Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

OBJECTIVE: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. METHODS: We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. RESULTS: Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). INTERPRETATION: Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.

Global and regional functional connectivity maps of neural oscillations in focal epilepsy.

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning.

Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epilepsy surgery.

OBJECTIVE: The efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the presurgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure outcomes or small sample size. METHODS: We performed a retrospective cohort study of patients with focal epilepsy who received MEG for interictal spike mapping followed by surgical resection at our institution. RESULTS: We studied 132 surgical patients, with mean postoperative follow-up of 3.6 years (minimum 1 year). Dipole source modeling was successful in 103 patients (78%), whereas no interictal spikes were seen in others. Among patients with successful dipole modeling, MEG findings were concordant with and specific to the following: (1) the region of resection in 66% of patients, (2) invasive electrocorticography (ECoG) findings in 67% of individuals, and (3) the magnetic resonance imaging (MRI) abnormality in 74% of cases. MEG showed discordant lateralization in ~5% of cases. After surgery, 70% of all patients achieved seizure freedom (Engel class I outcome). Whereas 85% of patients with concordant and specific MEG findings became seizure-free, this outcome was achieved by only 37% of individuals with MEG findings that were nonspecific to or discordant with the region of resection (χ(2) = 26.4, p < 0.001). MEG reliability was comparable in patients with or without localized scalp electroencephalography (EEG), and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (95% confidence interval [CI] 2.23-11.8). SIGNIFICANCE: MEG is a valuable tool for noninvasive interictal spike mapping in epilepsy surgery, including patients with nonlocalized findings receiving long-term EEG monitoring, and localization of the epileptogenic zone using MEG is associated with improved seizure outcomes.

Concordance between routine interictal magnetoencephalography and simultaneous scalp electroencephalography in a sample of patients with epilepsy.

Both electroencephalography (EEG) and magnetoencephalography (MEG) localize epileptiform activity but may yield different results. This discordance may arise from different detection capabilities or from different data collection and interpretation techniques. Comparisons of MEG and EEG have focused on detection of individual spikes. However, side-by-side comparisons of results as used in the clinical setting is lacking. In this report, we present our empirical comparison. We reviewed 58 simultaneous MEG-EEG recordings (35 paired-sensors, 23 whole-head) from a diverse epilepsy population, comparing previous clinical MEG interpretations with new blinded EEG interpretations, noting lobar concordance of readers' judgments of regional abnormalities. A second-pass unblinded analysis, using all available clinical data, assessed the relative contribution and plausibility of the results of each technique. Concordance was high (85%) overall. Discordance was sometimes caused by constraints imposed by MEG dipole fitting techniques. Even when results of the techniques did not match, MEG often disambiguated the clinical scenario, especially when combined with imaging information. Thoughtful analysis of combined MEG-EEG datasets, beyond algorithm-based interictal spike detection, can help guide clinical decision-making even when concordance between techniques is imperfect. In some cases, EEG and MEG are synergistic and provide complementary information.

The sensitivity and significance of lateralized interictal slow activity on magnetoencephalography in focal epilepsy.

OBJECTIVE: Asymmetric large-amplitude slow activity is sometimes observed on interictal electroencephalography (EEG) in epilepsy. However, few studies have examined slowing during magnetoencephalography (MEG) recordings, which are performed primarily to localize interictal spikes. Also, no prior investigations have compared the sensitivity of MEG to scalp EEG in detecting slow rhythms. METHODS: We performed a retrospective cohort study of focal epilepsy patients who received MEG followed by surgical resection at our institution. We examined MEG, simultaneous EEG, and long-term EEG recordings for prominent asymmetric slow activity (delta-range, 1-4 Hz), and evaluated post-operative seizure outcomes. RESULTS: We studied 132 patients with ≥ 1 year post-operative follow-up (mean, 3.6 years). Mean age was 27 (range, 3-68) years, and 55% of patients were male. Asymmetric large-amplitude slow wave activity was observed on interictal MEG in 21 of 132 (16%) patients. Interictal slowing lateralized to the hemisphere of resection in all but one (95%) patient. Among the 21 patients with interictal MEG slowing, 11 (52%) individuals had similarly lateralized EEG slowing, 7 patients had no EEG slowing, and 3 had bilateral symmetric EEG slowing. Meanwhile, none of the 111 patients without lateralized MEG slowing had asymmetric EEG slowing, suggesting significantly higher sensitivity of MEG versus EEG in detecting asymmetric slowing (χ(2)=63.4, p<0.001). MEG slowing was associated with shorter epilepsy duration with an odds ratio of 5.4 (1.7-17.0, 95% confidence interval). At last follow-up, 92 (70%) patients were seizure free (Engel I outcome), with no difference in seizure freedom rates between patients with (71%) or without (69%) asymmetric MEG slowing (χ(2)=0.4, p=0.99). SIGNIFICANCE: MEG has higher sensitivity than scalp EEG in detecting asymmetric slow activity in focal epilepsy, which reliably lateralizes to the epileptogenic hemisphere. Other uses of MEG beyond spike localization may further improve presurgical evaluations in epilepsy.

Consistency of interictal and ictal onset localization using magnetoencephalography in patients with partial epilepsy.

OBJECT: The aim of this study was to evaluate the spatial accuracy of interictal magnetoencephalography (MEG) in localizing the primary epileptogenic focus in comparison with alternative MEG-derived estimates such as ictal onset recording or sensory mapping of the periphery where seizures manifest. METHODS: During this retrospective study of 12 patients with epilepsy who had undergone successful magnetic source (MS) imaging with the aid of a dual 37-channel biomagnetometer as well as simultaneous MEG/electroencephalography (EEG) recordings, ictal events were observed in five patients and quantitative comparisons of interictal spike and ictal seizure onset source localizations were made. In the eight patients who had presented with sensorimotor seizure, source localization of cortical sites concordant with seizure foci was determined using somatosensory functional mapping, and the results were quantitatively compared with interictal spike source localizations. Interictal spike sources demonstrated on MEG localized to the same region as the corresponding ictal event or somatosensory source localizations. The mean distance between the ictal foci and interictal spike sources was 1.1 +/- 0.3 cm. Results of functional somatosensory mapping in patients with sensorimotor seizures demonstrated that seizure sources consistently colocalized with interictal MEG spike sources, with a mean distance of 1.5 +/- 0.4 cm. No systematic directional bias was observed. Interictal sources tended to be tightly clustered, and the mean ellipsoid volume, defined by one standard deviation of the source spatial coordinates, was 1 cm3. CONCLUSIONS: Interictal spike localizations on MEG were concordant with ictal and, where relevant, functional somatosensory mapping localizations. These findings support the interpretation of interictal spikes on MEG as a useful and effective noninvasive method for localizing primary seizure foci.

Interictal MEG/MSI in intractable mesial temporal lobe epilepsy: spike yield and characterization.

OBJECTIVE: To evaluate the ability of MEG to detect medial temporal spikes in patients with known medial temporal lobe epilepsy (MTLE) and to use magnetic source imaging (MSI) with equivalent current dipoles to examine localization and orientation of spikes and their relation to surgical outcome. METHODS: We prospectively obtained MSI on a total of 25 patients previously diagnosed with intractable MTLE. MEG was recorded with a 275 channel whole-head system with simultaneous 21-channel scalp EEG during inpatient admission one day prior to surgical resection. The patients' surgical outcomes were classified based on one-year follow-up after surgery. RESULTS: Nineteen of the 22 patients (86.4%) had interictal spikes during the EEG and MEG recordings. Thirteen of 19 patients (68.4%) demonstrated unilateral temporal dipoles ipsilateral to the site of surgery. Among these patients, five (38.5%) patients had horizontal dipoles, one (7.7%) patient had vertical dipoles, and seven (53.8%) patients had both horizontal and vertical dipoles. Sixty percent of patients with non-localizing ictal scalp EEG had well-localized spikes on MSI ipsilateral to the side of surgery and 66.7% of patients with non-localizing MRI had well-localized spikes on MSI ipsilateral to the side of surgery. Concordance between MSI localization and the side of lobectomy was not associated with a likelihood of an excellent postsurgical outcome. CONCLUSIONS: MSI can detect medial temporal spikes. It may provide important localizing information in patients with MTLE, especially when MRI and/or ictal scalp EEG are not localizing. SIGNIFICANCE: This study demonstrates that MSI has a good ability to detect interictal spikes from mesial temporal structures.

Magnetic source imaging for the surgical evaluation of electroencephalography-confirmed secondary bilateral synchrony in intractable epilepsy.

OBJECT: Routine scalp electroencephalography (EEG) cannot always distinguish whether generalized epileptiform discharges are the result of primary bilateral synchrony or secondary bilateral synchrony (SBS) from a focal origin; this is an important distinction because the latter may be amenable to resection. Whole-head magnetoencephalography (MEG) has superior spatial resolution compared with traditional EEG, and can potentially elucidate seizure foci in challenging epilepsy cases in which patients are undergoing evaluation for surgery. METHODS: Sixteen patients with medically intractable epilepsy in whom SBS was suspected were referred for magnetic source (MS) imaging. All patients had bilateral, synchronous, widespread, and most often generalized spike-wave discharges on scalp EEG studies, plus some other clinical (for example, seizure semiology) or MR imaging feature (for example, focal lesion) suggesting focal onset and hence possible surgical candidacy. The MS imaging modality is the combination of whole-head MEG and parametric reconstruction of corresponding electrical brain sources. An MEG and simultaneous EEG studies were recorded with a 275-channel whole-head system. Single-equivalent current dipoles were estimated from the MEG data, and dipole locations and orientations were superimposed on patients' MR images. RESULTS: The MS imaging studies revealed focal dipole clusters in 12 (75%) of the 16 patients, of which a single dipole cluster was identified in 7 patients (44%). Patient age, seizure type, duration of disease, video-EEG telemetry, and MR imaging results were analyzed to determine factors predictive of having clusters revealed on MS imaging. Of these factors, only focal MR imaging anatomical abnormalities were associated with dipole clusters (chi-square test, p = 0.03). Selective resections (including the dipole cluster) in 7 (87%) of 8 patients resulted in seizure-free or rare seizure outcomes (Engel Classes I and II). CONCLUSIONS: Magnetic source imaging may provide noninvasive anatomical and neurophysiological confirmation of localization in patients in whom there is a suspicion of SBS (based on clinical or MR imaging data), especially in those with an anatomical lesion. Identification of a focal seizure origin has significant implications for both resective and nonresective treatment of intractable epilepsy.

Fast oscillations associated with interictal spikes localize the epileptogenic zone in patients with partial epilepsy.

Although interictal epileptic spikes are defined as fast transient activity, the spatial distribution of spike-related high-frequency power changes is unknown. In this study, we localized the sources of spike-locked power increases in the beta and gamma band with magnetoencephalography and an adaptive spatial filtering technique and tested the usefulness of these reconstructions for determining the epileptogenic zone in a population of 27 consecutive presurgical patients with medication refractory partial epilepsies. The reliability of this approach was compared to the performance of conventional MEG techniques such as equivalent current dipole (ECD) models. In patients with good surgical outcome after a mean follow-up time of 16 months (Engel class I or II), the surgically resected area was identified with an accuracy of 85% by sources of spike-locked beta/gamma activity, which compared favorably with the accuracy of 69% found for ECD models of single spikes. In patients with a total of more than 50 spikes in their recordings, the accuracies increased to 100% vs. 88%, respectively. Imaging of spike-locked beta/gamma power changes therefore seems to be a reliable and fast alternative to conventional MEG techniques for localizing epileptogenic tissue, in particular, if more than 50 interictal spikes can be recorded.