Mary Mantle

Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex

Background: The unambiguous identification of the epileptogenic tubers in individuals with tuberous sclerosis complex (TSC) can be challenging. We assessed whether magnetic source imaging (MSI) and coregistration of 18fluorodeoxyglucose PET (FDG-PET) with MRI could improve the identification of the epileptogenic regions noninvasively in children with TSC. Methods: In addition to standard presurgical evaluation, 28 children with intractable epilepsy from TSC referred from 2000 to 2007 had MSI and FDG-PET/MRI coregistration without extraoperative intracranial EEG. Results: Based on the concordance of test results, 18 patients with TSC (64%) underwent surgical resection, with the final resection zone confirmed by intraoperative electrocorticography. Twelve patients are seizure free postoperatively (67%), with an average follow-up of 4.1 years. Younger age at surgery and shorter seizure duration were associated with postoperative seizure freedom. Conversely, older age and longer seizure duration were linked with continued seizures postoperatively or prevented surgery because of nonlateralizing or bilateral independent epileptogenic zones. Complete removal of presurgery MSI dipole clusters correlated with postoperative seizure freedom. Conclusions: Magnetic source imaging and 18fluorodeoxyglucose PET/MRI coregistration noninvasively localized the epileptogenic zones in many children with intractable epilepsy from tuberous sclerosis complex (TSC), with 67% seizure free postoperatively. Seizure freedom after surgery correlated with younger age and shorter seizure duration. These findings support the concept that early epilepsy surgery is associated with seizure freedom in children with TSC and intractable epilepsy.

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.

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.

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

Seizures are more frequent in patients with Alzheimers 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.

Automated localization of magnetoencephalographic interictal spikes by adaptive spatial filtering.

OBJECTIVE Automated adaptive spatial filtering techniques can be applied to magnetoencephalographic (MEG) data collected from people with epilepsy. Source waveforms estimated by these methods have higher signal-to-noise ratio (SNR) than spontaneous MEG data, allowing identification and location of interictal spikes. The software tool SAM(g(2)) provides an adaptive spatial filtering algorithm for MEG data that yields source images of excess kurtosis and provides source time-courses in voxels exhibiting high excess kurtosis. The sensitivity and specificity of SAM(g(2)) in epilepsy is unknown. METHODS Interictal MEG data from 36 patients with intractable epilepsy were analyzed using SAM(g(2)), and results compared with equivalent current dipole (ECD) fit procedures. RESULTS When SNR of interictal spikes was high (compared to background) with a clear single focus, in most cases there was good agreement between ECD and SAM(g(2)). With multiple foci, there was typically overlap but imperfect concordance between results of ECD and SAM(g(2)). CONCLUSIONS SAM(g(2)) may in some cases be equivalent to manual ECD fit for localizing interictal spikes with single locus and good SNR. Further studies are required to validate SAM(g(2)) with multiple foci or poor SNR. SIGNIFICANCE In some cases, SAM(g(2)) might eventually assist or replace manual ECD analysis of MEG data.

Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epilepsy surgery

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.

Concordance Between Routine Interictal Magnetoencephalography and Simultaneous Scalp Electroencephalography in a Sample of Patients with Epilepsy

Summary: 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.

Effect of reference point on visual evoked potentials: clinical relevance

For clinical purposes the VEP is generally recorded from the mid-occipital region referenced to the vertex or mid-frontal region. This may lead to interpretive errors that can be avoided if a relatively inactive reference point, such as linked mastoids, is used simultaneously. The additional recording derivation may also be helpful in clarifying aberrant or ambiguous wave forms. The diagnostic yield from the two montages is similar, although the linked-mastoid reference provides a greater number of technically inadequate recordings due to smaller size of P100 and increased contamination by muscle artifact.

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.

Subclinical epileptiform activity in Alzheimer's disease

Background: Pro-inflammatory cytokines have been detected in brains of individuals with Alzheimer’s disease (AD) andmay play a significant role in the pathogenesis of AD. Our earlier reports investigated glial cell responses to LPS and A b, by upregulating the expression of cytokines TNFa, IL-1 b, and IL-6, as well as iNOS and COX-2. The present study was undertaken to investigate the therapeutic benefits of AICAR (a potent activator of AMP-activated protein kinase) in blocking the pro-oxidant/proinflammatory responses inmicroglia. Objectives: Ourmain objectives were a) to understand the activation aswell release of cytokines from activatedmicroglia in response to accumulated A b, and possible therapeutic benefits of AICAR. Methods: BV-2 microglia were used in these studies to understand LPS/ SMase/A b stimulated signaling mechanisms of NF k B pathway leading to the release of NO, ROS generation , release of inflammatory cytokine (TNFa, IL-1 b, IL-6) as well the scavenging macrophage like phagocytic functions of microglia.Results:AICAR inhibits LPS, and Smase activated cytokine release and NO production. AICAR also does promote A b phagocytosis. Further we observed a reduction in the stress signalingwith a significant lowering in p-ERK, p-p38, p-Akt (ser 473) as well as significant reduction of proteins such as p-NIK, p-IKK a/b and in p-p65 translocation. Conclusions: Microglia play an active role in triggering the immune cytokine responses in the neuro-inflammatory process ofAD. AICAR treatment effectively blocked cytokine release, A b phagocytosis by regulating NF k B pathways and perhaps is effective for therapeutics of AD.