Spike-microstates correlate with interictal epileptogenic discharges: a marker for hidden epileptic activity.

Objectively estimating disease severity and treatment success is a main problem in outpatient managing of epilepsy. Self-reported seizures diaries are well-known to underestimate the actual seizure count, and repeated EEGs might not show interictal epileptiform discharges (IEDs), although patients suffer from seizures. In this prospective study, we investigate the potential of microstate analysis to monitor epilepsy patients independently of their IED count. From our databank of candidates for epilepsy surgery, we included 18 patients who underwent controlled resting EEG sessions (with eyes closed, 30 min), at around the same time of the day, during at least four days (range: 4-8 days; mean: 5). Nine patients with temporal foci, six with extratemporal foci, and three with generalized epilepsy were included. Each patient's IEDs were marked and the topographic voltage maps of the IED peaks were averaged, and an individual average spike topography (AST) was created. The AST was then backfitted to each timepoint of the whole EEG resulting in the Spike-Microstate (SMS). The presence of the SMS in the residual EEG outside of the short IEDs epochs was determined for each recording session in each patient and correlated with the occurrence of the IEDs across all recording session, as well as with the drug charge of each day. Overall, SMS was much more represented in the routine EEG than the IEDs: they were identified 262 times more often than IEDs. The SMS time coverage correlated significantly with the IED occurrence rate (rho = 0.56; P < 0.001). If only patients with focal epilepsy were considered, this correlation was even higher rho = 0.69 (P < 0.001). Drug charge per day did not correlate with SMS. In this proof-of-concept study, the time coverage of SMS correlated strongly with the occurrence rate of the IEDs, they can be retrieved in the scalp EEG at a much higher occurrence rate. We conclude that SMS, once obtained for a given patient, are a more abundant marker of hidden epileptic activity than IEDs, in particular in focal epilepsy, and can be used also in absence of IEDs. Future larger studies are needed to verify its potential as monitoring tool and to determine cut-off values when drug protection becomes imperfect.

Early-onset leukoencephalomyelopathy due to a biallelic NDUFV1 variant in a mid-forties patient.

We present a patient who developed, after an early-onset, a stable course of spastic paraplegia and ataxia for 4 decades and eventually succumbed to two episodes of postinfectious lactic acidosis. Diagnostic workup including muscle biopsy and postmortem analysis, oxymetric analysis, spectrophotometric enzyme analysis, and MitoExome sequencing revealed a necrotizing leukoencephalomyelopathy due to the so far unreported biallelic variant of the NDUFV1 gene (p.(Pro122Leu)). This case extends our understanding of NDUFV1 variants with a 14-fold longer lifetime than so far reported cases, and will foster sensitivity toward respiratory chain disease also in adult patients with sudden deteriorating neurological deficits.

Automated long-term EEG analysis to localize the epileptogenic zone.

Objective: We investigated the performance of automatic spike detection and subsequent electroencephalogram (EEG) source imaging to localize the epileptogenic zone (EZ) from long-term EEG recorded during video-EEG monitoring. Methods: In 32 patients, spikes were automatically detected in the EEG and clustered according to their morphology. The two spike clusters with most single events in each patient were averaged and localized in the brain at the half-rising time and peak of the spike using EEG source imaging. On the basis of the distance from the sources to the resection and the known patient outcome after surgery, the performance of the automated EEG analysis to localize the EZ was quantified. Results: In 28 out of the 32 patients, the automatically detected spike clusters corresponded with the reported interictal findings. The median distance to the resection in patients with Engel class I outcome was 6.5 and 15 mm for spike cluster 1 and 27 and 26 mm for cluster 2, at the peak and the half-rising time of the spike, respectively. Spike occurrence (cluster 1 vs. cluster 2) and spike timing (peak vs. half-rising) significantly influenced the distance to the resection (p < 0.05). For patients with Engel class II, III, and IV outcomes, the median distance increased to 36 and 36 mm for cluster 1. Localizing spike cluster 1 at the peak resulted in a sensitivity of 70% and specificity of 100%, positive prediction value (PPV) of 100%, and negative predictive value (NPV) of 53%. Including the results of spike cluster 2 led to an increased sensitivity of 79% NPV of 55% and diagnostic OR of 11.4, while the specificity dropped to 75% and the PPV to 90%. Significance: We showed that automated analysis of long-term EEG recordings results in a high sensitivity and specificity to localize the epileptogenic focus.

Seizure Onset Zone Localization from Ictal High-Density EEG in Refractory Focal Epilepsy.

Epilepsy surgery is the most efficient treatment option for patients with refractory epilepsy. Before surgery, it is of utmost importance to accurately delineate the seizure onset zone (SOZ). Non-invasive EEG is the most used neuroimaging technique to diagnose epilepsy, but it is hard to localize the SOZ from EEG due to its low spatial resolution and because epilepsy is a network disease, with several brain regions becoming active during a seizure. In this work, we propose and validate an approach based on EEG source imaging (ESI) combined with functional connectivity analysis to overcome these problems. We considered both simulations and real data of patients. Ictal epochs of 204-channel EEG and subsets down to 32 channels were analyzed. ESI was done using realistic head models and LORETA was used as inverse technique. The connectivity pattern between the reconstructed sources was calculated, and the source with the highest number of outgoing connections was selected as SOZ. We compared this algorithm with a more straightforward approach, i.e. selecting the source with the highest power after ESI as the SOZ. We found that functional connectivity analysis estimated the SOZ consistently closer to the simulated EZ/RZ than localization based on maximal power. Performance, however, decreased when 128 electrodes or less were used, especially in the realistic data. The results show the added value of functional connectivity analysis for SOZ localization, when the EEG is obtained with a high-density setup. Next to this, the method can potentially be used as objective tool in clinical settings.

Modern management of seizures and epilepsy.

Complete seizure control is achieved in 40-50% of all epileptic patients with drug treatment, as reported in most epidemiological studies. Many effective antiepileptic drugs with a favourable profile are available in Switzerland, allowing treatment tailored to the patient's needs. Unfortunately, up to 40-50% of all patients will eventually relapse (pharmacoresistant epilepsy). These patients run a high risk of additional morbidity and mortality. Possible pharmacoresistant epilepsy should be considered early in the disease, when there is a lack of response to the first antiepileptic drug, since only 14% of those will respond to a second drug, and only 2% to a third drug if the second fails too. Epilepsy surgery is a viable option for these patients. It requires in-depth evaluation in specialized centres, and is related to complete seizure control in 50-90% of the patients, depending on the lesion type and site. Only for patients in whom surgery cannot be offered should neuromodulation treatments be considered. Today, two different approaches are approved, vagal nerve stimulation (VNS) and deep brain stimulation in the anterior thalamic nuclei (DBS-ANT). Although only a minority of patients become totally seizure-free. Both VNS and DBS-ANT represent an important adjunct in the therapeutic armamentarium. In the present review, we outline a practical approach for the different steps in therapeutic decisions and we summarise the profiles of modern antiepileptic drugs as well outcome of surgical and neuromodulatory therapies. The goal of any approach should be to obtain complete seizure control. In general, if two antiepileptic drugs are not successful, in-depth evaluation of the patient in a specialised center is strongly recommended.