Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Bitemporal seizure spread and its effect on autonomic dysfunction.

OBJECTIVE: Autonomic dysregulation is a possible pathomechanism of sudden unexpected death in epilepsy (SUDEP). Cardiac arrhythmias and autonomic symptoms are most commonly associated with seizures arising from the temporal lobes. The aim of this study was to investigate whether simultaneous seizure activity in both temporal lobes affects the autonomic nervous system differently from seizure activity in one temporal lobe as assessed by heart rate variability (HRV). METHODS: Electrocardiography (ECG) and intracranial electroencephalography (iEEG) data from 13 patients with refractory temporal lobe epilepsy who had seizures that propagated electrically from one temporal lobe to the other during video-EEG-ECG monitoring were retrospectively reviewed. The time domain, frequency domain, and nonlinear parameters of HRV were evaluated by analyzing 4-minute-long ECG epochs, sampling from baseline, preictal and postictal periods as well as epochs constituting unitemporal and bitemporal ictal activity. RESULTS: Heart rate was significantly higher during bitemporal ictal activity compared with all other time points. The time domain and nonlinear parameters of HRV were significantly decreased during bitemporal activity compared with baseline, and multiple components of HRV (standard deviation of RR intervals (SDNN), coefficient of variation (CV), root mean square of successive differences (RMSSD), and standard deviation of short-term variability (SD1)) were significantly lower during bitemporal activity compared with unitemporal activity. Frequency domain analysis showed no significant differences. CONCLUSION: This study shows that bitemporal seizure activity significantly increases heart rate and decreases HRV, indicating increased autonomic imbalance with a shift towards sympathetic predominance, and this may increase the risk of SUDEP.

Epilepsy causing pupillary hippus: an unusual semiology.

Altered pupillary behavior is commonly present during and following epileptic seizures, but symptomatic pupillary hippus as the main feature of a seizure has not been reported in the modern literature. We present the case of a woman with epileptic seizures consisting of sustained fluctuation of perception of brightness. Bilateral pupillary hippus is the main semiologic feature.This autonomic phenomenon is selective for the pupils and does not involve other autonomic-mediated responses. An ictal video illustrates this phenomenon. The epileptogenic region, determined by ictal scalp and intracranial electroencephalography (EEG), is localized in the right posterior parietooccipital areas. Pupillary reflexes can be overridden by cortical input; here authors review the literature and discus the physiologic mechanisms underlying this autonomic phenomenon. Fluctuation in perceptual brightness during epileptic seizures may have a basis in ictal pupillary hippus.

Hippocampus-dependent and -independent theta-networks of active maintenance.

Recent studies in humans and animals raise the possibility that actively maintaining a detailed memory of a scene within working memory may require the hippocampus, a brain structure better known for its role in long-term memory. We show that the hippocampus is behaviorally and functionally critical for configural-relational (CR) maintenance by orchestrating the synchrony of occipital and temporal brain regions in the theta-frequency range. Using magnetoencephalography in healthy adults and patients with bilateral hippocampal sclerosis, we distinguish this hippocampus-dependent theta-network from one that is independent of the hippocampus and used for non-CR scene maintenance. This non-CR theta-network involved frontal and parietal brain regions. We also show that the functional and topographical dissociation between these two networks cannot be accounted for by perceptual difficulty or the amount of information to be maintained ("load"). Also, we confirm in healthy adults that active maintenance of the CR arrangement of objects within a scene is impaired by task-interference during the delay in a manner akin to working-memory maintenance processes. Together, these findings demand reconsideration of the classical functional-anatomical distinctions between long- and short-term memory.

Diffusion imaging in epilepsy.

Epilepsy is the most common serious neurological disease. Seizures are refractory to medication in approximately 30% of patients with focal epilepsy, and surgical treatment is potentially curative should the epileptic focus be accurately localized. MRI has revolutionized the investigation of such patients; however, up to 20% of patients with refractory focal epilepsy have an undetermined etiological basis for their epilepsy despite extensive investigation. Diffusion imaging is an advanced MRI technique that is sensitive to the molecular displacement of water molecules and provides additional information on the microstructural arrangement of tissue. Both qualitative and quantitative analyses of the interictal and peri-ictal states are possible and provide valuable insights into the epileptic brain in vivo. Furthermore, advanced postacquisition processing can reveal additional information on, for example, anatomical connectivity. The description, application and limitations of diffusion imaging in epilepsy are the focus of this review. Future directions of research required in this area are also discussed in the context of existing literature.

Evaluation of quantitative magnetic resonance imaging contrasts in MRI-negative refractory focal epilepsy.

PURPOSE: Conventional optimal MRI is unremarkable in 20%-30% of patients with intractable focal epilepsy. These MRI-negative patients are the most challenging in surgical programs. Our aim was to evaluate the yield and utility of quantitative MRI with novel contrasts in MRI-negative patients with refractory focal epilepsy, who were potential surgical candidates. METHODS: Ninety-three consecutive potential surgical candidates with refractory focal epilepsy, 44 with temporal lobe epilepsy, and 49 with frontal lobe epilepsy as determined with ictal scalp video-EEG; and normal optimal conventional MRI, including hippocampal volumes and T2 measures were investigated with quantitative MRI contrasts. The contrasts comprised fast fluid attenuated inversion recovery based T2 measurement (FFT2), double inversion recovery (DIR), magnetization transfer ratio (MTR), and voxel-based morphometry of gray matter (VBM). Voxel-based analyses of whole brain data were used to compare each patient with a control group. RESULTS: In patients with a putative single focus on scalp video-EEG telemetry, 16% had concordant FFT2 abnormalities, as did 16% with DIR, 5% with MTR and 9% with VBM. The greatest agreement in the localization of abnormalities was between FFT2 and DIR. Altogether, 31% patients had a focal abnormality with at least one contrast in the lobe of seizure onset. Signal changes outside the lobe of the putative focus were found with FFT2 in 36% patients, with DIR in 42%, with MTR in 6% and with VBM in 7%. DISCUSSION: Quantitative analysis of MRI contrasts had a low yield of identifying focal abnormalities concordant with putative epileptic foci in patients with unremarkable conventional MRI. Specificity was low for FFT2 and DIR. With the low specificity, data must be interpreted with caution, but in some patients may assist in creating a hypothesis for testing with intracranial electrodes.

Imaging the neocortex in epilepsy with double inversion recovery imaging.

The neocortices of 10 patients with partial seizures and acquired lesions, 14 patients with malformations of cortical development (MCD) and 33 patients with partial seizures and normal conventional MRI were quantitatively evaluated using whole brain double inversion recovery imaging (DIR) and Statistical Parametric Mapping (SPM). Compared to a group of 30 control subjects, DIR and objective voxel-by-voxel statistical comparison identified regions of significantly abnormal DIR signal intensity (DSI) in 9 out of 10 patients with acquired nonprogressive cerebral lesions and partial seizures. In all 9 patients, the areas of abnormal DSI concurred with abnormalities identified on visual inspection of conventional MRI. In all 14 patients with MCD, SPM detected regions of significantly abnormal DSI; all of which corresponded to abnormalities identified on visual inspection of conventional MRI. In addition, in both groups, there were areas that were normal on conventional imaging, which demonstrated abnormal DSI. Voxel-by-voxel statistical analysis identified significantly abnormal DSI in 15 of the 33 patients with cryptogenic focal epilepsy. In 10 of these, the areas of abnormal DSI concurred with epileptic EEG abnormality and clinical seizure semiology. Group analysis of MRI-negative patients with electroclinical seizure onset localising to the left temporal and left and right frontal regions revealed significantly abnormal DSI within the white matter of each respective lobe. DIR analysed using SPM was sensitive in patients with MCDs and acquired cerebral damage. Significant abnormalities in DSI in individual and grouped MRI-negative patients suggest that occult epileptogenic cerebral lesions are associated with subtle structural abnormalities. DIR is, therefore, a useful quantitative MRI technique for characterising epileptic foci and may contribute to presurgical evaluation.

Cardiac arrhythmias in focal epilepsy: a prospective long-term study.

BACKGROUND: Patients with epilepsy are at risk of sudden unexpected death. Neurogenic cardiac arrhythmias have been postulated as a cause. Electrocardiograms (ECG) can be monitored by use of an implantable loop recorder for up to 18 months. We aimed to determine the frequency of cardiac arrhythmias in patients with refractory focal seizures over an extended period. METHODS: 20 patients received an implantable loop recorder at one hospital in the UK. Devices were programmed to record automatically if bradycardia (<40 beats per min) or tachycardia (>140 beats per min) were detected. Additionally, in the event of a seizure, patients and relatives could initiate ECG recording with an external activator device. Data were analysed at regular intervals and correlated with seizure diaries. FINDINGS: More than 220000 patient-hours were monitored over 24 months, during which ECGs were captured on implantable loop recorders in 377 seizures. One patient withdrew from the study. In 16 patients, median heart rate during habitual seizures exceeded 100 beats per min. Ictal bradycardia (<40 beats per min) was rare, occurring in eight (2.1%) recorded events, in seven patients. Four patients (21%) had bradycardia or periods of asystole with subsequent permanent pacemaker insertion. Three of these four (16% of total) had potentially fatal asystole. INTERPRETATION: Clinical characteristics of patients with peri-ictal cardiac abnormalities are closely similar to those at greatest risk of sudden unexpected death in epilepsy. Asystole might underlie many of these deaths, which would have important implications for the investigation of similar patients and affect present cardiac-pacing policies.

Novel MR contrasts to reveal more about the brain.

Twenty percent of patients with refractory focal epilepsy have an undetermined etiologic basis for their epilepsy despite extensive investigation, including optimal MR imaging. Surgical treatment of this group is associated with a less favorable postoperative outcome. Even with improvements in imaging techniques, a proportion of these patients will remain "MR imaging-negative." It is likely, however, that some of the discrete macroscopic focal lesions that are currently occult will be identified by imaging techniques interrogating different microstructural characteristics. Furthermore, these methods may provide pathologic specificity when used in combination. The description and application of these techniques in epilepsy are the focus of this article.

Exploring white matter tracts in band heterotopia using diffusion tractography.

Band heterotopia is a malformation of cortical development characterized by bands of gray matter in the white matter parallel to the surface of the neocortex. Histopathological studies have suggested that small white matter tracts pass through the heterotopia, and functional magnetic resonance imaging studies have shown activation in the malformation. We used diffusion tractography to explore the anatomical connectivity of band heterotopia and, in particular, whether in vivo white matter tracts traverse the heterotopic gray matter. Five patients with band heterotopia and five control subjects were scanned with whole brain diffusion tensor imaging. Anisotropy maps were calculated. Using fast marching tractography, we produced maps of connectivity and tract traces from two seed points, in the splenium of the corpus callosum and the right parietal lobe. Eigenvectors were found to pass through the band heterotopia in an aligned fashion. Patterns for maps of connectivity were similar in patients and control subjects. Areas of high connectivity were found in the band heterotopia and in cortical areas on the far side of the malformation from the seed point. The tracts hence appeared to traverse or end within the band heterotopia. The results are in agreement with previous histopathological studies and indicate the structural basis of the functional connectivity and absence of focal deficits in these patients.

Diffusion tensor imaging in refractory epilepsy.

Diffusion tensor imaging is an imaging method that is sensitive to the molecular movement of water, which indicates cellular integrity and pathology. A patient with refractory epilepsy and normal conventional MRI was examined with diffusion tensor imaging. An area of abnormal diffusion in the right frontal lobe was identified and surgically resected. The patient had a good clinical outcome. Histopathological examination of the resected tissue showed gliosis. Our findings may affect the investigation of similar patients, and provide histopathological confirmation of diffusion abnormalities.