Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis.

BACKGROUND: People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of life because of the elimination of adverse events. The risk with this action, however, is seizure recurrence. The objectives of our study were to identify predictors of seizure recurrence and long-term seizure outcomes and to produce nomograms for estimation of individualised outcomes. METHODS: We did a systematic review and meta-analysis, and identified eligible articles and candidate predictors, using PubMed and Embase databases with a last update on Nov 6, 2014. Eligible articles had to report on cohorts of patients with epilepsy who were seizure-free and had started withdrawal of antiepileptic drugs; articles also had to contain information regarding seizure recurrences during and after withdrawal. We excluded surgical cohorts, reports with fewer than 30 patients, and reports on acute symptomatic seizures because these topics were beyond the scope of our objective. Risk of bias was assessed using the Quality in Prognosis Studies system. Data analysis was based on individual participant data. Survival curves and proportional hazards were computed. The strongest predictors were selected with backward selection. Models were converted to nomograms and a web-based tool to determine individual risks. FINDINGS: We identified 45 studies with 7082 patients; ten studies (22%) with 1769 patients (25%) were included in the meta-analysis. Median follow-up was 5·3 years (IQR 3·0-10·0, maximum 23 years). Prospective and retrospective studies and randomised controlled trials were included, covering non-selected and selected populations of both children and adults. Relapse occurred in 812 (46%) of 1769 patients; 136 (9%) of 1455 for whom data were available had seizures in their last year of follow-up, suggesting enduring seizure control was not regained by this timepoint. Independent predictors of seizure recurrence were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on electroencephalogram (EEG) before withdrawal. Independent predictors of seizures in the last year of follow-up were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, number of antiepileptic drugs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal. Adjusted concordance statistics were 0·65 (95% CI 0·65-0·66) for predicting seizure recurrence and 0·71 (0·70-0·71) for predicting long-term seizure freedom. Validation was stable across the individual study populations. INTERPRETATION: We present evidence-based nomograms with robust performance across populations of children and adults. The nomograms facilitate prediction of outcomes following drug withdrawal for the individual patient, including both the risk of relapse and the chance of long-term freedom from seizures. The main limitations were the absence of a control group continuing antiepileptic drug treatment and a consistent definition of long-term seizure freedom. FUNDING: Epilepsiefonds.

Delayed Effects of Transcutaneous Organophosphate Poisoning in Four Children.

Contamination or transcutaneous absorption of organophosphates (OP) is rare and there exist only few reports of such manner of poisoning. We report four children from the same family in whom temporal proximity of the disease onset, a detailed interrogation of parents and exclusion of other clinical differentials, led to the diagnosis of transcutaneous intoxication with organophosphates (diazinon). The contamination occurred during the game with a freshly used poison can. Uncommon clinical picture was marked by delayed signs predominantly reflecting certain nicotinic effects (muscle weakness, cramps) along with subtle neuropathic features occurring throughout a few weeks after initial event. Our illustrative cases can further contribute to the better awareness and understanding of variable spectrum of transcutaneous route of OP poisoning.

The microcephaly-capillary malformation syndrome in two brothers with novel clinical features.

BACKGROUND: Microcephaly-capillary malformation syndrome is a newly described neurocutaneous entity that is characterized by congenital and progressive microcephaly, intractable epilepsy, profound developmental delay, multiple small capillary malformations on the skin, and poor somatic growth. Recently, mutations in the STAMBP gene have been identified as causative in the pathogenesis of this syndrome. PATIENTS: We describe two brothers (ages 7 and 12 years) from consanguineous parents of Saudi ancestry. Along with the established main clinical features of this syndrome, these boys exhibited certain novel and distinctive phenotypic features (congenital hypothyroidism and autistic-like behavior with intermittent repetitive hand-flapping movements). Genetic studies revealed the presence of homozygous pathogenic STAMPB mutation. CONCLUSION: This report presents the longest follow-up of patients with microcephaly-capillary syndrome so far reported and emphasize the syndrome's phenotype variability.

Withdrawal of antiepileptic drugs in young patients with cryptogenic focal epilepsies.

PURPOSE: The goal of the study was to assess the outcome of antiepileptic drug (AED) withdrawal in children and adolescents with cryptogenic focal epilepsies (CFE). METHODS: Medical records of consecutive patients with CFE from two referral hospitals were retrospectively evaluated over a nine-year period. Inclusion criteria were: (1) diagnosis of CFE according to the ILAE criteria, (2) less than 16 years of age at onset of epilepsy, (3) established clinical remission of at least two years before AED withdrawal, and (4) follow-up period of at least two years after withdrawal (or until seizure relapse in patients who relapsed). Time to seizure relapse and predictive factors were analyzed by survival methods. RESULTS: The cohort consisted of 52 patients (16 females, 36 males). Relapse rate was 37.85%. Most relapses occurred during the first 12 months after withdrawal. Univariate analyses indicated the following factors as significantly correlated with seizure recurrences: (1) female sex; (2) age at withdrawal of AED 14 years or higher; (3) abnormal EEG before withdrawal; and (4) abnormal EEG during and after AED withdrawal. Multivariate Cox regression analyses revealed that female sex, age at withdrawal of AED 14 years or higher; and abnormal EEG during and after withdrawal were significant independent predictive factors for seizure recurrences. CONCLUSION: The relapse rate in our cohort was similar to the most commonly reported overall rates for childhood-onset epilepsy. Distinguishing variables-female sex, age at withdrawal greater than 14 years, and abnormal EEG - need to be considered when choosing and further following of eligible candidates for AED withdrawal.

Antiepileptic drugs withdrawal in patients with idiopathic generalized epilepsy.

OBJECTIVES: To estimate the risk of seizure recurrence after antiepileptic drugs (AED) withdrawal and to identify related predictive features in patients with idiopathic generalized epilepsy (IGE) commencing at developing age (up to 16 year). METHODS: Medical records of consecutive patients with IGE from two refferal hospitals were evaluated between 2001 and 2009. Inclusion criteria were clinical and EEG diagnosis of IGE and follow up for at least 2years after the AED withdrawal. The cohort consisted of 59 patients (38 females, 21 males). Follow up after withdrawal lasted 2-10years (median 3) Time to seizure relapse and predictive factors were analyzed by survival methods. RESULTS: There were 21 (35.6%) patients with childhood absence epilepsy (CAE), 11 (18.6%) with juvenile absence epilepsy (JAE), 10 (16.9%) with isolated primary GTC seizures, and 17 (28.8%) with juvenile myoclonic epilepsy (JME). The relapses occured in 23 (52.2%) patients: one (6.2%) with CAE, 4 (50%) with JAE, 8 (80%) with IGE with GTC seizures and all with JME. During the first 6 months 54.5% patients relapsed (20% during withdrawal), 63.6% within 12 months, 81.8% within18 months and 95.4% within 24 months after withdrawal. Female gender, age at onset of seizures, seizure types, EEG worsening during/after AED withdrawal and age at withdrawal were significantly associated with relapse risk according to univariate analysis. In multivariate analysis, retained significant factors were: seizure types and EEG worsening. CONCLUSION: Diagnosis of the specific IGE syndrome strongly affects relapse rate: the lowest was in CAE, the highest in JME. Independent risk factors for seizure relapse were: seizure type and EEG worsening during and/or after withdrawal.

[Mortality in primary malignant brain tumors in the population of Belgrade]. / Mortalitet kod primarnih malignih tumora mozga u populaciji Beograda.

BACKGROUND: The aim of this investigation was the analysis of primary malignant brain tumors (PMBT)-related mortality in the Belgrade population during the period 1983-2000. METHODS: Mortality data (based on death records) for the period observed, as well as population data, were obtained from the unpublished material of the Municipal Institute of Statistics, Belgrade. The data analysis was adjusted to specific and standardized mortality rates and linear trend, using the world population as a standard. Regression coefficient was determined by Fisher's test. RESULTS: During the period 1983-2000, in the Belgrade population standardized mortality rates from PMBT were 6.29/100,000 (95% CI-confidence interval 5.33-7.24) for males, 4.50/100,000 (95% CI 3.84-5.17) for females, and 5.91/100,000 (95% CI 5.20-6.63) for total population. The age-specific mortality rates increased with age up to the age group 65-74, with the highest value of 21.21/100,000 (95% CI 16.03-26.39), and decreased in persons of 75 and more years of age. CONCLUSION: Mortality rates from PMBT in Belgrade had slightly increasing tendency in male (5.725 + 0.0592x, p = 0.545), and decreasing tendency in female population (y = 4.703-0.0213x, p = 0.756), while statistically significant increasing mortality rate was registered only in the age group 65-74 (y = 435 + 1.7707x, p = 0.0001).