Multimodal Prognostic Features of Seizure Freedom in Epilepsy Surgery

Abstract found in DocWire News

OBJECTIVE: Accurate preoperative predictions of seizure freedom following surgery for focal drug resistant epilepsy remain elusive. Our objective was to systematically evaluate all meta-analyses of epilepsy surgery with seizure freedom as the primary outcome, to identify clinical features that are consistently prognostic and should be included in the future models.

METHODS: We searched PubMed and Cochrane using free-text and Medical Subject Heading (MeSH) terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. This study was registered on PROSPERO. We classified features as prognostic, non-prognostic and uncertain and into seven subcategories: ‘clinical’, ‘imaging’, ‘neurophysiology’, ‘multimodal concordance’, ‘genetic’, ‘surgical technique’ and ‘pathology’. We propose a structural causal model based on these features.

RESULTS: We found 46 features from 38 meta-analyses over 22 years. The following were consistently prognostic across meta-analyses: febrile convulsions, hippocampal sclerosis, focal abnormal MRI, Single-Photon Emission Computed Tomography (SPECT) coregistered to MRI, focal ictal/interictal EEG, EEG-MRI concordance, temporal lobe resections, complete excision, histopathological lesions, tumours and focal cortical dysplasia type IIb. Severe learning disability was predictive of poor prognosis. Others, including sex and side of resection, were non-prognostic. There were limited meta-analyses investigating genetic contributions, structural connectivity or multimodal concordance and few adjusted for known confounders or performed corrections for multiple comparisons.

SIGNIFICANCE: Seizure-free outcomes have not improved over decades of epilepsy surgery and despite a multitude of models, none prognosticate accurately. Our list of multimodal population-invariant prognostic features and proposed structural causal model may serve as an objective foundation for statistical adjustments of plausible confounders for use in high-dimensional models.

Interictal Pattern on Scalp Electroencephalogram Predicts Excellent Surgical Outcome of Epilepsy Caused by Focal Cortical Dysplasia

Abstract found in Wiley Online Library

Objective: Focal cortical dysplasia (FCD) represents an essential cause of drug-resistant epilepsy with surgery as an effective treatment option. This study aimed to identify the important predictors of favorable surgical outcomes and the impact of the interictal scalp electroencephalogram (EEG) patterns in predicting postsurgical seizure outcomes.

Methods: We retrospectively evaluated 210 consecutive patients between 2015 and 2019. They were diagnosed with FCD by pathology, underwent resection, and had at least one year of postsurgical follow-up. Predictors of seizure freedom were analyzed.

Results: Based on the information at the latest follow-up, seizure outcome was classified as Engel Class I (seizure-free) in 81.4% and Engel Class II-IV (non-seizure-free) in 18.6% of patients. There were 43, 105, and 62 cases of FCD type I, type II, and type III, respectively. The interictal EEG showed a repetitive discharge pattern (REDP) in 87 (41.4%) patients, polyspike discharge pattern (PDP) in 41 (19.5%), and the coexistence of REDP and PDP in the same location in 32 (15.2%) patients. The analyzed patterns in order of frequency were repetitive discharges lasting 5 seconds or more (32.4%); polyspikes (16.7%); RED type 1 (11.4%); continuous epileptiform discharges occupying >80% of the recording (11.4%); RED type 2 (6.2%); brushes (3.3%); focal, fast, continuous spikes (2.4%); focal fast rhythmic epileptiform discharges (1.43%); and frequent rhythmic bursting epileptiform activity (1.4%). The coexistence of REDP and PDP in the same location on scalp EEG and complete resection of the assumed epileptogenic zone (EZ) was independently associated with favorable postsurgical prognosis.

Significance: Resective epilepsy surgery for intractable epilepsy caused by FCD has favorable outcomes. Interictal scalp EEG patterns were revealed to be predictive of excellent surgical outcomes and may help clinical decision-making and enable better presurgical evaluation.

Science One Step Closer to Turning Off Seizures, Sleep Disturbances Linked to Intellectual Disability

Article published in Science Daily

Science is one step closer to developing targeted drug therapies that may reduce seizures, sleep disorders, and related symptoms common in people with intellectual disabilities.

Research led by a team of UNLV neuroscientists has shown the potential to zero in on the root-level cause of a host of adverse symptoms associated with unique subtypes of neurodevelopmental disorders, work that could one day improve the lives of millions worldwide.

The study, published Feb. 15 in the Nature journal Molecular Psychiatry, builds on previous research by UNLV neuroscientist Rochelle Hines and collaborators, which discovered that two key proteins — collybistin and the GABAA receptor ?2 subunit — control the firing of brain cells and contribute to epileptic seizures, learning and memory deficiencies, sleep disturbances, and other symptoms frequently associated with various forms of intellectual disability including Down syndrome, autism, and ADHD.

The team’s newest findings unveiled that mutations in ARHGEF9 — the gene that codes for collybistin — lead to intellectual disability through impaired ?2 subunit function. The team further showed that ?2 is a central hub for many of the adverse neurological symptoms characteristic of multiple intellectual disability subtypes.

In addition to patients with neurodevelopmental disorders, researchers said their study has the potential to improve the quality of life more broadly for people who grapple with sleep dysfunction, epilepsy, anxiety, hyperactivity, and other neurological abnormalities.

Surgical Outcome of Temporal Plus Epilepsy is Improved by Multilobar Resection

Abstract found in PubMed and originally published in Epilepsia

Objective: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE.

Methods: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations (“temporal lobe epilepsy [TLE] surgery”) or multilobar interventions including the temporal lobe (“TPE surgery”), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson ?2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate.

Results: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery.

Significance: This study suggests that surgical outcome in patients with temporal plus epilepsy can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a temporal plus epilepsy is suspected.

Incidence and Prevalence of Major Epilepsy-Associated Brain Lesions

Abstract found in ScienceDirect and originally published in Epilepsy & Behavior

Epilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections. We also assessed the relative proportion of brain lesions using post-surgical histopathological findings from 541 surgical patients from the Cleveland Clinic and 9,523 patients from a European multi-center cohort. Data were combined to generate surgical candidate incidence and prevalence estimates and the first lesion-specific estimates for hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), malformations of cortical development (MCD), glial scars, vascular malformations, and encephalitis. The most frequently diagnosed brain lesions were HS (incidence = 2.32 ± 0.26 in 100,000, prevalence = 19.40 ± 2.16 in 100,000) for adults and MCD (incidence = 1.15 ± 0.34 in 100,000, prevalence = 6.52 ± 1.89 in 100,000) for children. Our estimates can guide patient advocacy groups, clinicians, researchers, policymakers in education, development of health care strategy, resource allocation, and reimbursement schedules.

Standardization of Seizure Response Times and Data Collection in an Epilepsy Monitoring Unit

Abstract found in PubMed

Objective: We sought to improve seizure response times in the epilepsy monitoring unit (EMU), improve the accuracy and reliability of seizure response time data collection, and develop a standardized and automated approach for seizure response data collection in the EMU.

Methods: We used Quality Improvement (QI) methodology to understand the EMU workflow involved in responding to seizures (a process map); to create a theory of change that stated the desired aim, potential drivers/barriers and interventions (i.e., key driver diagram) and perform iterative interventions to address some of the drivers plan-do-study-act (PDSA) cycles. We performed three PDSA cycles with a focus on improving the seizure alert system in our EMU. Adjustments were made to the methodology as it became clear that this was a systems issue, and our project would need to focus on improving the system rather than iteratively improving a functioning (stable) system.

Results: Over a 6-month period, 252 seizure response times were recorded and analyzed. We performed 3 interventions. The first was initiating twice monthly meetings with nursing and EEG techs to discuss the project and provide feedback on response times. The second was the implementation of a new Hill-Rom seizure alert system to reduce alert times and automate data tracking. The third was implementing a new alert deactivation system to reduce variability in the data. Following these 3 interventions, variation, and data collection methods were improved while also maintaining improvements in seizure response times.

Significance: We identified and implemented an alert system in our epilepsy monitoring unit which led to more efficient and accurate data collection while maintaining improved response times that resulted from the first intervention. This lays the groundwork for future quality improvement initiatives and has created a framework for standardizing seizure response time recording and data collection that can be replicated at other centers with similar infrastructure, personnel and workflows.

Substantial Early Changes in Bone and Calcium Metabolism Among Adult Pharmacoresistant Epilepsy Patients on a Modified Atkins Diet

Abstract appeared in Wiley Online Library

Objective: The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism.

Methods: Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin.

Results: After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (?25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant.

Significance: Twelve weeks of modified Atkins diet (MAD) treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

The Effect of Epilepsy Surgery on Productivity

Abstract appeared in Wiley Online Library

 Objectives: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people’s ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes.

Methods: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews – Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes.

Results: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07–1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15–0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90–0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94–0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies – of Interventions and was low for most variables except ”measurement of exposure.”

Significance: There is clear evidence that resective surgery in eligible surgical drug-resistant epilepsy (DRE) patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

Effectiveness of Zonisamide (Zonegran®) in Childhood Refractory Epilepsy

Abstract appeared in PubMed

Introduction: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy.

Method: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients.

Results: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant.

Conclusion: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.

The Beneficial Effect of Probiotics Supplementation on Penicillin-Induced Focal Seizure in Rats

Abstract published in PubMed

The focal epilepsy is a chronic neurological brain disorder which affects millions of people in the world. There is emerging evidence that changes in the gut microbiota may have effects on epileptic seizures. In the present study, we examined the effect of probiotics on penicillin-induced focal seizure model in rats. Male Wistar Albino rats (n: 21) were randomly divided into three groups: control (no medication), penicillin and penicillin + probiotic. Probiotic VSL#3 (12.86 bn living bacteria/kg/day) was given by gavage for 30 days. The seizures were induced by intracortical injection of penicillin G (500 IU) into the cortex. An ECoG recordings were made for 180 min after penicillin G application. The spike frequency and the amplitude were used to assess the severity of seizures. Tumor necrosis factor (TNF-?), nitric oxide (NO) and interleukin (IL-6) levels in the brain were studied biochemically. Our results indicated that probiotic supplementation improved focal seizures through increasing the latency (p < 0.001) and decreasing the spike frequency (p < 0.01) compared to the penicillin group. Penicillin-induced seizure in rats significantly enhanced TNF-? (p < 0.01), NO (p < 0.01) and IL-6 (p < 0.05) compared to the control. Probiotic supplementation significantly decreased IL-6 (p < 0.05), TNF-? (p < 0.01) and NO (p < 0.001) compared to the penicillin group. When the body weights were compared before and after the experiment, there was no difference between the control and penicillin groups, but it was observed that the body weight decreased after probiotic supplementation in the penicillin + probiotic group.

Probiotic supplementation may have anti-seizure effect by reducing proinflammatory cytokine and nitric oxide levels in epileptic rat brain.