Childhood-onset epilepsy: Longitudinal seizure outcomes in a large single-center cohort.

Epilepsy affects approximately 470,000 children in the United States. The estimated median incidence is 50.4 cases per 100,000 persons per year. There are approximately 3.1 million seizure-related emergency department (ED) visits per year among children. Vagus nerve stimulation (VNS) is a treatment option for drug-resistant epilepsy (DRE). While its primary goal is to decrease seizure burden, VNS may decrease seizure intensity and improve quality of life. The authors assessed whether VNS decreased the number of seizure-related ED visits in a cohort of children with DRE. The authors performed a retrospective chart review of pediatric patients (aged 0-21 years) who underwent implantation of a vagus nerve stimulator between January 2009 and January 2020 at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh. They used paired t-tests to assess differences in the number of ED visits 2 years before versus 2 years after VNS device implantation. Univariable linear regression analyses were used to test associations of preoperative characteristics with change in the number of ED visits following vagus nerve stimulator insertion. This study included 240 patients. Compared with patients without seizure-related ED visits before VNS, patients with ≥ 1 ED visits were younger in age at first VNS surgery (9.5 vs 10.8 years), had a shorter epilepsy duration before VNS surgery (5.8 vs 7.4 years), had a later year of device implantation (2014 vs 2012), and on average took more antiseizure medications (ASMs; 2.4 vs 2.1). There was no significant difference between the total number of seizure-related ED visits pre- versus post-VNS surgery (1.72 vs 1.59, p = 0.50), and no difference in status epilepticus-related visits (0.59 vs 0.46, p = 0.17). Univariable linear regression analyses revealed a mean change in ED visits of +0.3 for each year prior to 2022 and -0.5 for each additional ASM that patients took before vagus nerve stimulator insertion. This single-institution analysis demonstrated no significant change in the number of seizure-related ED visits within 2 years following VNS device implantation. Earlier VNS surgery was associated with more seizure-related ED visits after device insertion, suggesting that medical management and center experience may play a role in decreasing seizure-related ED visits. A greater number of ASMs was associated with fewer seizure-related ED visits after VNS device insertion, suggesting the role of medical management, patient baseline seizure threshold, and caregiver comfort with at-home seizure management.

SUDEP and other causes of mortality in childhood-onset epilepsy

To study the impact of childhood-onset epilepsy on a variety of outcomes across the life span. A population-based cohort of 245 subjects with childhood-onset epilepsy was assessed for outcomes at 45 years. In addition, 51 of 78 surviving subjects with uncomplicated epilepsy and 52 of 99 originally matched controls participated in a detailed evaluation including electroencephalography (EEG), imaging, and laboratory studies at 50 years. Of 179 surviving subjects, 61% were in terminal 10-year remission and 43% in remission off medications. At 45 years, 95% of the idiopathic group, 72% of the cryptogenic group, and 47% of the remote symptomatic group were in terminal remission (p < 0.001). Abnormal neurologic signs were significantly more common in subjects with uncomplicated epilepsy than in controls. Mortality during period 1992-2012 was higher in subjects than in controls (9% vs. 1%, p = 0.02). The rate of 3T MRI abnormalities was higher in subjects than in controls (risk ratio [RR] 2.0; 1.3-3.1) specifically including findings considered markers of cerebrovascular disease (RR 2.5; 1.04-5.9). Even subjects with idiopathic epilepsy had higher rates of imaging abnormalities than controls (73% vs. 34%, p = 0.002). Long-term seizure outcomes are excellent and a function of etiology. The presence of imaging abnormalities suggestive of vascular disease may put these subjects at higher risk for clinically evident stroke and cognitive changes as they age.

Background:Malformation of cortical development (MCD) is one of the most common causes of pharmacoresistant epilepsy. Improving the knowledge of antiseizure medications (ASMs) treatment response in epileptic patients with MCD is crucial for optimal treatment options, either pharmacological therapy or non-pharmacological intervention.Aim:To investigate the patterns of medical treatment outcome and the predictors for seizure freedom (SF) with ASM regimens in epilepsy caused by MCD.Methods:The epileptic patients with MCD were consecutively enrolled from March 2013 to June 2019. SF was defined as no seizures for at least 12 months or three times the longest pretreatment inter-seizure interval, whichever was longer. Outcomes were classified into three patterns: pattern A: patients achieved SF at one point and remained so throughout follow-up; pattern B: patients’ seizures fluctuated between periods of SF and relapse; pattern C: SF never attained. The terminal SF was defined if the patients remained SF at the last follow-up visit.Results:A total of 164 epileptic patients with MCD were included. Pattern A was observed in 22, pattern B in 42, and pattern C in 100 patients. SF was ever achieved in 64 (pattern A and B) patients. Twenty-nine patients had terminal SF after a median follow-up time of 4.3 years. With continuing ASM treatment, seizure relapse risk was very low after a 5-year seizure-free period. The pretreatment seizure frequency was the only independent predictor for pattern A and seizure relapse. Sodium channel blockers monotherapy (33.8%) was more effective than levetiracetam (4.5%) in rendering SF in the initial ASM regimen.Conclusion:Medical treatment can be successful in a minority of epileptic patients with MCD, and pretreatment seizure frequency helps to predict the treatment outcome. An unequal efficacy of ASMs in epilepsy caused by MCD suggests etiological evaluation is vital in the management of focal epilepsy.

Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date. Authors performed a retrospective chart review of patients with EMAS who received care at the authors' institutions. A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P=.005, χ2 ). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P<.001), seizure recorded on subsequent EEGs (P=.027), and failure to respond to diet therapy (P=.005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P<.001) and failure to achieve seizure freedom (P<.001). This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.

Clinical conditions of long-term cure in childhood-onset epilepsy: A 45-year follow-up study

Background Prior data has been conflicting about how age at diagnosis impacts patient outcomes and survival. Some studies suggest that younger age at diagnosis may negatively affect survival, independent of other disease characteristics. Accurate predictions of outcomes and patterns of relapse provide invaluable information to patients and help inform physician treatment recommendations, such as the role of extended adjuvant endocrine therapy. Purpose To determine the relapse free survival and overall survival data for all patients diagnosed with invasive breast cancer and treated at BC Cancer from 2005 to 2014. Methods Using the BC Cancer Breast Cancer Outcomes Unit (BCOU) database, we identified all patients referred with newly diagnosed invasive breast cancer at any stage between 2005 and 2014. For descriptive statistics, we analyzed clinical and pathological features at diagnosis and treatment specific variables compared across the following age cohorts: &amp;lt; 35, 35-39, 40-49, 50-59, 60-69, 70-79, and 80 years of age or more. To model the non-linear relationship of age at diagnosis as a continuous variable with the risk of relapse and death, we used an additive Cox proportional hazards model adjusting for subtype, LVI status, use of RT, chemotherapy, hormone therapy, and nodal status. We employed the fitted model to extract estimates for specific values of age while fixing other covariates at different values to create high and low risk cohorts. For subtypes Luminal B, HER2 positive and triple negative breast cancer, high-risk subgroups were defined as node-positive plus treatment with chemotherapy. Low risk was defined as Luminal A and node-negative. The extracted estimates were used to investigate the patterns of relapse among different ages via the means of adjusted cumulative incidence curves and to report the 10 year adjusted relapse free survival and overall survival estimates. Results We identified 24,469 patients who met the inclusion criteria with a median follow-up of 11.5 years. Patients &amp;lt; 35 and between 35-39 years of age were more likely to be diagnosed with breast cancer that was ductal histology, grade 3, LVI positive, HER2 positive, triple negative, and more advanced TNM stage at diagnosis. These younger patients were also more likely to undergo mastectomy, neoadjuvant and adjuvant chemotherapy compared to older age cohorts. Additive Cox proportional hazards revealed a statistically significant and clinically meaningful reduction in 10-year relapse free survival amongst patients with early-stage disease aged 30 and 35 as well as those aged 80, compared to patients aged 50 when adjusted for stage and treatment exposure. This was consistent across all high- and low-risk subgroups (Table 1). 10-year overall survival was significantly and meaningfully reduced in patients aged 30 and 80 compared to age 50 only amongst the high-risk patient populations. Conclusion Both younger and elderly age at breast cancer diagnosis were independent risk factors for poorer prognosis. To our knowledge, this is the largest patient cohort detailing such outcomes differences. Furthermore, this represents a more contemporary clinical context, compared to earlier publications. This work will help clinicians more accurately estimate disease trajectory, and may influence treatments recommendations. Other parameters for the entire cohort will be presented, including a more detailed identification and assessment of patient risk categories and its impact on outcomes. Table 1: 10 year estimates of relapse-free survival and overall survival age estimates by additive Cox proportional hazards model adjusting for subtype, LVI status, use of RT, chemotherapy, hormone therapy, and nodal status. Citation Format: Emily B. Jackson, Lovedeep Gondara, Caroline H. Speers, Karen Gelmon. Does age affect outcome? Data from a large cohort from British Columbia, 2005-2014 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-15.

Epilepsy is among the most common serious neurologic disorders in childhood. Epidemiologic studies over the past few decades have greatly increased current knowledge of the incidence and prognosis of seizures. Newer epidemiologic studies have used population- or community-based cohorts, and careful attention has been given to etiology and specific epilepsy syndromes, the two most important factors affecting prognosis. Risk of epilepsy is highest in patients with an associated serious neurologic abnormality, such as mental retardation or cerebral palsy. More than two thirds of patients with childhood-onset epilepsy ultimately achieve remission. Of those attaining remission on medications, approximately 70% remain seizure free when medications are discontinued. Mortality is increased in patients with epilepsy, but the increased mortality risk in childhood-onset epilepsy is primarily seen in patients with neurologic abnormalities or intractable epilepsy. Although long-term seizure outcomes are generally favorable, childhood-onset epilepsy is associated with adverse long-term psychosocial outcomes, even in patients attaining remission. This review summarizes recent data on the epidemiology and prognosis of pediatric epilepsy.

Oligoepilepsy and lifelong seizure susceptibility in epilepsy with generalized tonic-clonic seizures alone: Experience at an adult tertiary center

Changes in seizure duration during acute course electroconvulsive therapy

Individualised prediction of seizure recurrence and long-term outcome after antiepileptic drug withdrawal

In clinical practice, it is important to predict as soon as possible after diagnosis and starting treatment, which children are destined to develop medically intractable seizures and be at risk of increased mortality. In this study, we determined factors predictive of long-term seizure and mortality outcome in a population-based cohort of 102 children. At the end of the 40-year median follow-up, since their first seizure before the age of 16 years, 95 (93%) of 102 patients had entered one or more one-year remissions (1YR). In contrast, 7 (7%) patients never experienced any 1YR and their epilepsy was considered drug-resistant. Two factors present early in the course of treatment were found to be associated with adverse outcome. Having weekly seizures during the first year of treatment carried an 8-fold risk [hazard ratio 8.2 (1.6-43.0), P = 0.0125] of developing drug resistant epilepsy and a 2-fold risk of never entering terminal 1YR [hazard ratio 2.7 (1.5-5.0), P = 0.0010]. Having weekly seizures prior to treatment only slightly increased the risk to never enter terminal 1YR [hazard ratio 1.7 (1.04-2.9), P = 0.0350]. Thirteen of 102 patients (13%) died during follow-up. Long-term mortality was 9-fold higher for patients with symptomatic epilepsy [hazard ratio 9.0 (1.8-44.8), P = 0.0071]. Mortality was not, however, increased by having weekly seizures prior to or during the first year of treatment versus fewer seizures. Early seizure frequency can predict long-term seizure control during antiepileptic drug treatment, but not mortality. Aetiology, however, is predictive of both seizure outcome and mortality in childhood-onset epilepsy. Using these criteria allows early identification of children destined to develop intractable epilepsy and increased mortality.

To provide evidence of whether seizure clustering is associated with drug resistance and increased mortality in childhood-onset epilepsy, a prospective, long-term population-based study was performed. One hundred and twenty patients who had been followed since disease onset (average age 37.0 years, SD 7.1, median 40.0, range 11-42; incident cases) were included. At the end of the follow-up period, 26 (11 boys) of these patients (22%) had recorded clusters of seizures. Fourteen recorded pre-treatment clusters, including 10 patients with clusters as first seizures; and in 12 patients, clusters occurred during treatment. In these 12 patients, first clustering began after 16 (range 0-35; median 15) years of treatment. Compared with the patients without clusters, those with clusters more often had at least one seizure per week at the initial stage (63% versus 32%, P = 0.0178) and during the follow-up period (P-value varied from 0.0464 to 0.0064). Patients having seizure clusters during drug therapy were more likely to have drug resistant epilepsy compared to those not experiencing seizure clusters (42% versus 13%; P = 0.0102) and had a lower rate of entering 5-year terminal remission (P = 0.0039) and 5-year remission (P = 0.0230). In addition, the risk of death was significantly increased among patients with seizure clusters during drug therapy compared with those who had not experienced any clustering (42% versus 14%; P = 0.0299 two-sided Fisher's exact test). The risk ratio for patients with clusters was 3.49 (95%CI 1.25-9.78). In contrast, patients with seizure clustering prior to, but not during, treatment versus those with no clustering showed no difference in seizure outcome or mortality risk. In conclusion, clustering of seizures during treatment, but not prior to treatment, is associated with a poorer long-term seizure and mortality outcome.

Seizure Clustering During Drug Treatment Affects Seizure Outcome and Mortality of Childhood-Onset Epilepsy. Sillanpää M, Schmidt D. Brain 2008;131(Pt 4):938–944. To provide evidence of whether seizure clustering is associated with drug resistance and increased mortality in childhood-onset epilepsy, a prospective, long-term population-based study was performed. One hundred and twenty patients who had been followed since disease onset (average age 37.0 years, SD 7.1, median 40.0, range 11–42; incident cases) were included. At the end of the follow-up period, 26 (11 boys) of these patients (22%) had recorded clusters of seizures. Fourteen recorded pre-treatment clusters, including 10 patients with clusters as first seizures; and in 12 patients, clusters occurred during treatment. In these 12 patients, first clustering began after 16 (range 0–35; median 15) years of treatment. Compared with the patients without clusters, those with clusters more often had at least one seizure per week at the initial stage (63% versus 32%, P = 0.0178) and during the follow-up period ( P-value varied from 0.0464 to 0.0064). Patients having seizure clusters during drug therapy were more likely to have drug resistant epilepsy compared to those not experiencing seizure clusters (42% versus 13%; P = 0.0102) and had a lower rate of entering 5-year terminal remission ( P = 0.0039) and 5-year remission ( P = 0.0230). In addition, the risk of death was significantly increased among patients with seizure clusters during drug therapy compared with those who had not experienced any clustering (42% versus 14%; P = 0.0299 two-sided Fisher's exact test). The risk ratio for patients with clusters was 3.49 (95%CI1.25–9.78). In contrast, patients with seizure clustering prior to, but not during, treatment versus those with no clustering showed no difference in seizure outcome or mortality risk. In conclusion, clustering of seizures during treatment, but not prior to treatment, is associated with a poorer long-term seizure and mortality outcome.

Long-term seizure outcome and antiseizure medication use in autoimmune encephalitis