Individualized prediction of seizure relapse and outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery

The objective of this study was to create a clinically useful tool for individualized prediction of seizure outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery. We used data from the European retrospective TimeToStop study, which included 766 children from 15 centers, to perform a proportional hazard regression analysis. The 2 outcome measures were seizure recurrence and seizure freedom in the last year of follow‐up. Prognostic factors were identified through systematic review of the literature. The strongest predictors for each outcome were selected through backward selection, after which nomograms were created. The final models included 3 to 5 factors per model. Discrimination in terms of adjusted concordance statistic was 0.68 (95% confidence interval [CI] 0.67‐0.69) for predicting seizure recurrence and 0.73 (95% CI 0.72‐0.75) for predicting eventual seizure freedom. An online prediction tool is provided on www.epilepsypredictiontools.info/ttswithdrawal . The presented models can improve counseling of patients and parents regarding postoperative antiepileptic drug policies, by estimating individualized risks of seizure recurrence and eventual outcome.     

Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: A long-term population-based study of childhood-onset epilepsy

The long-term outcome with respect to seizure relapse after planned discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is not well known. Relapse and its treatment outcome were evaluated in a longitudinal population-based study of 148 patients from the onset of their epilepsy to an average follow-up of 37 years. During the study, AEDs were completely discontinued by 90 patients; 58 patients remained on medication. Seizure relapse after AED discontinuation was observed in 33 (37%) of 90 patients at an average follow-up of 32 years. Among 8 of the 33 patients who elected to restart AEDs, 2 achieved 5-year terminal remission (5YTR), but only 10–19 years after restarting treatment. The other 6 patients never achieved 5YTR, and 2 of the 6 never entered a 5-year remission period during follow-up. Factors associated with failure to reach 5YTR after treatment of relapse were symptomatic etiology and localization-related epilepsy. In conclusion, drug discontinuation after seizure freedom results in relapse in one-third of patients. Reinstitution of a medication that worked for years fails to achieve control in one of four patients. These risks need to be considered, although there is no evidence that discontinuation is responsible for the poor prognosis for treatment of seizure recurrence.     

Time to relapse after epilepsy surgery in children: AED withdrawal policies are a contributing factor

Aim. It was recently suggested that early postoperative seizure relapse implicates a failure to define and resect the epileptogenic zone, that late recurrences reflect the persistence or re‐emergence of epileptogenic pathology, and that early recurrences are associated with poor treatment response. Timing of antiepileptic drugs withdrawal policies, however, have never been taken into account when investigating time to relapse following epilepsy surgery. Methods. Of the European paediatric epilepsy surgery cohort from the “TimeToStop” study, all 95 children with postoperative seizure recurrence following antiepileptic drug (AED) withdrawal were selected. We investigated how time intervals from surgery to AED withdrawal, as well as other previously suggested determinants of (timing of) seizure recurrence, related to time to relapse and to relapse treatability. Uni‐ and multivariable linear and logistic regression models were used. Results. Based on multivariable analysis, a shorter interval to AED reduction was the only independent predictor of a shorter time to relapse. Based on univariable analysis, incomplete resection of the epileptogenic zone related to a shorter time to recurrence. Timing of recurrence was not related to the chance of regaining seizure freedom after reinstallation of medical treatment. Conclusion. For children in whom AED reduction is initiated following epilepsy surgery, the time to relapse is largely influenced by the timing of AED withdrawal, rather than by disease or surgery‐specific factors. We could not confirm a relationship between time to recurrence and treatment response. Timing of AED withdrawal should be taken into account when studying time to relapse following epilepsy surgery, as early withdrawal reveals more rapidly whether surgery had the intended curative effect, independently of the other factors involved.     

Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience

PURPOSE: We reviewed the impact of planned discontinuation of antiepileptic drugs (AEDs) in seizure-free patients on seizure recurrence and the seizure outcome of reinstituted treatment. METHODS: A literature review was performed yielding 14 clinical observations of seizure recurrence after discontinuation and its treatment outcome. RESULTS: Seizure recurrence rate after AED discontinuation ranged between 12 and 66% (mean 34%, 95%CI: 27-43) in the 13 reviewed studies (no data in one study). Reinstitution of AEDs after recurrence was efficacious between 64-91% (mean of 14 studies, 80%, 95%CI: 75-85%) at follow-up. Mean follow-up ranged from 1-9 years. Seizure outcome of resumed treatment was not different for series in children and adolescents (84%, mean of 4 studies, 95%CI: 75-93) or in adults only (80%, mean of 9 studies, 95%CI: 74-86). Although seizure control was regained within approximately one year in half of the cases becoming seizure free, it took some patients as many as 5-12 years. In addition, in 19% (mean of 14 studies, 95%CI: 15-24%), resuming medication did not control the epilepsy as before, and chronic drug-resistant epilepsy with many seizures over as many as five years was seen in up to 23% of patients with a recurrence. Factors associated with poor treatment outcome of treating recurrences were symptomatic etiology, partial epilepsy and cognitive deficits. CONCLUSIONS: These serious and substantial risks weigh against discontinuation of AEDs in seizure-free patients, except perhaps for selected patients with idiopathic epilepsy syndromes of childhood or patients with rare seizures.     

Challenges in the first seizure clinic for adult patients with epilepsy

Aims. (1) To delineate the challenges in seizure diagnosis in the first seizure clinic setting for adult patients of a teaching hospital, and (2) quantify the diagnostic accuracy of the referral source and the yield of routine investigations, including blood tests, EEGs, and neuroimaging. Methods. We retrospectively reviewed medical records of patients referred by the emergency department to the adult first seizure clinic and seen by the same epilepsy specialist between June 2007 and June 2011. The diagnostic accuracy in the emergency department was calculated by comparing with the final diagnosis made by an epilepsy specialist. Results. In total, 219 patients were referred to the first seizure clinic. Median age was 45 and 60% of patients were male. From the cohort, 38 (17%) patients presented with seizure mimickers; the most common were reflex syncope (74%) and psychogenic non‐epileptic seizures (16%). From the remaining 181 patients presenting with seizures, only 110 (61%) of these patients were diagnosed with true first seizures, and 71 (39%) patients had evidence of previous seizures. Nineteen (17%) of true first‐ever seizures were provoked. The most frequent cause of provoked seizures was alcohol and illicit drugs (65%). In the emergency department, sensitivity and specificity in seizure diagnosis were 0.74 and 0.32, respectively. In our true first seizure patients, the EEG demonstrated epileptiform discharges in 22 (21%) patients. In the same cohort, computed tomography and magnetic resonance neuroimaging conferred 16% and 20% probability of finding a potentially epileptogenic structural abnormality, respectively. The most common epileptogenic abnormality found on magnetic resonance neuroimaging was cortical infarct. Conclusions. The diagnosis and management of first seizure remains challenging due to the variety of seizure mimickers and low yield of investigations. Our data highlight the potential pitfalls and practical challenges in this process, as well as the need for these patients to be assessed in dedicated first seizure clinics.     

Changes in autonomic cardiac control in patients with epilepsy after discontinuation of antiepileptic drugs: a randomized controlled withdrawal study

The aim of this study was to assess cardiac autonomic control in patients with epilepsy before and after withdrawal of antiepileptic drugs (AEDs). The study was prospective, randomized and double blinded. Spectral analysis of heart rate variability (HRV) in 24 h ECG-registration before and after withdrawal of AEDs was used to assess autonomic cardiac control. The assessment of HRV with spectral analysis was based on sinus rhythm and normal heart beats [normal to normal beat (NN)]. Thirty-nine patients had 24 h rhythms free from any ectopic beats both before and after intervention, and were included in the analysis. Significant differences were found in the withdrawal group: filtered RR intervals for all 5 min segments of the analysis; percentage of differences between adjacent filtered RR intervals that are greater than 50 ms for the whole analysis; very low frequency power; low frequency power and high frequency power. The results demonstrate that slow withdrawal of AEDs in seizure-free patients with epilepsy on drug mono-therapy resulted in an increase in both parasympathetic and sympathetic functions, indicative of increased power amongst patients following cessation of AED treatment. As low HRV has been associated with increased mortality in patients with other diseases, this increased HRV may be beneficial.     

Machine learning for prediction of delirium in patients with extensive burns after surgery

Aims

Machine learning-based identification of key variables and prediction of postoperative delirium in patients with extensive burns.

Methods

Five hundred and eighteen patients with extensive burns who underwent surgery were included and randomly divided into a training set, a validation set, and a testing set. Multifactorial logistic regression analysis was used to screen for significant variables. Nine prediction models were constructed in the training and validation sets (80% of dataset). The testing set (20% of dataset) was used to further evaluate the model. The area under the receiver operating curve (AUROC) was used to compare model performance. SHapley Additive exPlanations (SHAP) was used to interpret the best one and to externally validate it in another large tertiary hospital.

Results

Seven variables were used in the development of nine prediction models: physical restraint, diabetes, sex, preoperative hemoglobin, acute physiological and chronic health assessment, time in the Burn Intensive Care Unit and total body surface area. Random Forest (RF) outperformed the other eight models in terms of predictive performance (ROC:84.00%) When external validation was performed, RF performed well (accuracy: 77.12%, sensitivity: 67.74% and specificity: 80.46%).

Conclusion

The first machine learning-based delirium prediction model for patients with extensive burns was successfully developed and validated. High-risk patients for delirium can be effectively identified and targeted interventions can be made to reduce the incidence of delirium.     

Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models

Summary. The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.     

Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience

PURPOSE: Although epilepsy surgery, especially temporal lobe epilepsy surgery, is well established to control seizures in patients remaining on antiepileptic drug (AED) treatment, less information is available about how many seizure-free surgical patients will relapse after discontinuation of AEDs under medical supervision. METHODS: A literature review yielded six retrospective clinical observations. RESULTS: After planned discontinuation of AEDs in patients rendered seizure free after epilepsy surgery, most often various forms of temporal lobe surgery, the mean percentage recurrence rate in adults in four studies was 33.8%[95% confidence interval (CI), 32.4-35.2%], with maximum follow-up ranging from 1 to 5 years. Seizure recurrence increased during the follow-up of 1 to 3 years and occurred within 3 years of AED discontinuation. In one study of children with temporal lobe epilepsy, the recurrence rate was 20%. More than 90% of adult patients with seizure recurrence regained seizure control with reinstitution of previous AED therapy. Seizure recurrence was unaffected by the duration of postoperative AED treatment; as a consequence, delaying discontinuation beyond 1 to 2 years of complete postoperative seizure control seems to have no added benefit. The occurrence of rare seizures or auras after surgery did not eliminate the possibility of eventual successful AED discontinuation. CONCLUSIONS: AED discontinuation is associated with a seizure recurrence in one in three patients rendered seizure free by epilepsy surgery. These results will be useful in counseling patients about discontinuing AED treatment after successful epilepsy surgery.     

Outcomes of the second withdrawal of anti-seizure medication in patients with pediatric-onset epilepsy

Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success rate and recurrence risk factors after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of a self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were negative factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure-free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.     

Antiepileptic drug withdrawal in medically and surgically treated patients: a meta‐analysis of seizure recurrence and systematic review of its predictors

Aim. Many seizure‐free patients consider withdrawal of antiepileptic drugs, both when seizure control is achieved by medication alone, or once they became seizure‐free following epilepsy surgery. The risk of recurrence is consequently of very important prognostic value. However, estimations of recurrence risks are outdated for both populations. In addition, although many publications have reported predictors of seizure relapse, no comprehensive overview of prognostic factors is available. Methods. A systematic review of the databases of PubMed and EMBASE was conducted, identifying articles on antiepileptic drug withdrawal in patient cohorts. Recurrence risk meta‐analyses were performed for both populations at one, two, three to four, and five or more years of follow‐up. Within the selected articles, studies presenting multivariable analysis of predictors were identified; all studied predictors were listed, as well as all significant independent predictors. The quality of separate analyses of predictors was assessed. Results. There was no significant difference of long‐term cumulative recurrence risk between surgical and medication‐only populations, with respectively 29% and 34% recurrences. In medication‐only treated patients, 25 factors have been reported as significant independent predictors; 12 have been reported in surgical cohorts. The quality of most analyses of predictors was low to moderate. No predictor was consistently found among all analyses, and for most predictors, study results were contradictory. Conclusion. No consistent set of predictors could be identified because a large number of variables have been identified in the literature, many studies reported contradicting results, study populations varied considerably, and the quality of the original studies was often low. Meta‐analysis of individual participant data is necessary, because it allows for (1) correction for differences in follow‐up duration between subjects and studies, (2) a study of interaction effects, (3) calculation of more accurate estimates valid across several populations, and (4) the assessment of each predictor's effect size.     

Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs

Purpose: To classify the grade of antiepileptic drug (AED) resistance in a cohort of patients with focal epilepsies, to recognize the risk factors for AED resistance, and to estimate the helpfulness of “new‐generation” AEDs. Methods: We included 1,155 adults with focal epilepsies who were observed consecutively after 1990 and followed regularly at two epilepsy centers. We systematically collected the clinical, diagnostic, and therapeutic data using a custom‐written database. We classified the patients as seizure‐free or AED resistant according to the International League Against Epilepsy (ILAE) criteria, and we evaluated the risk factors associated with AED resistance using logistic regression analysis. We further grouped AED‐resistant patients in different grades (I, II, and III) according to the number of AEDs already tried as proposed by Perucca. Key Findings: AED resistance occurred in 57.8% of the 729 patients with symptomatic focal epilepsies and was positively associated with electroencephalography (EEG) abnormalities, seizure type, and the presence of mesial temporal sclerosis. Among 426 patients without detectable causes, the percentage of AED resistance was significantly lower (39.2%) and correlated with EEG abnormalities and psychiatric symptoms. Among AED‐resistant patients, the majority (64.6%) had tried three or more AEDs, which fit the more severe grade III proposed by Perucca. Among seizure‐free patients, more than one‐half (57%) needed to try two or more AEDs before reaching seizure control (14.9% needed three or more AEDs). Furthermore, among seizure‐free patients who could be previously classified as resistant to two or more AEDs, 52.2% reached seizure freedom while receiving treatment with “new generation” AEDs. Significance: The ILAE classification of AED resistance, as well the graded classification proposed by Perucca, was easily exploitable in our patients, although these classifications systems appear to have a limited value in predicting seizure outcome. Actually, a small but not negligible percentage of patients reached seizure freedom after trying several AEDs (including “new” AEDs), suggesting repeated trials may be necessary for seizure control.     

单侧慢性硬膜下血肿钻孔引流术后复发的临床预测模型建立与验证

目的 研究基于临床资料建立并验证单侧慢性硬膜下血肿(CSDH)钻孔引流术后复发的预测模型.方法 纳入采用钻孔引流治疗的366例单侧CSDH患者.根据首次钻孔后3个月内是否CSDH复发,将患者分为复发组和非复发组;分析比较与CSDH术后复发可能相关的15项因素.采用最小绝对收缩和选择算子(LASSO)回归来降低数据维度和...     

Caregiver measures for seizure control, efficacy, and tolerability of antiepileptic drugs for childhood epilepsy: results of a preference survey

We sought to identify and quantify caregiver-defined characteristics of efficacy related to the perceived success of antiepileptic drug (AED) use. A 22-question survey was designed using physician input, focus groups, and clinical trial endpoints. Responses were pooled and analyzed with regard to seizure type and treatment, categorized as controlled (exposure to 1 AED), adjunctive (exposure to 2 AEDs), or refractory (exposure to ≥ 3 AEDs). Two hundred ninety-five surveys were completed: 109 (37%) controlled, 84 (28%) adjunctive, and 102 (35%) refractory. Seizure freedom and median seizure reduction > 90% maintained for > 1 year were reported as the most important indicators of medication efficacy by the majority of respondents. These measures were the same regardless of seizure type or treatment category. Our results demonstrate that current trial design may be inadequate to address the expectations of patients. Incorporating patient-defined AED efficacy measures may improve satisfaction and informed decision making regarding epilepsy treatment.     

External validation of the Epilepsy Surgery Grading Scale in a Japanese cohort of patients with epilepsy

Objective: The Epilepsy Surgery Grading Scale (ESGS) is a simple method to predict the likelihood of a patient with epilepsy proceeding to surgery and achieving seizure freedom. Usefulness of the ESGS has been confirmed in established epilepsy centres in the United States and Belgium for adult patients with drug‐resistant focal epilepsy undergoing presurgical evaluation. However, the applicability of the ESGS has not yet been evaluated in a wider range of epilepsy patients that may reflect the general spectrum of epilepsy. The present study validated the ESGS in a Japanese epilepsy centre in which admission‐based comprehensive epilepsy studies were indicated beyond presurgical evaluation. Methods: This single‐centre retrospective study included adult patients with epilepsy admitted to the Epilepsy Monitoring Unit from 2010 to June 2019. Patients were classified as ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favourable). Patients were grouped into three cohorts: all patients, patients with drug‐resistant focal epilepsy, and patients who underwent resective epilepsy surgery. We assessed progression to surgery and seizure freedom at one year after surgery. Results: Of the 1,158 total admissions, 670 patients met the inclusion criteria and formed the total cohort. Of these, 435 (64.9%) had drug‐resistant focal epilepsy and 78 (11.6%) proceeded to resective surgery. Overall, progression to surgery was observed in 41.3%, 16.6%, and 4.8% of patients with Grade 1, 2, and 3, respectively. In the surgical cohort, seizure freedom was observed in 85.2%, 65.2%, and 31.3% of patients with Grade 1, 2, and 3, respectively. Significance: Our results indicate that the ESGS is effective in predicting whether a patient proceeds to epilepsy surgery and achieves seizure freedom even in the general population of epilepsy patients, regardless of type or resistance to antiepileptic drugs.     

Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with the various antiepileptic drugs (clonazepam [CZP], oxcarbazepine [OXC], phenobarbital [PB], tiagabine [TGB], and valproate [VPA]), in the mouse 6 Hz psychomotor seizure model.Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel and non-parallel dose–response effects was used to characterize the consequent anticonvulsant interactions between the various drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CZP, OXC, PB, TGB, and VPA at the fixed-ratio of 1:1 were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip-strength (muscular strength) tests.LEV administered singly was associated with a dose–response relationship curve (DRRC) that was parallel to that for CZP and non-parallel to that for OXC, PB, TGB and VPA. With isobolography for parallel DRRCs, the combination of LEV with CZP at three fixed-ratios of 1:3, 1:1 and 3:1 was additive in nature. With isobolography for non-parallel DRRCs the combinations of LEV with OXC, TGB and VPA at the fixed-ratio of 1:1 were also additive. In contrast, the isobolography for non-parallel DRRCs revealed that the interaction for the combination of LEV with PB at the fixed-ratio of 1:1 was supra-additive (synergistic). None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength.LEV is associated with favorable anticonvulsant synergism with PB and is additive with regards to CZP, OXC, TGB and VPA in the mouse 6 Hz psychomotor seizure model.