Widespread EEG Changes Precede Focal Seizures

<div><p>The process by which the brain transitions into an epileptic seizure is unknown. In this study, we investigated whether the transition to seizure is associated with changes in brain dynamics detectable in the wideband EEG, and whether differences exist across underlying pathologies. Depth electrode ictal EEG recordings from 40 consecutive patients with pharmacoresistant lesional focal epilepsy were low-pass filtered at 500 Hz and sampled at 2,000 Hz. Predefined EEG sections were selected immediately before (immediate preictal), and 30 seconds before the earliest EEG sign suggestive of seizure activity (baseline). Spectral analysis, visual inspection and discrete wavelet transform were used to detect standard (delta, theta, alpha, beta and gamma) and high-frequency bands (ripples and fast ripples). At the group level, each EEG frequency band activity increased significantly from baseline to the immediate preictal section, mostly in a progressive manner and independently of any modification in the state of vigilance. Preictal increases in each frequency band activity were widespread, being observed in the seizure-onset zone and lesional tissue, as well as in remote regions. These changes occurred in all the investigated pathologies (mesial temporal atrophy/sclerosis, local/regional cortical atrophy, and malformations of cortical development), but were more pronounced in mesial temporal atrophy/sclerosis. Our findings indicate that a brain state change with distinctive features, in the form of unidirectional changes across the entire EEG bandwidth, occurs immediately prior to seizure onset. We postulate that these changes might reflect a facilitating state of the brain which enables a susceptible region to generate seizures.</p></div

Preictal changes in the activity of different frequency bands across four separate contact subsets in the three patient subgroups.

***<p>p<0.001; **p<0.01; *p≤0.05.</p>a<p>The preictal change in lesional/non-SOZ contacts was significantly different from that in non-lesional/non-SOZ contacts (Scheffe test; p = 0.05).</p>b<p>The preictal change in non-lesional/SOZ contacts was significantly different from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.01).</p>c<p>The preictal change in lesional/SOZ contacts was significantly different from that in non-lesional/SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; both p<0.001).</p>d<p>The preictal change in non-lesional/SOZ contacts was significantly different from that in lesional/SOZ contacts, from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.05, p<0.01 and p<0.05, respectively).</p>e<p>The preictal change in non-lesional/SOZ contacts was significantly different from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.05).</p>f<p>The preictal change in lesional/SOZ contacts was significantly different from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.05).</p>g<p>The preictal change in lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.01 and p<0.001, respectively).</p

Preictal changes in the activity of different frequency bands in the three separate patient subgroups.

<p>The groups were defined according to the underlying pathology: (A) mesial temporal atrophy/sclerosis (n = 15); (B) local/regional cortical atrophy (n = 10); and (C) malformations of cortical development (n = 18). ***p<0.001; **p<0.01; *p<0.05.</p

Definition of the “first EEG change suggestive of seizure activity”.

<p>This was the earliest potential ictal EEG sign, and could coincide with or precede the first unequivocal ictal EEG change. (A) Seizure recorded in a patient with a left centro-parietal porencephalic cyst, in which the sudden onset of polyspike/fast activity at LOP and LFO (arrow) was not preceded by any ictal-like EEG change. (B) Seizure recorded in a patient with right posterior quadrant periventricular nodular heterotopia, in which the first unequivocal ictal EEG change, a build-up of polyspikes at RP1-2 and 2-3 (arrow), was preceded 14 seconds earlier by the insidious appearance of polymorphic slowing with intermingled spikes at the same contacts (first EEG change suggestive of seizure activity, arrow). (C) Seizure recorded in a patient with left mesial temporal atrophy, in which the first unequivocal ictal EEG change, low-voltage fast activity at LP1-2 and 2-3 (arrow), was preceded 43 seconds earlier by the appearance of a run of repetitive sharp waves at the same contacts, which was not followed by a return to the usual EEG background (first EEG change suggestive of seizure activity, arrow). LOP = left frontal operculum; LFO = left orbito-frontal region; LAC =  left anterior cingulate gyrus; LO = left occipito-parietal region; RA = right amygdala; RH = right hippocampus; RP = heterotopic nodule in the right temporo-occipital quadrant; RS = heterotopic nodule in the right inferior parietal region; LA = left amygdala; LH = left hippocampus; LP = left posterior hippocampus.</p

Assessment of preictal EEG changes in a patient with left mesial temporal atrophy.

<p>(A) MRI images showing marked volume loss in the left hippocampal formation (coronal T1-weighted image), and the depth electrode implantation sites (amygdala and hippocampus on each side) aimed at ruling out the possibility of bilateral independent temporal lobe seizure foci (axial T1-weighted image). (B) Seizure in which the first unequivocal ictal EEG change, a build-up of medium-to-high amplitude polypsikes at LP1-2, 2-3 (arrow), was preceded 6 seconds earlier by an insidious increase in spiking activity at the same contacts (first EEG change suggestive of seizure activity, arrow). (C) Assessment of different EEG frequency bands at contacts RA3-4, which were located in the hemisphere contralateral to the seizure-onset zone. This was performed <i>at each section</i> and <i>over the entire period extending from one section to the other</i>: 1) identification of standard EEG frequency bands (delta, theta, alpha, beta and gamma) at each section using spectral analysis. Note the increase in spectral power across all bands from the baseline (blue line) to the immediate preictal section (red line). These increases in power, which were small in magnitude, were virtually undetectable by visual inspection of the raw EEG signal; 2) visual analysis of high-frequency oscillations at each section, after extension of the time scale and high-pass filtering at 80 Hz (ripples) and 250 Hz (fast ripples). The EEGs shown here correspond to the segment of the original EEG signal included in the black-framed box within each section. Note that, while no ripple was found in the baseline, occasional ripples were observed in the immediate preictal section (as indicated by the orange underscore). No fast ripple was found in either section; 3) assessment of the time course of EEG changes over the entire period extending from the beginning of the baseline to the end of the immediate preictal section using discrete wavelet transform. Preictal changes were not clearly visible on the time-frequency map. R = right; L = left; RA = right amygdala; RP = right posterior hippocampus; LA = left amygdala; LP = left posterior hippocampus; LFF = low-frequency filter; DWT = discrete wavelet transform.</p

Preictal changes in the activity of different frequency bands across four separate contact subsets in the entire patient sample.

<p>***p<0.001; **p<0.01; *p<0.05; (a) the preictal change in lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts (Scheffe test; p<0.05); (b) the preictal change in lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.001 and p<0.05, respectively). The preictal change in non-lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.001 and p<0.01, respectively); (c) the preictal change in lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.05 and p<0.01, respectively). The preictal change in non-lesional/SOZ contacts was significantly different from that in lesional/non-SOZ contacts, and from that in non-lesional/non-SOZ contacts (Scheffe test; p<0.01 and p<0.001, respectively).</p

Preictal increases in the activity of different frequency bands in the entire patient sample.

<p>***p<0.001; *p<0.05</p

Time course of changes in the activity of different frequency bands over the entire preictal period extending from the beginning of the baseline to the end of the immediate preictal section in the entire patient sample.

<p>The dashed line in each graph indicates the linear regression line. Note the significant linear increase over time in wavelet energy for three of the seven frequency bands (delta, theta and alpha).</p

Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.

Objective: To develop and validate a clinical prediction model for antiepileptic drug (AED)-resistant genetic generalized epilepsy (GGE). Method: We performed a case-control study of patients with and without drug-resistant GGE, nested within ongoing longitudinal observational studies of AED response at 2 tertiary epilepsy centers. Using a validation dataset, we tested the predictive performance of 3 candidate models, developed from a training dataset. We then tested the candidate models' predictive ability on an external testing dataset. Results: Of 5,189 patients in the ongoing longitudinal study, 121 met criteria for AED-resistant GGE and 468 met criteria for AED-responsive GGE. There were 66 patients with GGE in the external dataset, of whom 17 were cases. Catamenial epilepsy, history of a psychiatric condition, and seizure types were strongly related with drug-resistant GGE case status. Compared to women without catamenial epilepsy, women with catamenial epilepsy had about a fourfold increased risk for AED resistance. The calibration of 3 models, assessing the agreement between observed outcomes and predictions, was adequate. Discriminative ability, as measured with area under the receiver operating characteristic curve (AUC), ranged from 0.58 to 0.65. Conclusion: Catamenial epilepsy, history of a psychiatric condition, and the seizure type combination of generalized tonic clonic, myoclonic, and absence seizures are negative prognostic factors of drug-resistant GGE. The AUC of 0.6 is not consistent with truly effective separation of the groups, suggesting other unmeasured variables may need to be considered in future studies to improve predictability.</p

Rare genetic variation and outcome of surgery for mesial temporal lobe epilepsy

Objective: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. Methods: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Results: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. Interpretation: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.</p