Nonlesional Frontal Lobe Epilepsy Research Articles

Novel GATOR1 variants in focal epilepsy

IntroductionVariants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers. Patients and MethodsNinety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology. ResultsFour previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance. ConclusionGATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.

Stereotactic EEG Practices: A Survey of United States Tertiary Referral Epilepsy Centers.

Stereotactic EEG (SEEG) is being increasingly used in the intracranial evaluation of refractory epilepsy in the United States. In this study, the authors describe current practice of SEEG among National Association of Epilepsy Centers tertiary referral (level IV) centers. Using the Survey Monkey platform, a survey was sent to all National Association of Epilepsy Centers level IV center directors. Of 192 centers polled, 104 directors completed the survey (54% response rate). Ninety-two percent currently perform SEEG. Of these, 55% of institutions reported that greater than 75% of their invasive electrode cases used SEEG. Stereotactic EEG was commonly used over subdural electrodes in cases of suspected mesial temporal lobe epilepsy (87%), nonlesional frontal lobe epilepsy (79%), insular epilepsy (100%), and individuals with prior epilepsy surgery (74%). Most centers (72%) used single-lead electrocardiogram monitoring concurrently with SEEG, but less than half used continuous pulse oximetry (47%) and only a few used respiratory belts (3%). Other significant intercenter technical variabilities included electrode nomenclature and choice of reference electrode. Patient care protocols varied among centers in patient-to-nurse ratio and allowed patient activity. Half of all centers had personnel who had prior experience in SEEG (50.5%); 20% of centers had adopted SEEG without any formal training. Stereotactic EEG has become the principal method for intracranial EEG monitoring in the majority of epilepsy surgery centers in the United States. Most report similar indications for use of SEEG, though significant variability exists in the utilization of concurrent cardiopulmonary monitoring as well as several technical and patient care practices. There is significant variability in level of background training in SEEG among practitioners. The study highlights the need for consensus statements and guidelines to benchmark SEEG practice and develop uniform standards in the United States.

Surgical Technique and Outcome of Extensive Frontal Lobectomy for Treatment of Intracable Non-lesional Frontal Lobe Epilepsy.

Although extensive frontal lobectomy (eFL) is a common surgical procedure for intractable frontal lobe epilepsy (FLE), there have been very few reports regarding surgical techniques for eFL. This article provides step-by-step descriptions of our surgical technique for non-lesional FLE. Sixteen patients undergoing eFL were included in this study. The goals were to maximize gray matter removal, including the orbital gyrus and subcallosal area, and to spare the primary motor and premotor cortexes and anterior perforated substance. The eFL consists of three steps: (1) positioning, craniotomy, and exposure; (2) lateral frontal lobe resection; and (3), resection of the rectus gyrus and orbital gyrus. Resection ahead of bregma allows preservation of motor and premotor area function. To remove the orbital gyrus preserving anterior perforated substance, it is essential to visualize the olfactory trigone beneath the pia. It is important to observe the surface of the contralateral medial frontal lobe for complete removal of the subcallosal area of the frontal lobe. Thirteen patients (81.25%) became seizure-free and three patients (18.75%) continued to have seizures. None of the patients showed any complications. The eFL is a good surgical technique for the treatment of intractable non-lesional FLE. For treatment of epilepsy by eFL, it is important to resect the non-eloquent area of the frontal lobe as much as possible with preservation of the eloquent cortex.

Magnetoencephalography-guided surgery in frontal lobe epilepsy using neuronavigation and intraoperative MR imaging

BackgroundEspecially in hidden lesions causing drug-resistant frontal lobe epilepsy (FLE), the localization of the epileptic zone EZ can be a challenge. Magnetoencephalography (MEG) can raise the chances for localization of the (EZ) in combination with electroencephalography (EEG). We investigated the impact of MEG-guided epilepsy surgery with the aid of neuronavigation and intraoperative MR imaging (iopMRI) on seizure outcome of FLE patients. MethodsTwenty-eight patients (15 females, 13 males; mean age 31.0±11.1 years) underwent surgery in our department. All patients underwent presurgical MEG monitoring (two-sensor Magnes II or whole head WH3600 MEG system; 4-D Neuroimaging, San Diego, CA, USA). Of those, six patients (group 1) with MRI-negative FLE were operated on before 2002 with intraoperative electrocorticography (ECoG) and invasive EEG mapping only. Eleven patients with MRI-negative FLE (group 2) and eleven with lesional FLE (group 3) underwent surgery using 1.5T-iopMRI and neuronavigation, including intraoperative visualization of the MEG localizations in 22 and functional MR imaging (for motor and speech areas) as well as DTI fiber tracking (for language and pyramidal tracts) in 13 patients. ResultsIn the first group, complete resection of the defined EZ including the MEG localization according to the latest postoperative MRI was achieved in four out of six patients. Groups two and three had complete removal of the MEG localizations in 20/22 (91%, 10 of 11 each). Intraoperative MRI revealed incomplete resection of the MEG localizations of four patients (12%; two in both groups), leading to successful re-resection. Transient and permanent neurological deficits alike occurred in 7.1%, surgery-associated complications in 11% of all patients. In the first group, excellent seizure outcome (Engel Class IA) was achieved in three (50%), in the second in 7 patients (61%) and third group in 8 patients (64%, two iopMRI-based re-resections). Mean follow-up was 70.3 months (from 12 to 284 months). ConclusionIn our series, MEG-guided resection using neuronavigation and iopMR imaging led to promising seizure control rates. Even in non-lesional FLE, seizure control rates and the probability of complete resection of the MEG localizations was similar to lesional FLE using multimodal navigation.

Resolution of epileptic encephalopathy following treatment with transdermal nicotine

We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5-year-old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.

Combining EEG and fMRI in the study of epileptic discharges

The combining of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is a unique noninvasive method for investigating the brain regions involved at the time of epileptic discharges. The neuronal discharges taking place during an interictal spike or spike-wave burst result in an increase in metabolism and blood flow, which is reflected in the blood oxygen-level dependent (BOLD) signal measured by fMRI. This increase is most intense in the region generating the discharge but is also present in regions affected by the discharge. On occasion, epileptic discharges result in decreased metabolism, the origin of which is only partially understood. EEG-fMRI applied to focal epilepsy results in maxima of the BOLD signal most often concordant with other methods of localization and has been shown to help in localizing epileptic foci in nonlesional frontal lobe epilepsy. It has also demonstrated the involvement of the thalamus in generalized epileptic discharges. In patients with new-onset epilepsy it could be used to evaluate the source and extent of the brain structures involved during discharges and their evolution as the disease progresses.

Verapamil attenuates the malignant treatment course in recurrent status epilepticus

In the scenario of refractory status epilepticus, the recommended approach of intensive care treatment is limited with respect to the available pharmacodynamic variability and its impeding, severe side effects. Alternative treatment options are therefore urgently needed. In the case described, a patient with nonlesional frontal lobe epilepsy had a high-frequency series of tonic seizures, which evolved into a malignant form of status epilepticus. Co-administration of verapamil, a potent multidrug transporter inhibitor, was followed by significant reduction in seizure frequency. We discuss the putative role of verapamil and the specific risk factors for this malignant treatment course.

EEG-fMRI

In patients with nonlesional frontal lobe epilepsy (FLE), the delineation of the epileptogenic zone is difficult. Therefore these patients are often not considered for surgery due to an unclear seizure focus. The aim of this study was to investigate whether EEG-fMRI can add useful information in the preoperative evaluation of these patients. Nine nonlesional FLE patients were studied with EEG-fMRI using a 3 T scanner. Spike-related blood oxygen level dependent (BOLD) signal changes were compared to the topography of the spikes and to PET and SPECT results if available. The structural MRIs were reviewed for subtle abnormalities in areas that showed BOLD responses. For operated patients, postoperative resection and histology were compared to BOLD responses. Concordance between spike localization and positive BOLD response was found in 8 patients. PET and SPECT investigations corresponded with BOLD signal changes in 6 of 7 investigations. In 2 cases, reviewing the structural MRI guided by EEG-fMRI data resulted in considering a suspicious deep sulcus. Two patients were operated. In 1, the resected cortex corresponded with the suspicious sulcus and fMRI results and histology showed cortical dysplasia. In another, histology revealed an extended microdysgenesis not visible on structural MRI. EEG-fMRI had shown activation just adjacent to the resected pathologic area. Our study provides different types of support (topography, concordance with PET and SPECT, structural peculiarities, postoperative histology) that EEG-fMRI may help to delineate the epileptic focus in patients with nonlesional frontal lobe epilepsy, a challenging group in the preoperative evaluation.

Repeat magnetoencephalography and surgeries to eliminate atonic seizures of non-lesional frontal lobe epilepsy

A 7-year-old boy presented with intractable head nodding and atonic seizures since the age of 3 years and severe behavior problems unsuitable for video EEG monitoring. We performed magnetoencephalography (MEG) 4 times: before (1) corpus callosotomy, (2) left frontal cortical resection with multiple subpial transection and (3) resection of residual MEG spike sources, which eliminated seizures. Repeat MEGs consistently localized the epileptogenic zone in a patient with intractable residual non-lesional left frontal lobe epilepsy.

Nonlesional Frontal Lobe Epilepsy (FLE) of Childhood: Clinical Presentation, Response to Treatment and Comorbidity

Few studies have looked at long-term epileptic and cognitive outcome of frontal lobe epilepsy (FLE) in children. Most are limited by inclusion of lesional and nonlesional patients. To define the epileptic and functional outcome of children with nonlesional FLE. We reviewed medical records and neuropsychological evaluations of patients with nonlesional FLE diagnosed between 1994 and 2004. We included children with either focal or regional frontal EEG and/or functional imaging abnormalities. We reviewed their charts for seizure and neuropsychological outcome. We included 21 children. Twelve (57.1%) presented with daily seizures. Seizures were nocturnal in 8 of 21, secondarily generalized in 6 of 21, adversive in 5 of 21, and focal motor in 6 of 21. Although, initial seizure control was poor in 14 of 21, long-term control was achieved in 10 of 21 after 14.6+/-22.3 months. Early development was normal in 12 of 21 but at later formal neuropsychological evaluation only 3 of 12 still had a normal profile. The majority of children had learning difficulties requiring special education prior to seizure onset (6 of 10). A clearly defined regression after seizure onset was observed in three children. The majority exhibited attention deficit and hyperactivity or impulsivity (14 of 21), behavioral problems (8 of 21), and cognitive impairments (10 of 21). Early seizure control was associated with a better cognitive outcome. Nonlesional FLE is associated with poor seizure and behavioral outcomes. Whether this is secondary to MRI-silent developmental lesions or to the progressive repercussion of seizures on frontal lobe functions remains uncertain. A prospective study with early neuropsychological assessment could help confirm the latter.

Discriminating Patients With Frontal-Lobe Epilepsy and Temporal-Lobe Epilepsy: Utility of a Multilevel Design Fluency Test.

Patients with frontal-lobe epilepsy (FLE) or temporal-lobe epilepsy (TLE) and matched control participants were given a design fluency test that assessed nonverbal fluency and switching ability. Patients with FLE generated fewer designs in the switching condition relative to the TLE patients and controls, whereas group differences did not emerge in the basic fluency conditions. When the side of the seizure focus and the presence or absence of a structural lesion were considered in patients with FLE, only those with left-lesional FLE generated fewer designs than controls did in the switching condition. Furthermore, patients with left-lesional and nonlesional FLE produced a greater proportion of set-loss errors than did controls. These results indicate that patients with FLE are impaired when they must simultaneously generate new designs and engage in cognitive switching; however, the pattern of impairment may depend on the side of the seizure focus and the presence of a structural lesion.

Focal ictal beta discharge on scalp EEG predicts excellent outcome of frontal lobe epilepsy surgery.

To determine whether a focal beta-frequency discharge at seizure onset on scalp EEG predicts outcome of frontal lobe epilepsy (FLE) surgery. We identified 54 consecutive patients with intractable FLE who underwent epilepsy surgery between December 1987 and December 1996. A blind review of EEGs and magnetic resonance images (MRIs) was performed. Lesional epilepsy is defined as presence of an underlying structural abnormality on MRI. Overall, 28 (52%) patients were seizure free, with a mean follow-up of 46.5 months. Presence of a focal beta-frequency discharge at seizure onset on scalp EEG predicted seizure-free outcome in lesional (p = 0.02) and non-lesional (p = 0.01) epilepsy patients. At least 90% of patients who had either lesional or non-lesional epilepsy were seizure free if scalp EEG revealed a focal beta discharge at ictal onset. Moreover, logistic regression analysis showed that focal ictal beta pattern and completeness of lesion resection were independently predictive of seizure-free outcome. Ictal onset with lateralized EEG activity of any kind and postresection electrocorticographic spikes did not predict surgical outcome (p > 0.05). Only about 25% of FLE surgical patients have a focal beta-frequency discharge at seizure onset on scalp EEG. However, its presence is highly predictive of excellent postsurgical seizure control in either lesional or non-lesional FLE surgical patients.

Results of lesional vs. nonlesional frontal lobe epilepsy surgery.

Fifty-three seizure focus resections limited to the frontal lobe were performed. Forty-nine had adequate follow-up. Five of 17 (29%) nonlesional (NL) cases and 21 of 32 (66%) lesional (L) cases were seizure free (SF) at 1 year postoperatively. Eight of 9 (89%) L cases < or = 18 years old vs. 13 of 23 (57%) > 18 years old were SF. Eight of 10 (80%) tumor vs. 13 of 22 (59%) nontumor L cases were SF. Sixteen NL cases were localized by invasive recording. Five (31%) were SF. Ictal localization was obtained in 4 of 32 L cases. Three of 4 (75%) were SF. Eighteen of 24 (64%) L cases without ictal localization were SF. Nine of 12 (75%) lateral resections, 7 of 12 (58%) lobectomies, and 2 of 13 (15%) mesial resections were SF. Three of 20 cases with at least 90% reduction in seizures became SD > or = 2 years postresection. No case with < 90% seizure reduction at one year showed improvement with longer follow-up.