Transcranial magnetic stimulation-evoked electroencephalography responses as biomarkers for epilepsy: A review of study design and outcomes.

Transcranial magnetic stimulation (TMS) with electroencephalography (EEG), that is TMS-EEG, may assist in managing epilepsy. We systematically reviewed the quality of reporting and findings in TMS-EEG studies on people with epilepsy and healthy controls, and on healthy individuals taking anti-seizure medication. We searched the Cochrane Library, Embase, PubMed and Web of Science databases for original TMS-EEG studies comparing people with epilepsy and healthy controls, and healthy subjects before and after taking anti-seizure medication. Studies should involve quantitative analyses of TMS-evoked EEG responses. We evaluated the reporting of study population characteristics and TMS-EEG protocols (TMS sessions and equipment, TMS trials and EEG protocol), assessed the variation between protocols, and recorded the main TMS-EEG findings. We identified 20 articles reporting 14 unique study populations and TMS methodologies. The median reporting rate for the group of people with epilepsy parameters was 3.5/7 studies and for the TMS parameters was 13/14 studies. TMS protocols varied between studies. Fifteen out of 28 anti-seizure medication trials in total were evaluated with time-domain analyses of single-pulse TMS-EEG data. Anti-seizure medication significantly increased N45, and decreased N100 and P180 component amplitudes but in marginal numbers (N45: 8/15, N100: 7/15, P180: 6/15). Eight articles compared people with epilepsy and controls using different analyses, thus limiting comparability. The reporting quality and methodological uniformity between studies evaluating TMS-EEG as an epilepsy biomarker is poor. The inconsistent findings question the validity of TMS-EEG as an epilepsy biomarker. To demonstrate TMS-EEG clinical applicability, methodology and reporting standards are required.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Changes in motor nerve excitability in acute phase Guillain-Barré syndrome.

BACKGROUND: The most common subtypes of Guillain-Barré syndrome (GBS) are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). In the first days after the onset of weakness, standard nerve conduction studies (NCS) may not distinguish GBS subtypes. Reduced nerve excitability may be an early symptom of nerve dysfunction, which can be determined with the compound muscle action potential (CMAP) scan. The aim of this study was to explore whether early changes in motor nerve excitability in GBS patients are related to various subtypes. METHODS: Prospective case-control study in 19 GBS patients from The Netherlands and 22 from Bangladesh. CMAP scans were performed within 2 days of hospital admission and NCS 7-14 days after onset of weakness. CMAP scans were also performed in age- and country-matched controls. RESULTS: CMAP scan patterns of patients who were classified as AMAN were distinctly different compared to the CMAP scan patterns of the patients who were classified as AIDP. The most pronounced differences were found in the stimulus intensity parameters. CONCLUSIONS: CMAP scans made at hospital admission demonstrate several characteristics that can be used as an early indicator of GBS subtype.

Absence epilepsy: Characteristics, pathophysiology, attention impairments, and the related risk of accidents. A narrative review.

OBJECTIVE: Absence epilepsy (AE) is related to both cognitive and physical impairments. In this narrative review, we critically discuss the pathophysiology of AE and the impairment of attention in children and adolescents with AE. In particular, we contextualize the attentive dysfunctions of AE with the associated risks, such as accidental injuries. DATA SOURCE: An extensive literature search on attention deficits and the rate of accidental injuries in AE was run. The search was conducted on Scopus, Pubmed, and the online libraries of the University of Twente and Maastricht University. Relevant references of the included articles were added. Retrospective and prospective studies, case reports, meta-analysis, and narrative reviews were included. Only studies written in English were considered. Date of last search is February 2020. The keywords used were "absence epilepsy" AND "attention"/"awareness", "absence epilepsy" AND "accidental injuries"/"accident*"/"injuries". RESULTS: Ten retrospective and two prospective studies on cognition and AE were fully screened. Seventeen papers explicitly referring to attention in AE were reviewed. Just one paper was found to specifically focus on accidental injuries and AE, while twelve studies generally referring to epilepsy syndromes - among which AE - and related accidents were included. CONCLUSION: Absence epilepsy and attention deficits show some patterns of pathophysiological association. This relation may account for dysfunctions in everyday activities in the pediatric population. Particular metrics, such as the risk related to biking in children with AE, should be used in future studies to address the problem in a novel way and to impact clinical indications.

Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study.

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

BACKGROUND: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker. OBJECTIVE: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura. METHODS: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing. RESULTS: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls. CONCLUSION: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.

Automated video-based detection of nocturnal convulsive seizures in a residential care setting.

People with epilepsy need assistance and are at risk of sudden death when having convulsive seizures (CS). Automated real-time seizure detection systems can help alert caregivers, but wearable sensors are not always tolerated. We determined algorithm settings and investigated detection performance of a video algorithm to detect CS in a residential care setting. The algorithm calculates power in the 2-6 Hz range relative to 0.5-12.5 Hz range in group velocity signals derived from video-sequence optical flow. A detection threshold was found using a training set consisting of video-electroencephalogaphy (EEG) recordings of 72 CS. A test set consisting of 24 full nights of 12 new subjects in residential care and additional recordings of 50 CS selected randomly was used to estimate performance. All data were analyzed retrospectively. The start and end of CS (generalized clonic and tonic-clonic seizures) and other seizures considered desirable to detect (long generalized tonic, hyperkinetic, and other major seizures) were annotated. The detection threshold was set to the value that obtained 97% sensitivity in the training set. Sensitivity, latency, and false detection rate (FDR) per night were calculated in the test set. A seizure was detected when the algorithm output exceeded the threshold continuously for 2 seconds. With the detection threshold determined in the training set, all CS were detected in the test set (100% sensitivity). Latency was ≤10 seconds in 78% of detections. Three/five hyperkinetic and 6/9 other major seizures were detected. Median FDR was 0.78 per night and no false detections occurred in 9/24 nights. Our algorithm could improve safety unobtrusively by automated real-time detection of CS in video registrations, with an acceptable latency and FDR. The algorithm can also detect some other motor seizures requiring assistance.

Dynamics of convulsive seizure termination and postictal generalized EEG suppression.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Caffeine and seizures: A systematic review and quantitative analysis.

PURPOSE: Caffeine is the most commonly used central nervous system (CNS) stimulant. The relationship between caffeine, seizures, epilepsy, and antiepileptic drugs (AEDs) is complex and not fully understood. Case reports suggest that caffeine triggers seizures in susceptible people. Our systematic review reports on the relationship between caffeine, seizures, and drugs in animal and human studies. Quantitative analyses were also done on animal studies regarding the effects of caffeine on AEDs. METHODS: PubMed was searched for studies assessing the effects of caffeine on seizure susceptibility, epilepsy, and drug interactions in people and in animal models. To quantify the interaction between AEDs and caffeine, the data of six animal studies were pooled and analyzed using a general linear model univariate analysis or One-way Analysis of Variance (ANOVA). RESULTS: In total, 442 items were identified from which we included 105 studies. Caffeine can increase seizure susceptibility and protect from seizures, depending on the dose, administration type (chronic or acute), and the developmental stage at which caffeine exposure started. In animal studies, caffeine decreased the antiepileptic potency of some drugs; this effect was strongest in topiramate. CONCLUSION: Preclinical studies suggest that caffeine increases seizure susceptibility. In some cases, chronic use of caffeine may protect against seizures. Caffeine lowers the efficacy of several drugs, especially topiramate. It is unclear how these findings in models can be translated to the clinical condition. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy.

Cortisol fluctuations relate to interictal epileptiform discharges in stress sensitive epilepsy.

People with epilepsy often report seizures precipitated by stress. This is believed to be due to effects of stress hormones, such as cortisol, on neuronal excitability. Cortisol, regardless of stress, is released in hourly pulses, whose effect on epileptic activity is unknown. We tested the relation between cortisol levels and the incidence of epileptiform abnormalities in the electroencephalogram of people with focal epilepsy. Morning cortisol levels were measured in saliva samples obtained every 15 min. Interictal epileptiform discharges were determined in the same time periods. We investigated the relationship between cortisol levels and the epileptiform discharges distinguishing persons with from those without stress-precipitated seizures (linear mixed model), and analysed the contribution of individual, epilepsy and recording characteristics with multivariable analysis. Twenty-nine recordings were performed in 21 individuals. Cortisol was positively related to incidence of epileptiform discharges (ß = 0.26, P = 0.002) in people reporting stress-sensitive seizures, but not those who did not report stress sensitivity (ß = -0.07, P = 0.64). The relationship between cortisol and epileptiform discharges was positively associated only with stress sensitivity of seizures (ß = 0.31, P = 0.005). The relationship between cortisol levels and incidence of interictal epileptiform discharges in people with stress-sensitive seizures suggests that stress hormones influence disease activity in epilepsy, also under basal conditions.