Diagnosis and Surgical Treatment of Drug-Resistant Epilepsy.
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ABSTRACT:
SUBMITTER: Anyanwu C
PROVIDER: S-EPMC5924385 | biostudies-other | 2018 Mar
REPOSITORIES: biostudies-other
Publications
Diagnosis and Surgical Treatment of Drug-Resistant Epilepsy.
Anyanwu Chinekwu C Motamedi Gholam K GK
Brain sciences 20180321 4
Despite appropriate trials of at least two antiepileptic drugs, about a third of patients with epilepsy remain drug resistant (intractable; refractory). Epilepsy surgery offers a potential cure or significant improvement to those with focal onset drug-resistant seizures. Unfortunately, epilepsy surgery is still underutilized which might be in part because of the complexity of presurgical evaluation. This process includes classifying the seizure type, lateralizing and localizing the seizure onset ...[more]
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Project description:Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.
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Project description:Background and objectiveDrug-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.MethodsThis 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.Key content and findingsThe 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.ConclusionsEvidence 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.
| S-EPMC9986775 | biostudies-literature
Project description:Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ?12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.Receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ?; 95% CI, 11.8 to ?; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution.clinicaltrials.gov Identifier: NCT00040326.
| S-EPMC4821633 | biostudies-literature
Project description:ImportanceStructural integrity of cortex following cortical resection for epilepsy management has been previously characterized, but only in adult patients.ObjectiveThis study sought to determine whether morphometrics of the preserved hemisphere in pediatric cortical resection patients differ from non-neurological controls.DesignThis was a case-control study, from 2013-2022.SettingThis was a single-site study.Participants32 patients with childhood epilepsy surgery and 51 age- and gender-matched controls participated.Main measuresWe quantified morphometrics of the preserved hemisphere at the level of gross anatomy (lateral ventricle size, volume of gray and white matter). Additionally, cortical thickness, volume, and surface area were measured for 34 cortical regions segmented with the Desikan-Killiany atlas, and, last, volumes of nine subcortical regions were also quantified.Results13 patients with left hemisphere (LH) surgery and a preserved right hemisphere (RH) (median age/median absolute deviation of age: 15.7/1.7 yr; 6 females, 7 males) and 19 patients with RH surgery and a preserved LH (15.4/3.7 yr; 11 females, 8 males) were compared to 51 controls (14.8/4.9 yr; 24 females, 27 males). Patient groups had larger ventricles and reduced total white matter volume relative to controls, and only patients with a preserved RH, but not patients with a preserved LH, had reduced total gray matter volume relative to controls. Furthermore, patients with a preserved RH had lower cortical thickness and volume and greater surface area of several cortical regions, relative to controls. Patients with a preserved LH had no differences in thickness, volume, or area, of any of the 34 cortical regions, relative to controls. Moreover, both LH and RH patients showed reduced volumes in select subcortical structures, relative to controls.Conclusions and relevanceThat left-sided, but not right-sided, resection is associated with more pronounced reduction in cortical thickness and volume and increased cortical surface area relative to typically developing, age-matched controls suggests that the preserved RH undergoes structural plasticity to an extent not observed in cases of right-sided pediatric resection. Future work probing the association of the current findings with neuropsychological outcomes will be necessary to understand the implications of these structural findings for clinical practice.
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Project description:ObjectiveEarly onset drug-resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure-free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug-resistant epilepsy and evaluate whether the findings can provide information on patient management.MethodsWe include patients with drug-resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first-tier analysis of the exome data, we aimed to identify disease-causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome-wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsWe recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation.SignificanceOur study suggests that singleton WES is an effective diagnostic tool for drug-resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.
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Project description:More than one-third of people with epilepsy develop drug-resistant epilepsy (DRE). Different hypotheses have been proposed to explain the origin of DRE. Accumulating evidence suggests the contribution of neuroinflammation, modifications in the integrity of the blood-brain barrier (BBB), and altered immune responses in the pathophysiology of DRE. The inflammatory response is mainly due to the increase of cytokines and related molecules; these molecules have neuromodulatory effects that contribute to hyperexcitability in neural networks that cause seizure generation. Some patients with DRE display the presence of autoantibodies in the serum and mainly cerebrospinal fluid. These patients are refractory to the different treatments with standard antiseizure medications (ASMs), and they could be responding well to immunomodulatory therapies. This observation emphasizes that the etiopathogenesis of DRE is involved with immunology responses and associated long-term events and chronic inflammation processes. Furthermore, multiple studies have shown that functional polymorphisms as risk factors are involved in inflammation processes. Several relevant polymorphisms could be considered risk factors involved in inflammation-related DRE such as receptor for advanced glycation end products (RAGE) and interleukin 1β (IL-1β). All these evidences sustained the hypothesis that the chronic inflammation process is associated with the DRE. However, the effect of the chronic inflammation process should be investigated in further clinical studies to promote the development of novel therapeutics useful in treatment of DRE.
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Project description:ObjectiveTo gather real-world evidence on antiseizure medications (ASMs) treatment patterns and related outcomes in patients with drug-resistant focal epilepsy.MethodsMedical insurance claims from the start of 2014 till the end of 2019 were used. Patient selection criteria included International Classification of Diseases (ICD) codes followed by documented ASM use. Baseline patient demographics along with ASM and rescue medication use patterns and related patient outcome were documented for first (index) ASM regimen. Patients who failed the first regimen and then failed the second regimen were considered drug resistant. Multivariate analyses were performed to identify risks and other characteristics for positive or negative treatment outcomes.ResultsStudy cohort consisted of 46 474 patients with a mean age of 47.23 (SD: 16.94). Levetiracetam was the most first-encountered ASM (37.94%). At baseline, 87.14% were treated with ASMs prior to having study-confirmed diagnoses. Mental comorbidities were present in 37.86% of patients. After first-year ASM treatment, 34.61% of patients persisted on their index regimen and 5.91% were seizure-free. Patients failing first ASM regimen numbered 12 868 (27.69%). Drug-resistant patients who failed first and then second ASM regimens numbered 6335 (49.23%). Percentages of patients who had successful second treatment and seizure-free were 21.32 and 3.65, respectively. Initiating patients on lamotrigine or carbamazepine (relative to levetiracetam), baseline use of index ASM, rescue medications, and older age or male gender all lowered the risk for treatment failure. Having higher comorbidity, comorbid mental illness, headache, or neoplasty increased such a risk. Baseline use of index ASM, depressive episode, or anxiety disorder all entailed higher risk of failing second ASM treatment.SignificanceOverall, reported findings indicated that patient history at baseline and the early selection of an ASM all influenced treatment outcomes. Findings pointed to the complex nature of ASM treatment in drug-resistant focal epilepsy patients calling for additional research to identify the optimal treatment to achieve beneficial patient outcomes.
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Project description:Background: Epilepsy is a complex chronic disease of the nervous system which influences the health of approximately 70 million patients worldwide. In the past few decades, despite the development of novel antiepileptic drugs, around one-third of patients with epilepsy have developed drug-resistant epilepsy. We performed a bioinformatic analysis to explore the underlying diagnostic markers and mechanisms of drug-resistant epilepsy. Methods: Weighted correlation network analysis (WGCNA) was applied to genes in epilepsy samples downloaded from the Gene Expression Omnibus database to determine key modules. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to screen the genes resistant to carbamazepine, phenytoin, and valproate, and sensitivity of the three-class classification SVM model was verified through the receiver operator characteristic (ROC) curve. A protein-protein interaction (PPI) network was utilized to analyze the protein interaction relationship. Finally, ingenuity pathway analysis (IPA) was adopted to conduct disease and function pathway and network analysis. Results: Through WGCNA, 72 genes stood out from the key modules related to drug resistance and were identified as candidate resistance genes. Intersection analysis of the results of the LASSO and SVM-RFE algorithms selected 11, 4, and 5 drug-resistant genes for carbamazepine, phenytoin, and valproate, respectively. Subsequent union analysis obtained 17 hub resistance genes to construct a three-class classification SVM model. ROC showed that the model could accurately predict patient resistance. Expression of 17 hub resistance genes in healthy subjects and patients was significantly different. The PPI showed that there are six resistance genes (CD247, CTSW, IL2RB, MATK, NKG7, and PRF1) that may play a central role in the resistance of epilepsy patients. Finally, IPA revealed that resistance genes (PRKCH and S1PR5) were involved in "CREB signaling in Neurons." Conclusion: We obtained a three-class SVM model that can accurately predict the drug resistance of patients with epilepsy, which provides a new theoretical basis for research and treatment in the field of drug-resistant epilepsy. Moreover, resistance genes PRKCH and S1PR5 may cooperate with other resistance genes to exhibit resistance effects by regulation of the cAMP-response element-binding protein (CREB) signaling pathway.
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