Evelien Carrette

Functional brain connectivity from EEG in epilepsy: Seizure prediction and epileptogenic focus localization

Today, neuroimaging techniques are frequently used to investigate the integration of functionally specialized brain regions in a network. Functional connectivity, which quantifies the statistical dependencies among the dynamics of simultaneously recorded signals, allows to infer the dynamical interactions of segregated brain regions. In this review we discuss how the functional connectivity patterns obtained from intracranial and scalp electroencephalographic (EEG) recordings reveal information about the dynamics of the epileptic brain and can be used to predict upcoming seizures and to localize the seizure onset zone. The added value of extracting information that is not visibly identifiable in the EEG data using functional connectivity analysis is stressed. Despite the fact that many studies have showed promising results, we must conclude that functional connectivity analysis has not made its way into clinical practice yet.

The cognitive effects of amygdalohippocampal deep brain stimulation in patients with temporal lobe epilepsy

The aim of this study was to examine the effects of amygdalohippocampal deep brain stimulation (AH-DBS) on cognitive functioning in patients with refractory temporal lobe epilepsy. The population consisted of 10 patients (7 men) who underwent ipsilateral (n=8) or bilateral (n=2) AH-DBS. Intellectual and neuropsychological evaluation was performed before and 6 months after initiation of AH-DBS. Group analyses revealed no overall pattern of change in cognitive measures, but improvement was seen in emotional well-being. Individual results varied over a broad spectrum ranging from no cognitive effects to negative effects on intelligence capacities, divided attention, and concept formation, to positive effects on speed of information processing and speed of finger movements. AH-DBS is a valuable treatment alternative for patients with refractory epilepsy that appears to have no major adverse neuropsychological consequences and enhances emotional well-being on the group level. Individual results are too diverse at this moment to allow viable interpretation. Additional studies are needed to confirm these preliminary results.

The P3 Event-Related Potential is a Biomarker for the Efficacy of Vagus Nerve Stimulation in Patients with Epilepsy

Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient’s response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18xa0months. Patients were divided into 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50xa0%) and 10 nonresponders (≤50xa0%). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.

The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus

It has been shown that vagus nerve stimulation (VNS) has an antidepressant-like effect in the forced swim test. The mechanism of action underlying this effect is incompletely understood, but there is evidence suggesting that the locus coeruleus (LC) may play an important role. In this study, noradrenergic LC neurons were selectively lesioned to test their involvement in the antidepressant-like effect of VNS in the forced swim test. Forced swim test behavior was assessed in rats that were subjected to VNS or sham treatment. In half of the VNS-treated animals, the noradrenergic neurons from the LC were lesioned using the selective neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride], yielding three experimental arms: sham, VNS and DSP-4-VNS (n = 8 per group). Furthermore, the open field test was performed to evaluate locomotor activity. A dopamine-β-hydroxylase immunostaining was performed to confirm lesioning of noradrenergic LC neurons. VNS significantly reduced the percentage of immobility time in the forced swim test compared to sham treatment (median: 56%, interquartile range: 41% vs. median: 75%, interquartile range: 12%). This antidepressant-like effect of VNS could not be demonstrated in the DSP-4-VNS group (median: 79%, interquartile range: 33%). Locomotor activity in the open field test was not different between the three treatment arms. The absence of hippocampal dopamine-β-hydroxylase immunostaining in the DSP-4-treated rats confirmed the lesioning of noradrenergic neurons originating from the brainstem LC. The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS.

The systemic kainic acid rat model of temporal lobe epilepsy: Long-term EEG monitoring

Animal models reproducing the characteristics of human epilepsy are essential for the elucidation of the pathophysiological mechanisms. In epilepsy research there is ongoing debate on whether the epileptogenic process is a continuous process rather than a step function. The aim of this study was to assess progression of epileptogenesis over the long term and to evaluate possible correlations between SE duration and severity with the disease progression in the kainic acid model. Rats received repeated KA injections (5mg/kg) until a self-sustained SE was elicited. Continuous depth EEG recording started before KA injection and continued for 30 weeks. Mean seizure rate progression could be expressed as a sigmoid function and increased from 1 ± 0.2 seizures per day during the second week after SE to 24.4 ± 6.4 seizures per day during week 30. Seizure rate progressed to a plateau phase 122 ± 9 days after SE. However, the individual seizure rate during this plateau phase varied between 14.5 seizures and 48.6 seizures per day. A circadian rhythm in seizure occurrence was observed in all rats. Histological characterization of damage to the dentate gyrus in the KA treated rats confirmed the presence of astrogliosis and aberrant mossy fiber sprouting in the dentate gyrus. This long-term EEG monitoring study confirms that epileptogenesis is a continuous process rather than a step function.

Vagus Nerve Stimulation Applied with a Rapid Cycle Has More Profound Influence on Hippocampal Electrophysiology Than a Standard Cycle

Although vagus nerve stimulation (VNS) is widely used, therapeutic mechanisms and optimal stimulation parameters remain elusive. In the present study, we investigated the effect of VNS on hippocampal field activity and compared the efficiency of different VNS paradigms. Hippocampal electroencephalography (EEG) and perforant path dentate field-evoked potentials were acquired before and during VNS in freely moving rats, using 2 VNS duty cycles: a rapid cycle (7xa0s on, 18xa0s off) and standard cycle (30xa0s on, 300xa0s off) and various output currents. VNS modulated the evoked potentials, reduced total power of the hippocampal EEG, and slowed the theta rhythm. In the hippocampal EEG, theta (4–8xa0Hz) and high gamma (75–150xa0Hz) activity displayed strong phase amplitude coupling that was reduced by VNS. Rapid-cycle VNS had a greater effect than standard-cycle VNS on all outcome measures. Using rapid cycle VNS, a maximal effect on EEG parameters was found at 300xa0μA, beyond which effects saturated. The findings suggest that rapid-cycle VNS produces a more robust outcome than standard cycle VNS and support already existing preclinical evidence that relatively low output currents are sufficient to produce changes in brain physiology and thus likely also therapeutic efficacy.

Epileptogenic focus localization through connectivity analysis of the intracranial EEG: A retrospective study in 2 patients

Some patients with refractory epilepsy can benefit from surgical removal of the brain region responsible for causing the epileptic seizures, i.e. the epileptogenic focus. In several cases the patient is admitted for Invasive Video Electroencephalography Monitoring (IVEM) to delineate the ictal onset zone based on intracranial electroencephalographic (IEEG) signals. However, in clinical practice this delineation is based on a visual identification strategy out of the IEEG signals. The purpose of this study is to identify the epileptogenic focus based on the concept of functional brain connectivity. The full frequency Adapted Directed Transfer Function (ffADTF) values were calculated for each seizure of the 2 investigated patients. The mean out-degree, i.e. the sum of outgoing connections, over all seizures for each patient was calculated out of the ffADTF-values. The epileptogenic focus was identified based on the mean out-degree. The localization of the hypothesized epileptogenic focus in the 2 patients was concordant with post-operative findings. We showed that connectivity patterns derived out of the ffADTF analysis can provide useful information about seizure propagation and may improve the accuracy of the presurgical evaluation in patients affected by refractory epilepsy.

Accelerated Cognitive Ageing in Epilepsy: A Neuropsychological Evaluation of Cognitive Deterioration

OBJECTIVEnShed light on cognitive deterioration in Accelerated Cognitive Ageing (ACA) in epilepsy from a neuropsychological point of view in order to improve clinical diagnostics.nnnMETHODSnWe compared the IQ-profile including GAI, OPIE IV-premorbid IQ and deterioration-scores of 21 epilepsy patients with ACA with 21 matched epilepsy patients without ACA (Epilepsy Controls) and 16 age- and education-matched Healthy Controls. Memory was also evaluated.nnnRESULTSnPremorbid IQs were equal in all groups. Deterioration was apparent in the ACA-group in the WAIS-IV FSIQ and PRI, whereas no deterioration was found in the two control groups. PSI was impaired in both epilepsy groups, though with more impairment seen in the ACA-group. The VCI remained unimpaired. The FSIQ-GAI discrepancy was equal in both patient groups and significantly larger than in the Healthy Controls. WMS-IV memory indices were of average level in all groups. Memory impairment in ACA was not statistically different from the Epilepsy Controls. 85.7% of ACA-patients could be correctly classified through factors DET_FSIQ and PSI.nnnCONCLUSIONSnCognitive deterioration in ACA is characterized by an average drop of 19 IQ-points in FSIQ and PRI. Verbal abilities remain unimpaired. Impairments in fluid functions compromise cognitive abilities in epilepsy, but only partially contribute to cognitive deterioration in ACA. PSI proved to have some diagnostic value in differentiating epilepsy patients from healthy controls, but fails to differentiate between ACA and Epilepsy Controls. A comparison made between OPIE-IV equations and obtained IQs leads to a significant better detection of cognitive deterioration in epilepsy than the use of GAI-FSIQ discrepancies alone.

P061 Continuous thetaburst stimulation for the treatment of refractory epilepsy – Case report

Introduction Thetaburst stimulation (TBS) is a repetitive transcranial magnetic stimulation (rTMS) protocol that may induce long lasting neuroplasticity. Continuous TBS (cTBS), a cortical excitability reducing protocol, would be the stimulation protocol of choice for the treatment of epilepsy. The lower stimulation intensity and number of pulses compared to conventional rTMS may imply superiority with regards to safety, tolerability and applicability in the clinic. Methods Two patients with refractory focal epilepsy due to a low-grade tumor in the rolandic area were treated with cTBS and followed-up for effect on seizure frequency and adverse effects. The stimulation protocol consisted of 5 spaced cTBS trains (600 pulses/train, 80% resting motor threshold) during 4 consecutive days delivered over the ictal onset zone using online neuronavigation. Seizure frequency was assessed over a 4xa0week baseline period, a 1xa0week treatment period and an 8xa0week follow-up period. Results Patient 1 suffered from simple partial motor seizures (SPS), often leading to falls and post-ictal paresis, and myoclonic seizures of the left leg. During baseline 3 SPS and 12 myoclonic seizures occurred. In the first week following cTBS, the patient solely experienced isolated auras consisting of a descending sensation towards the left leg. No SPS occurred. Thereafter, overall SPS frequency was unchanged during follow-up, but the patient reported diminished seizure severity with regards to duration, jerking and paresis. This gradually returned to baseline during follow-up. Notably, myoclonic seizures were completely suppressed for a duration of 6xa0weeks. Patient 2 suffered from frequent SPS with jerking of the right truncal muscles, spreading to the right arm, head and less often the right leg. Sixteen SPS occurred during baseline, whereas the patient remained seizure-free throughout the treatment week and 13xa0days thereafter, for a total of nearly three weeks. Follow-up is ongoing at the moment of this report. Stimulation with cTBS was well-tolerated and did not induce adverse effects in either of the patients. Conclusion This case report describes safety and potential anti-epileptic effects of cTBS. Both patients experienced a period of diminished seizure frequency, for a duration of 3–6xa0weeks following a cTBS treatment protocol.

LP6: Ictal tachycardia in childhood epilepsy

Results: Out of all examined patients with epilepsy and a specific comorbid disease, 916 (56.4%) patients have diffuse changes in the background activity, 32 (2%) patients have generalized paroxysmal activity, 157 (9.6%) patients have disorganized background activity with generalized paroxysmal activity, 591 (32%) of the patients have focal activity. There is a dependency between the EEG changes of some most often encountered somatic and neurological diseases. Conclusions: The presence of comorbid diseases relates to a higher risk for aggravating the condition of the patient, increasing the EEG changes, a presence of interdependence between the separate diseases, as well as between their treatment.