Pharmacoresistant Focal Epilepsy Research Articles

Quadrimodal localisation of epileptic focus using simultaneous EEG, (f)MRI and PET imaging

Purpose: In patients suffering from pharmaco-resistant focal epilepsy, resection of the epileptic focus can lead to seizure-freedom or significant improvement. The localisation of the epileptic focus relies on structural and functional brain imaging and multimodal concordance is associated with a better post-operative outcome. The existence of epileptogenic lesions detectable on structural MRI and the presence of focal hypometabolism on FDG-PET, especially after coregistration with MRI are widely accepted localising findings. In addition, other tools for localising epileptic activity, such as EEG-based electric source imaging (ESI) and simultaneous EEG and functional MRI (EEG-fMRI) are increasingly used. We here report the feasibility to record in a single session combined EEG-PET, MRI, EEG-fMRI and ESI using high-density EEG and a PET-MRI hybrid scanner.

Biomarkers of epileptogenic zone defined by quantified stereo‐EEG analysis

In one third of patients with a diagnosis of pharmacoresistant focal epilepsy who are candidates for therapeutic surgery, cerebral areas responsible for seizure generation can be defined exclusively with invasive intracranial recordings. A correct presurgical identification of the epileptogenic zone (EZ) with intracranial electrodes has a direct impact on postsurgical outcome. We aimed at identifying biomarkers of the EZ based on computer-assisted inspection of intracranial electroencephalography (EEG). Computer-driven intracranial EEG analysis in the domains of time, frequency, and space was retrospectively applied to a population of 10 patients with focal epilepsy to detect EZ electrophysiologic markers. Next, a prospective study was performed on 14 surgery candidate patients. The stereo-EEG computer-assisted analysis of EZ boundaries performed blind from patients data was compared to that defined with the traditional visual inspection completed by neurophysiologists. In the retrospective study, the EZ was characterized by the combined detection of three biomarkers observed at seizure onset: (1) fast activity at 80-120Hz associated with (2) very slow transient polarizing shift and (3) voltage depression (flattening). Correlations between these indexes were calculated for each seizure. In the prospective study, the quantified analysis based on the three biomarkers confirmed a complete overlap between leads within the EZ identified by expert clinicians. In 2 of 14 patients the proposed biomarkers partially identified the EZ. Our findings demonstrate and validate with a prospective unbiased study the use of three neurophysiologic intracranial EEG parameters as excellent biomarkers of ictogenesis and as reliable indicators of EZ boundaries.

U centru epilepsije - povodom proslave 90-godišnjice Neurološke klinike u Beogradu

The most important and simplest form of epilepsy treatment is the application of antiepileptic drugs. Its goal is to prevent the recurrence of epileptic attacks without provoking significant side effects. Unfortunately, in about 20-30% of patients antiepileptic drugs does not achieve seizure control. In a number of patients with pharmacoresistant focal epilepsy resective brain surgery is the optimal treatment method. Our experience as well as of the other epilepsy centers indicates that appropriate methods of preoperative evaluation and advanced techniques in epilepsy surgery are effective and safe methods of treatment resistant epilepsy, particularly temporal lobe epilepsy. Surgical treatment of pharmacoresistant focal epilepsy leads to full control of seizures in about 2/3 of the operated patients. In order to achieve the complete surgical success, it is necessary to remove or disconnect that area or part of the brain, which is responsible for the initiation of epileptic seizures. That part of the brain (i.e. cerebral cortex) is called the epileptogenic zone and should be removed with the maximum refrain from those parts of the brain responsible for an important function (i.e."eloquent" cortex). Different modalities of diagnostic tests that are now used as part of presurgical evaluation (video-EEG telemetry, magnetic resonance imaging, neuropsychological testing, functional neuroradiology), allow the precise localization of the epileptogenic zone in majority of patients.

GAMMA KNIFE RADIOSURGICAL TREATMENT OF MOTOR CORTEX EPILEPSY

In pharmacoresistant focal epilepsies involving primary motor cortex, risk of motor deficit generally contraindicates cortical resection. Gamma knife radiosurgery (GK) is an established treatment for certain focal epilepsies, notably mesial...

Efficacy of chronic stimulation of nucleus accumbens (NAC) and anterior thalamus (ANT) in patients with pharmacoresistant focal epilepsy

Efficacy of chronic stimulation of nucleus accumbens (NAC) and anterior thalamus (ANT) in patients with pharmacoresistant focal epilepsy

A Clinical-EEG Study of Sleepiness and Psychological Symptoms in Pharmacoresistant Epilepsy Patients Treated with Lacosamide

Our aim was to evaluate the EEG and clinical modifications induced by the new antiepileptic drug lacosamide (LCM) in patients with epilepsy. We evaluated 10 patients affected by focal pharmacoresistant epilepsy in which LCM (mean 250 mg/day) was added to the preexisting antiepileptic therapy, which was left unmodified. Morning waking EEG recording was performed before (t0) and at 6 months (t1) after starting LCM. At t0 and t1, patients were also administered questionnaires evaluating mood, anxiety, sleep, sleepiness, and fatigue (Beck Depression Inventory; State-Trait Anxiety Inventory Y1 and Y2; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Fatigue Severity Scale). We performed a quantitative analysis of EEG interictal abnormalities and background EEG power spectrum analysis. LCM as an add-on did not significantly affect anxiety, depression, sleepiness, sleep quality, and fatigue scales. Similarly, adding LCM to preexisting therapy did not modify significantly patient EEGs in terms of absolute power, relative power, mean frequency, and interictal abnormalities occurrence. In conclusion, in this small cohort of patients, we confirmed that LCM as an add-on does not affect subjective parameters which play a role, among others, in therapy tolerability, and our clinical impression was further supported by evaluation of EEG spectral analysis.

Cognitive outcomes of different surgical approaches in temporal lobe epilepsy

Epilepsy surgery is a successful treatment option for pharmacoresistant focal symptomatic epilepsies. However, cognitive impairment is very common in epilepsy patients and may be negatively or positively affected by surgery. Amidst the long-standing discussion of whether a particular surgical approach for temporal lobe epilepsy patients may be superior with regards to seizure control, a recent meta-analysis indicated that this is the case for more extended resections. Larger temporal lobe resections, however, raise concerns that more unaffected and functional tissues may be involved, thus causing worse cognitive outcome. This review is based on published reports collected over a long period, with changing diagnostics and surgical methods, and focuses mainly on the experiences of one epilepsy centre. The review highlights the effects of standard versus selective surgery, the different surgical approaches in selective surgery, determinants other than surgery which may affect cognitive outcome, and the methodologically-important question of outcome assessment and how neuropsychological test selection may bias the result. Overall, from a neuropsychological point of view, individual and selective surgery is preferred in which the aim is to achieve seizure control with minimal effect on the functional integrity of tissues or fibre tracts. Cognition is important for the functions of everyday life and this should be kept in mind, irrespective of which kind of surgery is preferred.

Disorganization of neocortical lamination in focal cortical dysplasia is brain-region dependent: evidence from layer-specific marker expression

BackgroundFocal cortical dysplasias (FCD) are local disturbances of neocortical architecture and a common cause of pharmaco-resistant focal epilepsy. Little is known about the pathomechanisms leading to architectural abnormalities associated with FCD.ResultsIn the present study we compared 52 FCD cases originating from the frontal or temporal lobe with or without Ammon’s horn sclerosis (AHS) with regard to structural and molecular differences. We applied layer-specific (ER81, RORß, SMI32, TLE4) and interneuron (calbindin, parvalbumin) markers by means of immunohistochemistry, in situ hybridization (ISH), and real time RT-PCR and correlated our findings with clinical parameters. We found that: (1) Structural abnormalities were most prominent in layers III-VI including changed morphology of individual neurons or dispersion, blurring and thinning of layers. These alterations were most pronounced in isolated frontal FCD, whereas the most homogeneous group was FCD IIIa. (2) Numbers of calbindin- and parvalbumin-positive interneurons varied considerably within the different FCD groups, but were not generally reduced. A significant decrease was only found for calbindin-positive interneurons in frontal FCD, and for parvalbumin-positive interneurons in FCD IIIa. (3) Interestingly, FCD IIIa presented with significant changes in the numbers of calbindin- or TLE4-positive neurons when compared to isolated FCD or controls. (4) Correlations between clinical and cellular parameters strongly depended on FCD localisation and age of the patients.ConclusionsIn summary, our data suggest that late cortical development is disturbed in FCD, yet most likely by different causes depending on brain region, FCD type and FCD severity.

THE IMPACT OF EPILEPSY ON COGNITIVE FUNCTION

Prof. Dr. phil. Christoph Helmstaedter, Dept. of Epileptology, University of Bonn, Bonn/Germany.Current position and activities: Head of the section of clinical neuropsychology of the department of Epileptology, University Clinic Bonn,...

The pathology of magnetic-resonance-imaging-negative epilepsy

Patients with magnetic-resonance-imaging (MRI)-negative (or ‘nonlesional‘) pharmacoresistant focal epilepsy are the most challenging group undergoing presurgical evaluation. Few large-scale studies have systematically reviewed the pathological substrates underlying MRI-negative epilepsies. In the current study, histopathological specimens were retrospectively reviewed from MRI-negative epilepsy patients (n=95, mean age=30 years, 50% female subjects). Focal cortical dysplasia cases were classified according to the International League Against Epilepsy (ILAE) and Palmini et al classifications. The most common pathologies found in this MRI-negative cohort included: focal cortical dysplasia (n=43, 45%), gliosis (n=21, 22%), hamartia+gliosis (n=12, 13%), and hippocampal sclerosis (n=9, 9%). The majority of focal cortical dysplasia were ILAE type I (n=37) or Palmini type I (n=39). Seven patients had no identifiable pathological abnormalities. The existence of positive pathology was not significantly associated with age or temporal/extratemporal resection. Follow-up data post surgery was available in 90 patients; 63 (70%) and 57 (63%) attained seizure freedom at 6 and 12 months, respectively. The finding of positive pathology was significantly associated with seizure-free outcome at 6 months (P=0.035), but not at 12 months. In subgroup analysis, the focal cortical dysplasia group was not significantly correlated with seizure-free outcome, as compared with the negative-pathology groups at either 6 or 12 months. Of note, the finding of hippocampal sclerosis had a significant positive correlation with seizure-free outcome when compared with the negative-pathology group (P=0.009 and 0.004 for 6- and 12-month outcome, respectively). Absence of a significant histopathology in the resected surgical specimen did not preclude seizure freedom. In conclusion, our study highlights the heterogeneity of epileptic pathologies in MRI-negative epilepsies, with focal cortical dysplasia being the most common finding. The existence of positive pathology in surgical specimen may be a good indication for short-term good seizure outcome. There is a small subset of cases in which no pathological abnormalities are identified.

Comparison of morphometric analysis based on T1- and T2-weighted MRI data for visualization of focal cortical dysplasia

Focal cortical dysplasias (FCD) are highly epileptogenic lesions frequently accounting for pharmaco-resistant focal epilepsy. Visual MRI analysis combined with morphometric analysis of T1-weighted MRI data was shown to be of higher diagnostic sensitivity in detecting and delineating FCD than conventional visual analysis alone. Here we investigate whether morphometric analysis of T2-weighted MRI volume data sets is of equal benefit or perhaps more helpful for visualizing FCD. Morphometric analysis was applied to T1- and T2-weighted MRI volume data sets of 20 epilepsy patients with FCD using a fully automated MATLAB script with scanner- and sequence-specific normal databases for T1 and T2 images. For each modality, a new feature map (i.e., 'junction image') highlighting the FCD-typical blurring of the gray-white matter junction and quantifying this feature in comparison to the normal database in terms of z-scores was calculated. The resulting T1 and T2 'junction images' were compared for conspicuity and recognizability of the FCD both qualitatively by visual assessment and quantitatively by analysis of the mean z-scores inside and outside the lesions. In 80% of the cases, the FCD presented with higher contrast and/or clearer delineation in the T2 than in the T1 'junction images' and were thus easier to recognize in these images. The quantitative analysis supported this impression: in 95% of cases, the ratio of mean z-scores inside and outside the FCD was higher in T2- than in T1-based 'junction images'. For the T2 'junction images', this ratio amounted to 8.7 on average and was thus more than twice as high as the corresponding T1 result of 3.7 (p<.003). Concerning visualization of FCD by highlighting blurring of the gray-white matter junction, the results of the present study indicate that morphometric analysis of T2-weighted MRI data on average is superior to T1-based morphometry.

Loss of Emotional Responsiveness Secondary to Left Amygdalohippocampectomy Performed for the Treatment of Complex, Drug-Resistant Partial Epilepsy

Loss of Emotional Responsiveness Secondary to Left Amygdalohippocampectomy Performed for the Treatment of Complex, Drug-Resistant Partial Epilepsy

Quantitative MRI of Pharmaco-Resistant Focal Epilepsy (PFE): Temporal and Extratemporal Lobe Epilepsy (P06.173)

Quantitative MRI of Pharmaco-Resistant Focal Epilepsy (PFE): Temporal and Extratemporal Lobe Epilepsy (P06.173)

Septal nuclei enlargement in human temporal lobe epilepsy without mesial temporal sclerosis

To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic. Subjects were recruited from 2 sites and consisted of patients with pharmacoresistant focal epilepsy (20 with TLE and mesial temporal sclerosis [MTS], 24 with TLE without MTS, 23 with extratemporal epilepsy) and 114 controls. Septal volume was measured using high-resolution MRI in association with newly developed probabilistic septal nuclei maps. Septal volume was compared between subject groups while controlling for relevant factors. Patients with TLE without MTS had significantly larger septal nuclei than patients with extratemporal epilepsy and controls. This was not true for patients with MTS. These results are interpreted with reference to prior studies demonstrating expansion of the septo-hippocampal cholinergic system in animal models of TLE and human TLE surgical specimens. Septal nuclei are enlarged in patients with TLE without MTS. Further investigation of septal nuclei and antiepileptic septo-hippocampal neurocircuitry could be relevant to development of new therapeutic interventions such as septal stimulation for refractory TLE.

Mapping interictal epileptic discharges using mutual information between concurrent EEG and fMRI

The mapping of haemodynamic changes related to interictal epileptic discharges (IED) in simultaneous electroencephalography (EEG) and functional MRI (fMRI) studies is usually carried out by means of EEG-correlated fMRI analyses where the EEG information specifies the model to test on the fMRI signal. The sensitivity and specificity critically depend on the accuracy of EEG detection and the validity of the haemodynamic model. In this study we investigated whether an information theoretic analysis based on the mutual information (MI) between the presence of epileptic activity on EEG and the fMRI data can provide further insights into the haemodynamic changes related to interictal epileptic activity. The important features of MI are that: 1) both recording modalities are treated symmetrically; 2) no requirement for a-priori models for the haemodynamic response function, or assumption of a linear relationship between the spiking activity and BOLD responses, and 3) no parametric model for the type of noise or its probability distribution is necessary for the computation of MI. Fourteen patients with pharmaco-resistant focal epilepsy underwent EEG-fMRI and intracranial EEG and/or surgical resection with positive postoperative outcome (seizure freedom or considerable reduction in seizure frequency) was available in 7/14 patients. We used nonparametric statistical assessment of the MI maps based on a four-dimensional wavelet packet resampling method. The results of MI were compared to the statistical parametric maps obtained with two conventional General Linear Model (GLM) analyses based on the informed basis set (canonical HRF and its temporal and dispersion derivatives) and the Finite Impulse Response (FIR) models. The MI results were concordant with the electro-clinically or surgically defined epileptogenic area in 8/14 patients and showed the same degree of concordance as the results obtained with the GLM-based methods in 12 patients (7 concordant and 5 discordant). In one patient, the information theoretic analysis improved the delineation of the irritative zone compared with the GLM-based methods. Our findings suggest that an information theoretic analysis can provide clinically relevant information about the BOLD signal changes associated with the generation and propagation of interictal epileptic discharges. The concordance between the MI, GLM and FIR maps support the validity of the assumptions adopted in GLM-based analyses of interictal epileptic activity with EEG-fMRI in such a manner that they do not significantly constrain the localization of the epileptogenic zone.

White matter abnormalities revealed by DTI correlate with interictal grey matter FDG‐PET metabolism in focal childhood epilepsies

For patients with focal epilepsy scheduled for surgery, including MRI-negative cases, (18)FDG-PET was shown to disclose hypometabolism in the seizure onset zone. However, it is not clear whether grey matter hypometabolism is informative of the integrity of the surrounding white matter cerebral tissue. In order to study the relationship between metabolism of the seizure onset zone grey matter and the integrity of the surrounding white matter measured by diffusion tensor imaging (DTI), we performed a monocentric prospective study (from 2006 to 2009) in 15 children with pharmacoresistant focal epilepsy, suitable for interictal (18)FDG-PET, T1-, T2-, FLAIR sequence MRI and DTI. Children had either positive or negative MRI (eight with symptomatic and seven with cryptogenic epilepsies, respectively). Seven children subsequently underwent surgery. Standardised uptake values of grey matter PET metabolism were compared with DTI indices (fractional anisotropy [FA], apparent diffusion coefficient [ADC], parallel diffusion coefficient [PDC], and transverse diffusion coefficient [TDC]) in grey matter within the seizure onset zone and adjacent white matter, using regions of interest automatically drawn from individual sulcal and gyral parcellation. Hypometabolism correlated positively with white matter ADC, PDC, and TDC, and negatively with white matter FA. In the cryptogenic group of children, hypometabolism correlated positively with white matter ADC. Our results demonstrate a relationship between abnormalities of grey matter metabolism in the seizure onset zone and adjacent white matter structural alterations in childhood focal epilepsies, even in cryptogenic epilepsy. This relationship supports the hypothesis that microstructural alterations of the white matter are related to epileptic networks and has potential implications for the evaluation of children with MRI-negative epilepsy.

Rapid loading of intravenous lacosamide: Efficacy and practicability during presurgical video‐EEG monitoring

This study investigates immediate efficacy and safety of intravenous application of de novo lacosamide (LCM) as add-on therapy in patients with pharmacoresistant focal epilepsy. During presurgical video-electroencephalography (EEG) monitoring, 17 adult inpatients received LCM infusion (200 mg every 12 h for 2-3 days) followed by oral formulation with the same regimen. Before and after intravenous application of LCM, seizures and interictal epileptiform discharges (IEDs) recorded with continuous video-EEG monitoring were analyzed, and an assessment of adverse events (AEs) was performed daily. To evaluate the midterm tolerability and efficacy, follow-up visits were conducted 1 and 3 months after discharge from hospital. In the acute phase, intravenous initiation of LCM was well tolerated with few mild or moderate AEs (3 of 17, 17.6%). A significant reduction of seizure frequency in the treatment phase as compared to mean seizure frequency in the 2-day baseline phase was achieved (p < 0.05 for the first treatment day, and p < 0.005 for the second treatment day). On the first treatment day, 61.5% of the patients were seizure free, and 84.6% on the second treatment day. IED reduction after intravenous application of LCM was not significant. After 1 month, the 50% responder rate was 46.6% and after the 3-month period, 42.8%. Our data suggest that rapid intravenous initiation of de novo LCM is safe and may protect against seizures in a rapid and midterm time window.

Pharmacoresistance and the role of surgery in difficult to treat epilepsy

Pharmacoresistance occurs in up to 30% of patients with epilepsy, and is most commonly associated with epilepsy of structural or metabolic origin, abnormal findings on brain imaging or examination, and failure to respond to the first two antiepileptic drugs. However, in patients presumed to have difficult to treat epilepsy, factors that might result in apparent treatment resistance (misdiagnosis of epilepsy, incorrect drug and/or dose, and lifestyle issues) must first be excluded and the diagnosis re-examined. Epilepsy is commonly misdiagnosed, especially in patients with syncope and psychogenic events. The initial steps in confirming the diagnoses of both epilepsy and pharmacoresistance are to obtain a detailed, reliable history and to conduct a careful review of all prior trials of antiepileptic drug therapy. Once the diagnoses of epilepsy and pharmacoresistance are confirmed, the seizure type, epilepsy syndrome, and expected course of the disorder dictate its medical and surgical management. Epilepsy surgery should be considered promptly in these patients, since few interventions are as effective as brain surgery in this setting, particularly in patients with focal pharmacoresistant epilepsy. This Review discusses the concept of pharmacoresistance and describes the approach to management of the patient with difficult to treat epilepsy, focusing on the important role of epilepsy surgery.

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

A disturbed balance between excitatory and inhibitory neurotransmission underlies epileptic activity, although reports concerning neurotransmitter systems involved remain controversial. We quantified densities of 15 receptors in neocortical biopsies from patients with pharmacoresistant focal temporal lobe epilepsy and autopsy controls, and searched for correlations between density alterations and clinical factors or the occurrence of spontaneous synaptic potentials in vitro. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-d-aspartate (NMDA), peripheral benzodiazepine, muscarinic (M)(1) , M(2) , nicotinic, α(1) , α(2h) , serotonin (5-HT)(1A) , and adenosine (A)(1) receptor densities were significantly altered in biopsies. The epileptic cohort was subdivided based on clinical (febrile seizures, hippocampal sclerosis, neocortical pathologies, surgery outcome) or electrophysiologic (spontaneous field potentials) criteria, resulting in different patterns of significantly altered receptor types when comparing a given epileptic group with controls. Only AMPA, kainate, M(2) , and 5-HT(1A) receptors were always significantly altered. γ-Aminobutyric acid (GABA)(A) , GABA(B) , and 5-HT(2) receptor alterations were never significant. Correlation patterns between receptor alterations and illness duration or seizure frequency varied depending on whether the epileptic cohort was considered as a whole or subdivided. Neocortical temporal lobe epilepsy is associated with a generalized receptor imbalance resulting in a net potentiation of excitatory neurotransmission. Peripheral benzodiazepine receptor alterations highlight that astrocytes are also impaired by seizure activity.

Imaging techniques for presurgical evaluation of temporal lobe epilepsy

The surgical treatment of pharmaco-resistant focal epilepsy has increased dramatically in recent years. This evolution is undoubtedly due to an improvement of electrophysiological and neuroradiological investigations to localize the epileptic focus. Temporal lobe epilepsy is the most frequent pharmacoresistent epileptic syndrome in adults and responds better to surgery than the so-called extratemporal epilepsy. Apart from the history and the clinical semiology, the investigations for temporal lobe epilepsy are based on core investigations, including electroencephalography (long-term video-EEG recordings) and MRI. Additional noninvasive imaging techniques to improve the localization of the epileptic focus include PET ictal and interictal SPECT, electric source imaging and magnetic source imaging, and simultaneous EEG and functional MRI. Advanced sequences and analysis of structural MRI data allow us to map subtle structural abnormalities as well as important white matter tracts while functional MRI of language/memory helps to identify eloquent cortical area and estimate the risk of postoperative deficits. Our aim is to review the current literature and summarize all available data on these validated imaging techniques for the assessment of focal temporal lobe epilepsy.