Surgery For Drug-resistant Epilepsy Research Articles

Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy.

Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

Focal cortical dysplasia: visual assessment of MRI and MR morphometry data

Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD). The study included 13 children after surgery for drug-resistant epilepsy caused by FCD type II and stable postoperative remission of seizures (Engel class IA, median follow-up 56 months). We analyzed the results of independent expert assessment of native MR data by three radiologists (HARNESS protocol) and MR morphometry data regarding accuracy of FCD localization. We considered 2 indicators, i.e. local cortical thickening and gray-white matter blurring. FCD detection rate was higher after MR morphometry compared to visual analysis of native MR data using the HARNESS protocol. MR morphometry also makes it possible to more often identify gray-white matter blurring as a sign often missed by radiologists (p<0.05). MR morphometry is an additional non-invasive method for assessing the localization of FCD.

Surgery for pediatric drug resistant epilepsy: a narrative review of its history, surgical implications, and treatment strategies.

Drug-resistant epilepsy (DRE), also known as medically refractory epilepsy, is a disorder of high prevalence and negatively impacts a patients quality of life, neurodevelopment, and life expectancy. Pediatric epilepsy surgery has been conducted since the late 1800s, and randomized controlled trials have demonstrated the marked effectiveness of surgery on seizure reduction and the potential for cure. Despite the strong evidence for pediatric epilepsy surgery, there is also strong evidence describing its underutilization. The objective of this narrative review is to describe the history, strength, and limitations in the evidence of surgery for pediatric drug resistant epilepsy. This narrative review was conducted utilizing standard search engines to include the relevant articles on the topic of surgery for drug resistant epilepsy in children, with main keywords including surgery in pediatric epilepsy and drug-refractory epilepsy. The first components describe the historical perspective of pediatric epilepsy surgery and the evidence that highlight the strengths and limitations of epilepsy surgery. We then highlight the importance of presurgical referral and evaluation, followed by a section detailing the surgical options for children with DRE. Lastly, we provide a perspective on the future of pediatric epilepsy surgery. Evidence supports the role for surgery in pediatric medically refractory epilepsy in seizure frequency reduction, improved curative rates, and improvements in neurodevelopment and quality of life.

Activity-Dependent Non-Coding RNA MAPK Interactome of the Human Epileptic Brain.

The human brain has evolved to have extraordinary capabilities, enabling complex behaviors. The uniqueness of the human brain is increasingly posited to be due in part to the functions of primate-specific, including human-specific, long non-coding RNA (lncRNA) genes, systemically less conserved than protein-coding genes in evolution. Patients who have surgery for drug-resistant epilepsy are subjected to extensive electrical recordings of the brain tissue that is subsequently removed in order to treat their epilepsy. Precise localization of brain tissues with distinct electrical properties offers a rare opportunity to explore the effects of brain activity on gene expression. Here, we identified 231 co-regulated, activity-dependent lncRNAs within the human MAPK signaling cascade. Six lncRNAs, four of which were antisense to known protein-coding genes, were further examined because of their high expression and potential impact on the disease phenotype. Using a model of repeated depolarizations in human neuronal-like cells (Sh-SY5Y), we show that five out of six lncRNAs were electrical activity-dependent, with three of four antisense lncRNAs having reciprocal expression patterns relative to their protein-coding gene partners. Some were directly regulated by MAPK signaling, while others effectively downregulated the expression of the protein-coding genes encoded on the opposite strands of their genomic loci. These lncRNAs, therefore, likely contribute to highly evolved and primate-specific human brain regulatory functions that could be therapeutically modulated to treat epilepsy.

Epilepsy Surgery in Adult Stroke Survivors with New-Onset Drug-Resistant Epilepsy.

Despite its effectiveness, surgery for drug-resistant epilepsy is underutilized. However, whether epilepsy surgery is also underutilized among patients with stroke-related drug-resistant epilepsy is unclear. Therefore, our objectives were to estimate the rates of epilepsy surgery assessment and receipt among patients with stroke-related drug-resistant epilepsy and to identify factors associated with these outcomes. We used linked health administrative databases to conduct a population-based retrospective cohort study of adult Ontario, Canada residents discharged from an Ontario acute care institution following the treatment of a stroke between January 1, 1997, and December 31, 2020, without prior evidence of seizures. We excluded patients who did not subsequently develop drug-resistant epilepsy and those with other epilepsy risk factors. We estimated the rates of epilepsy surgery assessment and receipt by March 31, 2021. We planned to use Fine-Gray subdistribution hazard models to identify covariates independently associated with our outcomes, controlling for the competing risk of death. We identified 265,081 patients who survived until discharge following inpatient stroke treatment, 1,902 (0.7%) of whom subsequently developed drug-resistant epilepsy (805 women; mean age: 67.0±13.1 years). Fewer than six (≤0.3%) of these patients were assessed for or received epilepsy surgery before the end of follow-up (≤55.5 per 100,000 person-years). Given that few outcomes were identified, we could not proceed with the multivariable analyses. Patients with stroke-related drug-resistant epilepsy are infrequently considered for epilepsy surgery that could reduce morbidity and mortality.

The expediency of using the registry method for patients with epilepsy who were operated on due to pharmacoresistance

The number of epilepsy patients in Ukraine and in the world is increas- ing every year. And a large part of these patients are patients who need a surgi- cal method of treatment. However, there is no method of re- gistration such patients, which would provide an opportunity to adequately evaluate the results of surgical treat- ment of epilepsy, preparation for surgi- cal intervention, step-by-step examina- tion of the patient and, subsequently, the appointment of adequate АED therapy. From 2014 to 2020, information was collected from 3 leading neuro- surgical centers of Ukraine, which are engaged in surgery for drug-resistant epilepsy. 359 patients who had a drug- resistant form of epilepsy were operated on during this period. However, there was and is not any information about the effectiveness of treatment, the fur- ther course of the disease in such pa- tients and information about the treat- ment of attacks after surgery. Our team decided to develop a register of patients who were oper- ated on due to drug-resistant epilepsy. Firstly, a questionnaire was created, which includes detailed information on the onset of the disease, its course, treatment, and information on diagno- sis. This questionnaire became the basis for the creation of an electronic regis- ter of operated patients with epilepsy, which allows you to conveniently and quickly enter all patient data into an electronic database. The created register is extremely important and expedient at a time when the number of patients with epi- lepsy who are operated on due to drug resistance is constantly increasing.

Quality of life in elderly patients after surgery for drug-resistant epilepsy – The impact of seizure outcome, neurological deficits and anxiety

IntroductionHealth related quality of life (HRQoL) has become a pivotal outcome parameter after surgery for drug-resistant epilepsy. The aim of the study was to investigate HRQoL and its relationship to seizure outcome, neurological deficits and anxiety after epilepsy surgery in a specific subpopulation of elderly patients. MethodsA total of 85 elderly patients (older than 50 years) answered a standardized HRQoL questionnaire one year after epilepsy surgery. The questionnaire addressed the present self-assessed HRQoL in four subdomains (physical function, cognitive function, mood, social interaction). The questionnaire was based on the “Epilepsy Surgery Inventory-55”, adapted for use in German speaking patients and validated by the QOLIE −10 and Beck Depression Inventory. ResultsA total of 51 patients (60%) were completely seizure free (ILAE1) at last available outcome (LAO). Permanent neurological deficits were observed in 8 patients (7%). Correlation analysis confirmed significant association between seizure outcome and overall HRQoL (r = −0.368, p < .001). New permanent neurological deficits showed impact on both HRQoL and the “cognitive function” subdomain. Anxiety and subjective assessment of postoperative status were strongly correlated with overall HRQoL (r = 0.692, p < .001 and r = 0.591, p < .001 respectively) and remained as independent prognostic factors in a multivariate regression analysis. ConclusionSurgery for drug-resistant epilepsy in elderly improves patients' HRQoL. Both seizure freedom and new neurological deficits influence overall HRQoL. Interestingly, anxiety and patients' subjective assessment of postoperative status showed the highest impact on HRQoL in this subpopulation of epilepsy patients.

Epilepsy surgery for focal cortical dysplasia: Seizure and quality of life (QOLIE-89) outcomes.

Surgery for drug resistant epilepsy (DRE) with focal cortical dysplasia (FCD) often requires multiple non-invasive as well as invasive pre-surgical evaluations and innovative surgical strategies. There is limited data regarding surgical management of people with FCD as the underlying substrate for DRE among the low and middle-income countries (LAMIC) including India. The presurgical evaluation, surgical strategy and outcome of 52 people who underwent resective surgery for DRE with FCD between January 2008 and December 2016 were analyzed. The 2011 classification proposed by Blumcke et al., was used for histo-pathological categorization. The Engel classification was used for defining the seizure outcome. The surgical outcome was correlated with the preoperative clinical presentation, video encephalogram (VEEG) recording, magnetic resonance imaging (MRI), invasive monitoring, surgical findings as well as histopathology and the quality of life in epilepsy (QOLIE)- 89 scores. Fifty-two patients underwent resective surgery for FCD (mean age at onset of seizure: 7.94 ± 6.23 years; duration of seizures prior to surgery: 12.95 ± 9.56 years; and, age at surgery: 20.88 ± 12.51 years). The following regional distribution was found; temporal-24 (language-13), frontal-15 (motor cortex- 5), parietal-5 (sensory cortex-4), occipital-1 and multilobar-7. Forty-seven percent of the cases had FCD in the right hemisphere and 53% had FCD in the left hemisphere. Invasive monitoring was performed for identification of the epileptogenic zone (EZ) as well as eloquent cortex in 7 cases and an intra-operative electro-corticography (ECoG) was used in 32 cases. Histopathology revealed the following distribution; FCD IA-4, IB- 1, IC-5, IIA-8, IIB-18, IIIA-13, IIIB -1, IIIC-1 and IIID-1. After a median follow up of 3.7 years after surgery, 84% of patients had Engel's Ia outcome. QOLIE-89 scores improved from 38.33 ± 4.7 (31.14-49.03) before surgery to 75.21 ± 8.44 (56.49-90.49) after surgery (P < 0.001). The younger age of the patient (<20 years) at surgery (P = 0.013), a lower pre-operative score (<9) on seizure severity scale (P = 0.012), focal discharges without propagation on ictal VEEG (P < 0.001), absence of acute post-operative seizures (P < 0.001) and Type II FCD (P = 0.045) were the significant predictors for a favorable seizure outcome. Surgical management of people with DRE and FCD is possible in countries with limited resources. Meticulous pre-surgical evaluation to localize the epileptogenic zone and complete resection of the focus and lesion can lead to the cure or control of epilepsy; and, improvement in the quality of life was observed along with seizure-free outcome.

Surgery for Drug-Resistant Epilepsy in Children

BackgroundNeurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials.MethodsIn this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet–Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory.ResultsAt 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet–Kamat intelligence quotient (difference, 2.5; 95% CI, −0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%).ConclusionsIn this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry–India number, CTRI/2010/091/000525.)

S56 Added value of EEG signal analysis in presurgical evaluation for drug-resistant epilepsy

Objectives To assess the role of signal analysis methods for accurate delineation of the epileptogenic zone during surgery for drug resistant epilepsy. Methods We used surface video EEG as well as invasive studies by means of the stereo-EEG method to identify the epileptogenic networks. Signal analysis tools have been applied systematically during pre surgical evaluation to study ictal as well as interictal activity and responses to different stimulation protocols. Connectivity charts were computed based on analysis of cortico-cortical evoked potentials on single pulse electrical stimulation (SPES). The results were interpreted according with an individual patient hypothesis and integrated with clinical and anatomic data. Results We explored 63 patients at the University Hospital of Bucharest in the National Program for Epilepsy Surgery between 2012 and 2016 of which 57 received either open surgeries or undergone a procedure of radio frequency thermocoagulation (RFTC) applied on intracranial electrodes. In the group of patients ( n = 34) with more than 2 years follow up after surgery, 25 (74%) are seizure free. Signal post processing analysis was critical for surgical planning in 12 cases (48%). Discussion Systematic use of signal analysis approach improved the definition of surgical resection limits, made the recording sessions shorter without sacrificing information, and allowed a better definition of targets for RFTC protocols during SEEG recordings. Conclusion Signal analysis tools added complementary information where the traditional visual analysis was not helpful for surgical planning. Significance Post processing methods of the EEG signal integrated with the anatomo-clinical hypothesis offer unbiased valuable data to improve surgical outcome.

Cognitive outcome after epilepsy surgery in children: A controlled longitudinal study.

To analyze the determinants of cognitive outcome two years after surgery for drug-resistant epilepsy in a cohort of 31 children when compared to a control group of 14 surgical candidates who had yet to undergo surgery two years after the first neuropsychological assessment. Controlled longitudinal study including three evaluations of IQ (Intelligence Quotient) scores or GDQ (General Developmental Quotient) for each group depending on the patient's age: prior to surgery (T0), one year (T1) and two years (T2) after surgery for the surgical group; baseline (T0) and one year (T1) and 2years (T2) after the first evaluation for the control-group. At follow-up, 25 children (80%) of the surgical group were seizure free, while seizure outcome was unsatisfactory in the remaining six (20%). To analyze language, visuomotor skills, memory, reading, visual attention, and behavior, we selected 11 school age children in the surgical group and nine controls. We reported performance prior to (T0) and one year after surgery (T1). There was a significant correlation between earlier age at seizure onset and lower IQ/GDQ at T0 (r=0.39; p=0.03) in the overall cohort. IQ/GDQ scores did not significantly differ between the surgical and control groups when analyzed at T0 and T2. However, they evolved differently with an improved developmental trajectory becoming identifiable only in the surgical group (F1,31=5.33 p=0.028; η2=0.15). There was also a significant increase of forward digit span (Z=2.33; p=0.02) and Rey recall scores (Z=1.97; p=0.049) in the surgical school age subgroup at T1 versus T0. We identified significantly different developmental trajectories in operated versus non- operated children with improved IQ/GDQ scores in operated children only. We also observed a significant increase of digit span scores and Rey recall scores a year after surgery. Further studies including larger samples with longer follow-ups are needed to confirm these preliminary findings.

Barriers to Referral for Epilepsy Surgery Evaluation

Marked underuse of resective surgery for drug-resistant focal epilepsy has not changed in recent decades. Although substantial accumulated evidence has

Health Technology Assessment report on the presurgical evaluation and surgical treatment of drug‐resistant epilepsy

Epilepsy is a neurologic disorder with major social impact. Surgery is a valuable option in patients who are not responding to antiepileptic drugs. The literature reports demonstrate that a proportion ranging from 40 to 100% of patients with epilepsy achieve seizure remission after surgery. A presurgical evaluation (clinical and instrumental) must be performed in all patients with drug-resistant epilepsy to assess their suitability for surgical intervention. Health Technology Assessment (HTA) represents a modern approach to the analysis of technologies used for health care. HTA could be considered a bridge between science that produces evidence and the decisions that can be taken on the basis of that evidence at different levels of the health care system. The aim of this study is the HTA of epilepsy surgery including clinical, ethical, social, and economic features. The present study includes an analysis of the diagnostic and surgical workup performed at the Italian centers for the diagnosis and treatment of drug-resistant epilepsy (DRE). The study includes the following issues: (1) social, ethical impact, and costs of the disease; (2) clinical results, efficacy, and safety of surgery; (3) ethics and quality of life after surgery; and (4) economic impact and productivity regained after surgery. The cost of managing a patient with DRE included in the presurgical study was estimated by the bottom-up microcosting technique that starts from a detailed collection of data on consumption of resources and full costing. The phases analyzed were (1) noninvasive diagnostic workup; (2) neurosurgical intervention; and (3) follow-up. The literature reports indicate epilepsy surgery as an effective treatment both on clinical results and on ethical, social, and quality of life aspects. The workup including the noninvasive presurgical study followed by surgery has a total cost of €20,827. Management of short-term follow-up increases the overhead to €22,291 at the first year, and then to €23,571 after 5years. According to the estimates made in this survey, funding based on diagnosis-related group (DRG) tariff for the noninvasive diagnostic stage involving hospital admission is not remunerative in Italy either at regional or national levels. Effectively the difference between full cost and DRG has a delta of €3,402 and €2,537 respectively. The total cost of the presurgical, surgical, and follow-up evaluation is not remunerative for €10,554 (national data). Economic surveys in Italy have shown that surgery for DRE is an advantageous treatment from the standpoint of third-party payers and is cost-effective for society. DRE presurgical evaluation and surgery are not remunerative either at regional or national levels.

Epilepsy surgery: Recommendations for India

The following article recommends guidelines for epilepsy surgery for India. This article reviews the indications, the various surgical options available and the outcome of surgery for drug resistant epilepsy based on current evidence. Epilepsy surgery is a well-established option for patients who have been diagnosed to have drug resistant epilepsy (DRE) (on at least two appropriate, adequate anti-epileptic drugs (AEDs) (either in monotherapy or in combination) with continuing seizures), where the presurgical work-up has shown concordance of structural imaging (magnetic resonance imaging) and electrical mapping data (electroencephalography (EEG), video EEG). There may be a requirement of functional imaging techniques in a certain number of DRE like positron emission tomography (PET), single photon emission tomography, (SPECT)). Invasive monitoring should be restricted to a few when all noninvasive investigations are inconclusive, there is a dual pathology or there is a discordance of noninvasive data. The types of surgery could be curative (resective surgeries: amygdalo hippocampectomy, lesionectomy and multilobar resections; functional surgeries: hemispherotomy) and palliative (multiple subpial transaction, corpus callosotomy, vagal nerve stimulation). Epilepsy surgery in indicated cases has a success range from 50 to 86% in achieving seizure freedom as compared with <5% success rate with AEDs only in persons with DRE. Centers performing surgery should be categorized into Level I and Level II.

Quality of life after epilepsy surgery

OBJECTIVETo assess the relation between seizure status and quality of life after surgery for drug resistant epilepsy, using a previously validated quality of life model developed for use in epilepsy.METHODSA...