Transcranial electrical stimulation during functional magnetic resonance imaging in patients with genetic generalized epilepsy: a pilot and feasibility study.

Objective: A third of patients with epilepsy continue to have seizures despite receiving adequate antiseizure medication. Transcranial direct current stimulation (tDCS) might be a viable adjunct treatment option, having been shown to reduce epileptic seizures in patients with focal epilepsy. Evidence for the use of tDCS in genetic generalized epilepsy (GGE) is scarce. We aimed to establish the feasibility of applying tDCS during fMRI in patients with GGE to study the acute neuromodulatory effects of tDCS, particularly on sensorimotor network activity. Methods: Seven healthy controls and three patients with GGE received tDCS with simultaneous fMRI acquisition while watching a movie. Three tDCS conditions were applied: anodal, cathodal and sham. Periods of 60 s without stimulation were applied between each stimulation condition. Changes in sensorimotor cortex connectivity were evaluated by calculating the mean degree centrality across eight nodes of the sensorimotor cortex defined by the Automated Anatomical Labeling atlas (primary motor cortex (precentral left and right), supplementary motor area (left and right), mid-cingulum (left and right), postcentral gyrus (left and right)), across each of the conditions, for each participant. Results: Simultaneous tDCS-fMRI was well tolerated in both healthy controls and patients without adverse effects. Anodal and cathodal stimulation reduced mean degree centrality of the sensorimotor network (Friedman's ANOVA with Dunn's multiple comparisons test; adjusted p = 0.02 and p = 0.03 respectively). Mean degree connectivity of the sensorimotor network during the sham condition was not different to the rest condition (adjusted p = 0.94). Conclusion: Applying tDCS during fMRI was shown to be feasible and safe in a small group of patients with GGE. Anodal and cathodal stimulation caused a significant reduction in network connectivity of the sensorimotor cortex across participants. This initial research supports the feasibility of using fMRI to guide and understand network modulation by tDCS that might facilitate its clinical application in GGE in the future.

Automatic and manual segmentation of the piriform cortex: Method development and validation in patients with temporal lobe epilepsy and Alzheimer's disease.

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm3 on the right and 461 mm3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3 in healthy controls, ~0.40/ ~28 mm3 in patients with TLE, and ~ 0.34/~29 mm3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale.

Camera-based Prospective Motion Correction in Paediatric Epilepsy Patients Enables EEG-fMRI Localization Even in High-motion States.

BACKGROUND: EEG-fMRI is a useful additional test to localize the epileptogenic zone (EZ) particularly in MRI negative cases. However subject motion presents a particular challenge owing to its large effects on both MRI and EEG signal. Traditionally it is assumed that prospective motion correction (PMC) of fMRI precludes EEG artifact correction. METHODS: Children undergoing presurgical assessment at Great Ormond Street Hospital were included into the study. PMC of fMRI was done using a commercial system with a Moiré Phase Tracking marker and MR-compatible camera. For retrospective EEG correction both a standard and a motion educated EEG artefact correction (REEGMAS) were compared to each other. RESULTS: Ten children underwent simultaneous EEG-fMRI. Overall head movement was high (mean RMS velocity < 1.5 mm/s) and showed high inter- and intra-individual variability. Comparing motion measured by the PMC camera and the (uncorrected residual) motion detected by realignment of fMRI images, there was a five-fold reduction in motion from its prospective correction. Retrospective EEG correction using both standard approaches and REEGMAS allowed the visualization and identification of physiological noise and epileptiform discharges. Seven of 10 children had significant maps, which were concordant with the clinical EZ hypothesis in 6 of these 7. CONCLUSION: To our knowledge this is the first application of camera-based PMC for MRI in a pediatric clinical setting. Despite large amount of movement PMC in combination with retrospective EEG correction recovered data and obtained clinically meaningful results during high levels of subject motion. Practical limitations may currently limit the widespread use of this technology.

Predictors and reasons for epilepsy patients to decline surgery: a prospective study.

BACKGROUND: In patients with drug-resistant focal epilepsy, resective surgery is the most successful treatment option to achieve seizure freedom. However, a surprisingly high rate of patients declines their physicians' recommendation to undergo removal of the seizure focus or-if necessary-further video-EEG monitoring (VEM). METHODS: In this prospective study, consecutive patients in presurgical assessment with at least one scalp VEM between 2016 and 2018 were included. We assessed both epilepsy-related and psychosocial variables as well as decision-making of physicians and patients, including reasons for decline in the latter. RESULTS: Out of 116 patients with a total of 165 VEM, 20 patients were eventually found to be ineligible for resection, 51 declined, and 45 agreed on recommendations for resection or further VEM diagnostics. Patients most frequently declined due to general fear of brain surgery (n = 30, 59%) and currently lower seizure frequency (n = 11, 22%). An independent predictor of patients' decline was less epilepsy-related fear (OR 0.43; p = 0.02) assessed in a standardised questionnaire. CONCLUSION: Half of the patients potentially eligible for resective surgery decline the operation or further VEM procedures. Patients who decline are more fearful of brain surgery than of ongoing disabling seizures. More insight is needed to improve counselling of patients.

Utility of 18F-fluorodeoxyglucose positron emission tomography in presurgical evaluation of patients with epilepsy: A multicenter study.

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant. METHODS: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible. RESULTS: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28). SIGNIFICANCE: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics.

[Imaging in the presurgical evaluation of epilepsy]. / Bildgebung in der prächirurgischen Epilepsiediagnostik.

While two thirds of patients with epilepsy become seizure-free with antiseizure medications, 30% remain drug-resistant. In drug-resistant focal epilepsy, epilepsy surgery offers an approximately 65% chance of becoming seizure-free; however, for a successful outcome of surgery a seizure focus must be precisely located, for which imaging techniques are essential. In recent years, the proportion of patients with apparently inconspicuous findings in magnetic resonance imaging (MRI) in the presurgical evaluation has increased. The sensitivity of MRI can be increased using special MRI sequences and MRI postprocessing techniques. Ictal and interictal source localization based on electroencephalography (EEG) and magnetencephalography (MEG) aim at determining the onset of interictal discharges and seizures. Nuclear medicine imaging techniques such as interictal positron emission tomography (PET) and ictal single photon emission computed tomography (SPECT) can detect chronic or acute seizure-related changes in brain metabolism and can indicate an epileptogenic focus even if MRI is inconspicuous. The results of these techniques are used to plan invasive EEG recordings and subsequently surgery. Concordant findings are associated with better surgical outcomes and show significantly higher rates of seizure freedom in the long-term seizure outcome.

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

BACKGROUND: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. DESIGN: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. RESULTS: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. CONCLUSION: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

Prediction of seizure freedom after epilepsy surgery - Critical reappraisal of significance of intracranial EEG parameters.

OBJECTIVE: To analyze the significance of intracranial electroencephalography (iEEG) parameters such as seizure onset patterns (SOP) and size of seizure onset zone (SOZ) with respect to prediction of seizure freedom after resective epilepsy surgery. METHODS: All patients who underwent iEEG with subdural electrodes between January 2006 and December 2015 in our epilepsy-center were included. Various iEEG parameters were retrospectively analyzed regarding their predictive value to post-operative seizure freedom. Furthermore, associations of specific SOPs with underlying histopathology and brain regions of the SOZ were examined. RESULTS: Eighty-one patients (34 female) with 324 seizures were assessed. Low-voltage fast activity (37%) and sharp activity <13 Hz (30%) were the most frequent SOPs. Focal SOZ (≤2 cm) was the only iEEG parameter independently associated with 1-year post-operative seizure freedom (OR 4.1, 95% CI 1.433-11.679). While no SOP was linked to specific histopathologies, some associations between SOPs and anatomical regions of SOZ were found. CONCLUSIONS: A circumscribed SOZ, but no specific SOP was predictive for seizure freedom after epilepsy surgery. SIGNIFICANCE: Intracranial EEG may be helpful to predict post-operative seizure freedom. Multicenter studies with larger numbers of patients are required to reliably assess the significance of specific SOPs for successful resective epilepsy surgery.

Referral to evaluation for epilepsy surgery: Reluctance by epileptologists and patients.

OBJECTIVE: Despite the obvious advantages of resective surgery in patients with drug-resistant focal epilepsy, namely high probability of seizure freedom, decreased mortality, and increased quality of life, referral rates from physicians and approval rates by patients for presurgical assessment remain constantly low. METHODS: In the outpatient clinics of a tertiary epilepsy center, checklists were implemented asking treating epileptologists whether they recommended presurgical evaluation with noninvasive video-electroencephalographic monitoring to adult patients with drug-resistant focal epilepsy and asking respective patients whether they followed this recommendation. RESULTS: Of 185 eligible patients, 80 (43%) were recommended presurgical evaluation by their epileptologists, and 24 (30%) of these patients consented. Nineteen of all patients (10%) actually underwent noninvasive presurgical assessment, and nine of these eventually proceeded to resection. The most frequent reason for nonreferral by epileptologists was their subjective appraisal of seizure frequency as low (31%), whereas patients declined most often due to overall fear of brain surgery (50%). Variables independently associated with nonreferral by epileptologists comprised older age of patients at questioning (odds ratio [OR] = 1.03), no previous evaluation for epilepsy surgery (OR = 4.04), the presence of legal guardianship (OR = 4.29), and ≥11 years of professional experience by the treating epileptologist (OR = 4.62). Independent predictors for patients' rejection of presurgical evaluation were older age at questioning (OR = 1.08), lifetime number of antiepileptic drugs ≥ 5 (OR = 4.47), presence of focal aware seizures (OR = 4.37), and absence of focal seizures with impaired awareness (OR = 11.24). SIGNIFICANCE: In both epileptologists and patients with difficult-to-treat epilepsy, we found high decision rates against presurgical assessment. Some reasons given by physicians for not recommending presurgical evaluation to patients may be understandable; others need further exploration. On the patients' side, early and thorough counseling on risks and benefits of epilepsy surgery is necessary to increase understanding and acceptance.

Hypothermia did not prevent epilepsy following experimental status epilepticus.

In epilepsy research, one of the major challenges is to prevent or at least mitigate development of epilepsy following acquired brain insult by early therapeutic interventions. So far, all pharmacological antiepileptogenic treatment approaches were largely unsuccessful in clinical trials and in experimental animal studies. In a well-established rat model of chronic epilepsy following self-sustaining status epilepticus (SSSE), we assessed the antiepileptogenic properties of 3-h-cooling induced directly after the end of SSSE. Occurrence of spontaneous seizures and seizure severity up to 8 weeks after SSSE were compared with normothermic SSSE controls. Furthermore, electrophysiological parameters assessing inhibition and excitation in the dentate gyrus were assessed at multiple time points. Post SSSE hypothermia did not prevent the occurrence of seizures in any animal. Eight weeks after SSSE, Racine motor seizures trended to be less severe following cooling (4.0±0.6) compared with normothermic controls (4.8±0.2) but the difference was not significant when testing for multiple comparisons. Early loss of inhibition that is typically seen following SSSE was somewhat attenuated in cooled animals 3h after SSSE as expressed by smaller paired-pulse ratios (PPR; 0.16±0.21) compared with normothermic controls (0.54±0.21) but difference was not significant either. Latency between stimulus artefact and excitatory post-synaptic potential 3h after SSSE, reciprocally reflecting neuronal excitation, was higher in animals that underwent hypothermia (8.29±2.45 ms) compared with controls (4.82±0.66 ms), difference was not significant after correction for multiple comparisons. In summary, the current experiments were not able to demonstrate prevention or mitigation of epileptogenesis with immediate short-term cooling following SSSE.