Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Association of Younger vs Older Ages With Changes in Incidence of Stroke and Other Vascular Events, 2002-2018.

Importance: Some studies have reported increasing stroke incidence at younger ages (<55 years) but have often relied only on administrative data, and more population-based studies of adjudicated stroke are required. An understanding of the drivers of any increase in incidence of young stroke also requires comparisons with stroke trends at older ages and with trends in incidence of other vascular events at younger ages. Objective: To determine temporal changes in incidence of stroke and other major vascular events at younger vs older ages. Design, Setting, and Participants: Prospective population-based incidence study conducted from April 2002 to March 2018 with a mean catchment population of 94 567 in Oxfordshire, England. Exposures: Calendar time, premorbid vascular risk factors, and occupation. Main Outcomes and Measures: Changes in incidence of stroke, transient ischemic attack (TIA), and other major vascular events (myocardial infarction, sudden cardiac death, and peripheral vascular events) stratified by age, sex, diagnostic workup, etiology, and severity. Results: A total of 2429 incident strokes were ascertained (mean age, 73.6 [SD, 14.4] years; 51.3% female). From 2002-2010 to 2010-2018, stroke incidence increased significantly among participants younger than 55 years (incidence rate ratio [IRR], 1.67; 95% CI, 1.31-2.14) but fell significantly among participants aged 55 years or older (IRR, 0.85; 95% CI, 0.78-0.92; P < .001 for difference). The significant increase in incidence at younger than 55 years was independent of sex, stroke severity, pathological subtype, and changes in investigation and was also seen for TIA (IRR, 1.87; 95% CI, 1.36-2.57) but not for myocardial infarction and other major vascular events (IRR, 0.73; 95% CI, 0.58-0.93). Although TIA and stroke at younger than 55 years were significantly associated with diabetes (risk ratio [RR], 3.47; 95% CI, 2.54-4.74), hypertension (RR, 2.52; 95% CI, 2.04-3.12), current smoking (RR, 2.38; 95% CI, 1.92-2.94), and obesity (RR, 1.36; 95% CI, 1.07-1.72), the significant increase in incidence from 2002-2010 to 2010-2018 was still seen in individuals without these risk factors. The increase was greatest in professional/managerial occupations (IRR, 2.52; 95% CI, 1.75-3.62) and least in partially skilled/unskilled occupations (IRR, 1.17; 95% CI, 0.79-1.74). The proportion of TIAs and strokes among those younger than 55 years without known vascular risk factors increased significantly over time (45 [30.4%] vs 115 [42.4%]; absolute difference, 12.0%; 95% CI, 2.6-21.5), especially in patients with cryptogenic events (10 [18.5%] vs 63 [49.2%]; absolute difference, 30.7%; 95% CI, 17.2-44.2; P < .001; P = .002 for heterogeneity). Conclusions and Relevance: Comparing persons living in Oxfordshire, England, in 2002-2010 vs 2010-2018, there was a significant increase in stroke incidence in those younger than 55 years, but a decrease in those aged 55 years or older. Given the absence of this divergence for other vascular events, further research is needed to understand the causes of this difference.

Trends in Stroke Incidence in High-Income Countries in the 21st Century: Population-Based Study and Systematic Review.

Background and Purpose- Population-based studies provide the most reliable data on stroke incidence. A previous systematic review of population-based studies suggested that stroke incidence in high-income countries decreased by 42% between the 1970s and early 2000s. However, it is uncertain whether this trend of steady decline has been maintained in more recent periods. Methods- Data from OCSP (Oxfordshire Community Stroke Project; 1981-1986) and OXVASC (Oxford Vascular Study; 2002-2017) along with other published population-based stroke incidence studies that reported temporal trends of stroke incidence since 1990 in high-income countries were included. Age-standardized relative incidence rate ratios were calculated for each study and then pooled with inverse-variance weighted random-effects meta-analysis. Projection estimates were calculated for the number of incident stroke patients in the United Kingdom from year 2015 to 2045. Results- In Oxfordshire, stroke incidence fell by 32% from OCSP to OXVASC, with a similar trend before or after year 2000. With the projected aging population, if the age-specific stroke incidence continued to decrease at its current rate (6% every 5 years), there would still be a 13% increase of the number of first-ever strokes in the United Kingdom up to year 2045. Incorporating the Oxfordshire data with other 12 population-based studies, stroke incidence declined steadily between the 1990s and 2010s within each study, resulting in a 28% decline over an average period of 16.5 years (pooled incidence rate ratio, 0.72 [95% CI, 0.66-0.79]; P<0.0001). The trend was the same for men (0.69 [95% CI, 0.61-0.77]; P<0.0001) and women (0.66 [95% CI, 0.59-0.74]; P<0.0001) and remained consistent after year 2010 in OXVASC. Proportion of disabling or fatal stroke also decreased over time (early versus later period, 53.6% versus 46.1%; P=0.02). Conclusions- Stroke incidence is continuing to decline with steady rate in Oxfordshire and in other high-income settings. However, the absolute number of strokes occurring is not falling.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

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

OBJECTIVE: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk. METHODS: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex. RESULTS: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging. SIGNIFICANCE: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

The long-term course of temporal lobe epilepsy: From unilateral to bilateral interictal epileptiform discharges in repeated video-EEG monitorings.

INTRODUCTION: Bilateral interictal epileptiform discharges (IED) and ictal patterns are common in temporal lobe epilepsy (TLE) and have been associated with decreased chances of seizure freedom after epilepsy surgery. It is unclear whether secondary epileptogenesis, although demonstrated in experimental models, exists in humans and may account for progression of epilepsy. MATERIAL AND METHODS: We reviewed consecutive video-EEG recordings from 1992 to 2014 repeated at least two years apart (mean interval 6.14years) in 100 people diagnosed with TLE. RESULTS: Ictal EEG patterns and IED remained restricted to one hemisphere in 36 people (group 1), 46 exhibited bilateral abnormalities from the first recording (group 2), 18 progressed from unilateral to bilateral EEG pathology over time (group 3). No significant differences between the three groups were seen with respect to age at epilepsy onset, duration, or underlying pathology. Extra-temporal IED during the first EEG recording were associated with an increased risk of developing bilateral epileptiform changes over time (hazard ratio 3.67; 95% CI 1.4, 9.4). CONCLUSION: Our findings provide some support of progression in TLE and raise the possibility of secondary epileptogenesis in humans. The development of an independent contra-lateral epileptogenic focus is known to be associated with a less favorable surgical outcome. We defined reliable EEG markers for an increased risk of progression to more widespread or independent bitemporal epileptogenicity at an early stage, thus allowing for individualized pre-surgical counselling.

Clinical significance of nonhabitual seizures during intracranial EEG monitoring.

This study sought to determine the frequency and clinical significance of nonhabitual seizures in 101 consecutive patients undergoing presurgical intracranial electroencephalography intracranial (icEEG) recording. We compared clinical data, recording details, and postsurgical outcome in patients with nonhabitual seizures to those without nonhabitual seizures during icEEG. In patients with nonhabitual seizures we compared icEEG recordings of nonhabitual seizures to recordings of habitual seizures. Nonhabitual seizures were recorded in 10% of patients. Those patients had a significantly higher rate of procedure-related complications compared to patients without nonhabitual seizures. Ultimate seizure outcome did not differ between the groups. Nonhabitual seizures often occurred within the first 3 days of icEEG recording and had larger seizure-onset zones compared to the patient's habitual seizures. Nonhabitual seizures have no effect on outcome of epilepsy surgery but may serve as important markers of procedure-related complications during icEEG.

Incidence and Types of Cardiac Arrhythmias in the Peri-Ictal Period in Patients Having a Generalized Convulsive Seizure.

BACKGROUND AND OBJECTIVES: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases. METHODS: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z-score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors. RESULTS: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers (p > 0.05). DISCUSSION: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Altered Amygdala Volumes and Microstructure in Focal Epilepsy Patients with Tonic-Clonic Seizures, Ictal and Post-Ictal Central Apnea.

Objectives: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by presence or absence of FBTCS, ictal central apnea (ICA) and post-ictal central apnea (PICA). Methods: 73 patients with only-focal seizures and 30 with FBTCS recorded during video EEG (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomical and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all epilepsy patients and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between healthy subjects, and patients with only-focal seizures or FBTCS The FBTCS group was further subdivided by presence of ICA and PICA, verified by VEEG. Results: Bilateral amygdala volumes were significantly increased in the FBTCS cohort compared to healthy controls and the focal cohort. Patients with recorded PICA had the highest increase in bilateral amygdala volume of the FBTCS cohort.Amygdala neurite density index (NDI) values were significantly decreased in both the focal and FBTCS groups relative to healthy controls, with values in the FBTCS group being the lowest of the two. The presence of PICA was associated with significantly lower NDI values vs the non-apnea FBTCS group (p=0.004). Significance: Individuals with FBTCS and PICA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Management of lymphadenitis due to non-tuberculous mycobacterial infection in children.

PURPOSE: Non-tuberculous mycobacterial (NTM) infection is an important cause of cervico-facial lymph node enlargement in young children. The optimal treatment is thought to be early complete excision without chemotherapy. We compared management of patients referred to our centre to this "gold standard" and determined clinical outcomes by type of primary surgical intervention (complete excision vs. incomplete excision). METHODS: Retrospective study of management and clinical outcomes of all children (<12 years) with NTM lymphadenitis referred to a single UK centre between May 1998 and May 2008. RESULTS: We identified 43 children. Median time from onset of swelling to operation was 6 weeks. Management was: no operation (n = 1, 2 %), complete excision (n = 20, 47 %), incision and drainage (n = 17, 40 %) and fine needle aspirate (n = 5, 12 %). Children not treated by primary complete excision were more likely to have: re-operation (91 vs. 30 %; χ(2) = 16.48; p < 0.0001); persistent lymphadenitis (77 vs. 30 %; χ(2) = 9.45; p = 0.002); sinus formation (26 vs. 5 %; χ2 = 3.74; p = 0.05). CONCLUSION: Failure to undertake primary complete excision leads to further morbidity. A high index of suspicion is required for timely appropriate management to avoid unnecessary morbidity and further intervention.

Diverging Temporal Trends in Stroke Incidence in Younger vs Older People: A Systematic Review and Meta-analysis.

Importance: Overall stroke incidence is falling in high-income countries, but data on time trends in incidence of young stroke (ie, stroke in individuals younger than 55 years) are conflicting. An age-specific divergence in incidence, with less favorable trends at younger vs older ages, might be a more consistent underlying finding across studies. Objective: To compare temporal trends in incidence of stroke at younger vs older ages in high-income countries. Data Sources: PubMed and EMBASE were searched from inception to February 2022. One additional population-based study (Oxford Vascular Study) was also included. Study Selection: Studies reporting age-specific stroke incidence in high-income countries at more than 1 time point. Data Extraction and Synthesis: For all retrieved studies, 2 authors independently reviewed the full text against the inclusion criteria to establish their eligibility. Meta-analysis was performed with the inverse variance-weighted random-effects model. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main Outcomes and Measures: The main outcome was age-specific divergence (<55 vs ≥55 years) in temporal trends in stroke incidence (relative temporal rate ratio [RTTR]) in studies extending to at least 2000. RTTRs were calculated for each study and pooled by random-effects meta-analysis, with stratification by administrative vs prospective population-based methodology, sex, stroke subtype (ischemic vs intracerebral hemorrhage vs subarachnoid hemorrhage) and geographical region. Results: Among 50 studies in 20 countries, 26 (13 prospective population-based and 13 administrative studies) reported data allowing calculation of the RTTR for stroke incidence at younger vs older ages across 2 or more periods, the latest extending beyond 2000. Reported trends in absolute incidence of young individuals with stroke were heterogeneous, but all studies showed a less favorable trend in incidence at younger vs older ages (pooled RTTR = 1.57 [95% CI, 1.42-1.74]). The overall RTTR was consistent by stroke subtype (ischemic, 1.62 [95% CI, 1.44-1.83]; intracerebral hemorrhage, 1.32 [95% CI, 0.91-1.92]; subarachnoid hemorrhage, 1.54 [95% CI, 1.00-2.35]); and by sex (men, 1.46 [95% CI, 1.34-1.60]; women, 1.41 [95% CI, 1.28-1.55]) but was greater in studies reporting trends solely after 2000 (1.51 [95% CI, 1.30-1.70]) vs solely before (1.18 [95% CI, 1.12-1.24]) and was highest in population-based studies in which the most recent reported period of ascertainment started after 2010 (1.87 [95% CI, 1.55-2.27]). Conclusions and Relevance: Temporal trends in stroke incidence are diverging by age in high-income countries, with less favorable trends at younger vs older ages, highlighting the urgent need to better understand etiology and prevention of stroke at younger ages.

Postictal increase in T-wave alternans after generalized tonic-clonic seizures.

PURPOSE: Sudden unexpected death in epilepsy (SUDEP) occurs most frequently in people with chronic uncontrolled epilepsy. Tonic-clonic seizures are a well-recognized risk factor for SUDEP. T-wave alternans (TWA) is a novel independent marker of risk of sudden cardiac death and cardiovascular mortality. The aim of this study was to determine if the level of TWA in patients with epilepsy differed after complex-partial and secondary generalized tonic-clonic seizures (sGTCS). METHODS: Electrocardiography (ECG) and electroencephalography (EEG) data from patients with drug-resistant focal epilepsy who had both complex partial and sGTCS during video-EEG telemetry were retrospectively reviewed. Periictal TWA, heart rate (HR), and heart rate variability (HRV) were analyzed. KEY FINDINGS: ECG and EEG data of 16 patients (31.6 ± 8.7 years, nine male) with focal epilepsies were analyzed. sGTCS led to a postictal increase in TWA for 15 min as well as a higher postictal HR and decreased postictal HRV for the whole observation time of 30 min. There was no significant association between postictal TWA or HR and seizure duration or duration of the tonic-clonic phase. SIGNIFICANCE: Our study demonstrates that derangements in autonomic function and TWA are highly prevalent after sGTCS in patients with chronic uncontrolled epilepsy. Further studies are warranted to investigate the value of TWA for risk stratification in epilepsy patients for sudden cardiac death and SUDEP.

Postictal generalized electroencephalographic suppression is associated with generalized seizures.

Postictal generalized electroencephalographic suppression (PGES) may be involved in sudden unexpected death in epilepsy (SUDEP). We examined whether the occurrence of PGES depends on seizure type and whether PGES occurs more frequently in people with epilepsy who died suddenly. EEG recordings of people with pharmacoresistant focal epilepsies who died from SUDEP after presurgical video/EEG telemetry were compared with recordings of living controls. To test if PGES depends on seizure type, EEG recordings of people with temporal lobe epilepsy who had complex partial seizures (CPS) and secondarily generalized tonic-clonic seizures (GTCS) were reviewed. A total of 122 seizures in 57 individuals have been included. PGES was observed in 15% of all seizures in 26% of all individuals. Secondarily GTCS were significantly associated with PGES. Neither presence nor duration of PGES differed between the SUDEP and control groups. In conclusion, PGES is facilitated by secondarily GTCS, but does not seem to be an independent risk factor for SUDEP.

Asymmetric hemispheric representation of periictal heart rate modulation is individually lateralised.

Asymmetric cortical representation of cardiac function is a matter of debate and large inter-individual variability of cortical autonomic networks and different study designs may contribute to this controversy. Lateralised seizure activity in individual patients may provide valuable insights into cortical regulation of cardiac function. We report two patients with focal epilepsy who had seizures arising from both hemispheres. In Patient 1, heart rate increased over two-fold with seizures arising from the right hemisphere, whereas heart rate increased invariably less with seizures arising from the left hemisphere. In Patient 2, heart rate increased 1.3 fold or less with seizures arising from the left hemisphere, whereas a seizure with right-sided onset was followed by bradycardia and asystole. Our findings support the notion that effects on autonomic function are lateralised, although lateralisation varies from patient to patient. This may partially explain the difficulty in determining cortical representation of cardiac autonomic function.

Distinct Patterns of Brain Metabolism in Patients at Risk of Sudden Unexpected Death in Epilepsy.

Objective: To characterize regional brain metabolic differences in patients at high risk of sudden unexpected death in epilepsy (SUDEP), using fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Methods: We studied patients with refractory focal epilepsy at high (n = 56) and low (n = 69) risk of SUDEP who underwent interictal 18FDG-PET as part of their pre-surgical evaluation. Binary SUDEP risk was ascertained by thresholding frequency of focal to bilateral tonic-clonic seizures (FBTCS). A whole brain analysis was employed to explore regional differences in interictal metabolic patterns. We contrasted these findings with regional brain metabolism more directly related to frequency of FBTCS. Results: Regions associated with cardiorespiratory and somatomotor regulation differed in interictal metabolism. In patients at relatively high risk of SUDEP, fluorodeoxyglucose (FDG) uptake was increased in the basal ganglia, ventral diencephalon, midbrain, pons, and deep cerebellar nuclei; uptake was decreased in the left planum temporale. These patterns were distinct from the effect of FBTCS frequency, where increasing frequency was associated with decreased uptake in bilateral medial superior frontal gyri, extending into the left dorsal anterior cingulate cortex. Significance: Regions critical to cardiorespiratory and somatomotor regulation and to recovery from vital challenges show altered interictal metabolic activity in patients with frequent FBTCS considered to be at relatively high-risk of SUDEP, and shed light on the processes that may predispose patients to SUDEP.

Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: a case-control study.

PURPOSE: To determine whether abnormal cardiac repolarization and other electrocardiography (ECG) predictors for cardiac mortality occur in epilepsy patients and whether they are associated with an increased risk for sudden unexpected death in epilepsy (SUDEP). METHODS: In a matched-pair case-control study, recordings of adult patients with pharmacoresistant focal epilepsies who died from SUDEP and who had previously had presurgical video-EEG (electroencephalography) telemetry were reviewed. Living controls were matched for age, gender, and date of admission for video-EEG telemetry. Periictal heart rate (HR), corrected QT interval (QTc), postictal HR recovery, HR variability, and cardiac rhythm were assessed. QT dispersion was analyzed with 12-lead ECG. RESULTS: A total of 38 patients (19 per group) had 91 recorded seizures. QTc was prolonged above pathologic upper limits in 9 of 89 seizures and 5 of 38 patients. Nine of 34 patients displayed pathologic QT dispersion. Presence of neither pathologic cardiac repolarization nor other ECG features were specifically associated with SUDEP. SUDEP patients were, however, more likely to lack pathologic cerebral magnetic resonance imaging (MRI) findings, less likely to experience antiepileptic drug reduction during telemetry, and had more secondarily generalized tonic-clonic seizures (SGTCS) per year. DISCUSSION: Our study did not reveal a clear-cut ECG predictor for SUDEP. Pathologic cardiac repolarization is not uncommon in adult patients with pharmacoresistant focal epilepsy and could favor occurrence of fatal tachyarrhythmia as one plausible cause for SUDEP. SGTCS are a risk factor for SUDEP, have, as compared to complex-partial seizures, a greater, unfavorable impact on heart activity, and may thereby additionally compromise cardiac function.

Peri-ictal atrioventricular conduction block in a patient with a lesion in the left insula: case report and review of the literature.

Seizure-induced syncope is uncommon and is usually due to peri-ictal bradycardia and asystole. In contrast, peri-ictal atrioventricular conduction block (AV block) has been reported only rarely. Here, we review the literature on peri-ictal AV block and describe a patient with recurrent episodes of epigastric auras that were occasionally followed by a sensation of dizziness and syncope because of transient third-degree AV block. After installation of a cardiac pacemaker, epigastric auras persisted, whereas the sensation of dizziness and syncope stopped. MRI revealed a lesion in the left insula, leading to the notion that recurrent syncope was most likely due to ictal activity in central autonomic networks.

Extratemporal ictal clinical features in hippocampal sclerosis: their relationship to the degree of hippocampal volume loss and to the outcome of temporal lobectomy.

PURPOSE: Since extratemporal clinical features in patients with unilateral hippocampal sclerosis (HS) are likely to indicate aberrant ictal spread or a more extensive epileptogenic zone, we asked whether such features are associated with more severe HS and a worse outcome following temporal lobectomy. PATIENTS AND METHODS: We reviewed all patients (174) who had undergone temporal lobectomy for histologically proven unilateral HS related temporal lobe epilepsy between 1997-2005 at the National Hospital for Neurology and Neurosurgery. We divided patients into those with severe HS (side-to-side ratio < 0.6) and those with mild HS (side-to-side ratio > 0.75). We examined all seizures recorded on electroencephalography (EEG) video telemetry in these patients for clinical features of temporal lobe epilepsy. The postsurgical outcome was classified using the Engel classification at the time of follow up (median 4.7 years, range 1-9 years). RESULTS: Patients (28 out 39) with severe HS had atypical features compared to 7 out of 27 in the mild HS [Chi square (chi(2)) test, p = 0.0013]. The mean number of atypical clinical features was 2.2 in the severe HS group and 0.62 in the mild HS group (Mann Whitney U Test, p < 0.001). The percentage of postsurgery seizure freedom (class 1 Engel classification) was 87%, and there was no significant effect of the presence of atypical clinical features. CONCLUSIONS: This study shows that atypical (extratemporal) clinical features tend to occur more frequently in patients with severe HS and do not correlate with worse surgical outcome.

Dysfunctional Brain Networking among Autonomic Regulatory Structures in Temporal Lobe Epilepsy Patients at High Risk of Sudden Unexpected Death in Epilepsy.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is common among young people with epilepsy. Individuals who are at high risk of SUDEP exhibit regional brain structural and functional connectivity (FC) alterations compared with low-risk patients. However, less is known about network-based FC differences among critical cortical and subcortical autonomic regulatory brain structures in temporal lobe epilepsy (TLE) patients at high risk of SUDEP. METHODS: 32 TLE patients were risk-stratified according to the following clinical criteria: age of epilepsy onset, duration of epilepsy, frequency of generalized tonic-clonic seizures, and presence of nocturnal seizures, resulting in 14 high-risk and 18 low-risk cases. Resting-state functional magnetic resonance imaging (rs-fMRI) signal time courses were extracted from 11 bilateral cortical and subcortical brain regions involved in autonomic and other regulatory processes. After computing all pairwise correlations, FC matrices were analyzed using the network-based statistic. FC strength among the 11 brain regions was compared between the high- and low-risk patients. Increases and decreases in FC were sought, using high-risk > low-risk and low-risk > high-risk contrasts (with covariates age, gender, lateralization of epilepsy, and presence of hippocampal sclerosis). RESULTS: High-risk TLE patients showed a subnetwork with significantly reduced FC (t = 2.5, p = 0.029) involving the thalamus, brain stem, anterior cingulate, putamen and amygdala, and a second subnetwork with significantly elevated FC (t = 2.1, p = 0.031), which extended to medial/orbital frontal cortex, insula, hippocampus, amygdala, subcallosal cortex, brain stem, thalamus, caudate, and putamen. CONCLUSION: TLE patients at high risk of SUDEP showed widespread FC differences between key autonomic regulatory brain regions compared to those at low risk. The altered FC revealed here may help to shed light on the functional correlates of autonomic disturbances in epilepsy and mechanisms involved in SUDEP. Furthermore, these findings represent possible objective biomarkers which could help to identify high-risk patients and enhance SUDEP risk stratification via the use of non-invasive neuroimaging, which would require validation in larger cohorts, with extension to patients with other epilepsies and subjects who succumb to SUDEP.

Meloxicam effectively inhibits preterm labor uterine contractions in a chronically catheterized pregnant sheep model: impact on fetal blood flow and fetal-maternal physiologic parameters.

OBJECTIVE: Preterm birth occurs in 5% to 10% of all pregnancies and is associated with considerable neonatal mortality and morbidity. Effective and safe drugs to prevent preterm labor are not currently available. We have hypothesized that the nonsteroidal anti-inflammatory drug meloxicam, a more selective cyclooxygenase-2 inhibitor will successfully inhibit labor but avoid the complications associated with inhibition of cyclooxygenase-1. STUDY DESIGN: Preterm labor was induced in chronically catheterized sheep by RU486 administration. Animals were then randomized to receive maternal infusions of saline (n = 5) or meloxicam (n = 4) for 48 hours or until delivery when the animals were killed and tissues and blood samples collected. RESULTS: Maternal infusion of meloxicam inhibited uterine contractions, increasing contraction duration, and attenuating frequency and amplitude. Saline-treated animals progressed to delivery. Administration of meloxicam was not associated with any change in fetal or maternal blood gas status, osmolality, arterial pressure, heart rate, or fetal blood flows. CONCLUSION: Meloxicam may represent a potentially safe and effective tocolytic agent.