Subjects with greater likelihood of atypical language representation should be evaluated more carefully, using more than one language paradigm.

To develop a clinically applicable memory functional MRI (fMRI) method of predicting postsurgical memory outcome in individual patients.In this prospective cohort study, 50 patients with temporal lobe epilepsy (23 left) and 26 controls underwent an fMRI memory encoding paradigm of words with a subsequent out-of-scanner recognition assessment. Neuropsychological assessment was performed preoperatively and 4 months after anterior temporal lobe resection, and at equal time intervals in controls. An event-related analysis was used to explore brain activations for words remembered and change in verbal memory scores 4 months after surgery was correlated with preoperative activations. Individual lateralization indices were calculated within a medial temporal and frontal region and compared with other clinical parameters (hippocampal volume, preoperative verbal memory, age at onset of epilepsy, and language lateralization) as a predictor of verbal memory outcome.In left temporal lobe epilepsy patients, left frontal and anterior medial temporal activations correlated significantly with greater verbal memory decline, while bilateral posterior hippocampal activation correlated with less verbal memory decline postoperatively. In a multivariate regression model, left lateralized memory lateralization index (≥0.5) within a medial temporal and frontal mask was the best predictor of verbal memory outcome after surgery in the dominant hemisphere in individual patients. Neither clinical nor functional MRI parameters predicted verbal memory decline after nondominant temporal lobe resection.We propose a clinically applicable memory fMRI paradigm to predict postoperative verbal memory decline after surgery in the language-dominant hemisphere in individual patients.

Anterior temporal lobe resection (ATLR) is an effective treatment for refractory temporal lobe epilepsy (TLE). Widespread abnormalities in diffusion parameters involving the ipsilateral temporal lobe white matter and extending into extratemporal white matter have been shown in cross-sectional studies in TLE. However longitudinal changes following surgery have been less well addressed. We systematically assess diffusion changes in white matter in patients with TLE in comparison to controls before surgery and look at the longitudinal changes following ATLR at two timepoints (3–4 months, 12 months) using a whole brain approach. We find predominantly unilateral baseline changes in temporal and extratemporal structures compatible with altered myelination (reduced fractional anisotropy, increased mean and radial diffusivity). Following surgery, these changes progress in efferent tracts from the resected temporal lobe compatible with Wallerian degeneration. However more superiorly in the corona radiata, internal and external capsules and nearby tracts, changes compatible with plasticity are observed (increased fractional anisotropy and axial diffusivity, reduced radial diffusivity). There is little progression between 3–4 months and 12 months following surgery in patients with left TLE, but the changes become more widespread in patients with right TLE suggesting that plasticity occurs more slowly in this population. The neuropsychological correlates of such plasticity should be explored further., Highlights • We study longitudinal changes in diffusion parameters after temporal lobe resection. • Changes consistent with Wallerian degeneration are seen in nearby efferent tracts. • More superiorly, diffusion changes compatible with plasticity are observed. • Most of these changes are present by 3–4 months following left-sided surgery. • Plasticity occurs more slowly after right-sided surgery with greater change by 1 year.

It has traditionally been held that the hippocampus is not part of the neural substrate of working memory (WM), and that WM is preserved in Temporal Lobe Epilepsy (TLE). Recent imaging and neuropsychological data suggest this view may need revision. The aim of this study was to investigate the neural correlates of WM in TLE using functional MRI (fMRI). We used a visuo-spatial ‘n-back’ paradigm to compare WM network activity in 38 unilateral hippocampal sclerosis (HS) patients (19 left) and 15 healthy controls. WM performance was impaired in both left and right HS groups compared to controls. The TLE groups showed reduced right superior parietal lobe activity during single- and multiple-item WM. No significant hippocampal activation was found during the active task in any group, but the hippocampi progressively deactivated as the task demand increased. This effect was bilateral for controls, whereas the TLE patients showed progressive unilateral deactivation only contralateral to the side of the hippocampal sclerosis and seizure focus. Progressive deactivation of the posterior medial temporal lobe was associated with better performance in all groups. Our results suggest that WM is impaired in unilateral HS and the underlying neural correlates of WM are disrupted. Our findings suggest that hippocampal activity is progressively suppressed as the WM load increases, with maintenance of good performance. Implications for understanding the role of the hippocampus in WM are discussed., Highlights ► We investigate working memory activity in Temporal Lobe Epilepsy. ► Patients show reduced parietal lobe activity compared to controls. ► Hippocampi progressively deactivate during working memory. ► In patients, only the contralesional hippocampus follows this pattern.

Acute skin inflammation occurs following topical aminolevulinic acid-photodynamic therapy (ALA-PDT), but its nature and mediation are ill defined. As we observed an urticarial response, a potential role for histamine was explored. In 13 healthy volunteers, we assessed the time course and dose-response of the acute cutaneous response(s) to ALA-PDT, the impact of H(1) antihistamine blockade, and measured dermal histamine release. An ALA dose series was iontophoresed into ventral forearm skin and exposed to red light. All participants exhibited an immediate urticarial response, both wheal and flare correlating with log ALA dose. Subsequently, a dose-related erythema developed at treatment sites by 3 hours and persisted at 24 hours. H(1) blockade with oral cetirizine doubled the median minimal urticating dose of ALA and reduced the slope of dose-response for wheal and flare, whereas at the highest ALA dose, mean wheal and flare areas reduced by 68 and 60%, respectively. In contrast, cetirizine did not influence the 24 hour minimal phototoxic dose or erythema dose-response. Histamine release after ALA-PDT mirrored the urticarial response, levels peaking within 30 minutes and returning to baseline by 24 hours. Thus, two discrete acute inflammatory responses to topical ALA-PDT occur in human skin; histamine mediates the immediate response, but does not appear involved in the delayed phototoxicity.

Objective To explore the neural substrates of affective psychopathology in temporal lobe epilepsy (TLE), using functional MRI (fMRI). Method A visuo-spatial “n-back” paradigm was used to compare working-memory network activation in 17 TLE patients (Median age: 40 , 14 female) with a lifetime diagnosis of depression and/or anxiety with 31 TLE patients (Median age: 38 , 17 female) with no formal psychiatric history and 30 healthy controls (Median age: 37, 18 female). There were no significant differences between the TLE groups with respect to age, gender, handedness, epilepsy onset/duration or pre-morbid IQ. All subjects completed the Beck Depression Inventory Fast Screen (BDI-FS) and Beck Anxiety Inventory (BAI) on the day of scanning. Imaging data were analysed using SPM8 software. Results Each group activated the fronto-parietal working memory networks, and deactivated the typical default mode network (DMN) in response to the increasing task demands. Group comparison revealed that TLE patients with a lifetime history of affective disorders showed significantly greater deactivation in bilateral subgenual prefrontal cortex than either the TLE without any psychiatric history and the healthy control groups (p Conclusion Hypometabolismof the subgenual prefrontal cortex bilaterally has been reported in association with primary mood disorders (1), and our findings further implicate this region. The subgenual prefrontal cortex shares extensive and reciprocal anatomical connections with areas implicated in emotional and behavioural regulation, such as the posterior orbitofrontal cortex, amygdala, hippocampus and hypothalamus. We hypothesise that altered modulation of this region with increased deactivation may be associated with a predisposition to develop mood disturbance. Our findings suggest that the same neurobiological substrate involved in the pathogenesis of primary mood disorders may also underpin affective psychopathology in TLE.

Purpose The contribution of the frontal lobes to memory encoding has been recently appreciated. Functional MRI (fMRI) studies have demonstrated material specific prefrontal cortex (PFC) activations with verbal and non-verbal memory tasks on the left and right respectively in healthy individuals. We investigated the patterns of PFC activations in memory encoding for both verbal and non-verbal episodic memory in Temporal Lobe Epilepsy (TLE) patients using fMRI. Methods 27 healthy controls and 42 patients with hippocampal sclerosis (21 Right) were scanned on a 3T MRI scanner. An fMRI paradigm of memory encoding of faces and words was employed. fMRI analysis was performed with SPM8. Results Word encoding: controls and right HS patients activated the left PFC. Patients with left HS showed bilateral HC activations and significant additional right PFC activations greater than in controls and the right HS group p Conclusion We showed material specific PFC lateralisation in healthy controls as previously described. Patients with HS ipsilateral to side of material encoding showed additional contralateral PFC activations, implying reorganisation of the underlying network to involve the contralateral frontal lobes.

Rationale Surgery for refractory temporal lobe epilepsy (TLE) relies on concordant laterality between neuroimaging, electrophysiology and neuropsychology. A third of patients have normal MRI scans. In hippocampal sclerosis (HS), widespread abnormalities seen with diffusion tensor imaging (DTI) are more pronounced in the ipsilateral temporal lobe. Could laterality of DTI data help lateralise non-lesional TLE? Methods DTI scans were acquired in 78 subjects (36 HS, 27 other temporal lesions, 15 non-lesional TLE). Laterality indices for average fractional anisotropy, mean, axial and perpendicular diffusivity in the temporal lobes were calculated and a logistic regression model was used to classify seizure laterality. The model was validated in a previous cohort of 28 subjects (16 HS, five other, seven non-lesional). Results Laterality indices for each diffusion measure were significantly different between left and right HS groups (p Conclusions Laterality indices have been applied to functional MRI data but only more recently to DTI data. Calculation can be automated and may prove a useful clinical tool for presurgical assessment of patients with non-lesional TLE.

Background Over the last 15 years bacterial meningitis has received considerable attention; viral central nervous system (CNS) infections have been relatively neglected. Aim: Examine the relative incidence, clinical features and management of suspected adult CNS infections across the Region. Methods Multicentre (10 hospitals) cross-sectional retrospective cohort study over 3 months. All patients with cerebrospinal fluid analysis or acyclovir and/or third-generation cephalosporin; those with clinical features suspicious of a CNS infection were included. Management was compared with the national meningitis and regional encephalitis guidelines. Results 385 patients were screened; 217 had a suspected CNS infection; 44 (20%) had a CNS infection: 18 aseptic meningitis (one herpes simplex virus (HSV)-2), 13 purulent meningitis (four Streptococcus pneumoniae ), and 13 encephalitis (3 HSV-1). The median (range) time from admission to suspicion of CNS infection and to LP was longer for patients with encephalitis than meningitis (4 (0.3–312) vs 0.3 (0.1–12) h, p Conclusions Encephalitis was as common as purulent meningitis, and HSV as common as S pneumoniae . However, the management of patients with encephalitis was worse than meningitis. National encephalitis guidelines are needed.