Comorbidities in patients with epilepsy: Frequency, mechanisms and effects on long-term outcome.

OBJECTIVE: To assess frequency, types, and mechanisms of comorbidities in people with epilepsy and verify their association with disease features and outcome. METHODS: This cohort study was performed in 13 Italian epilepsy centers with nationwide distribution and accurate records. Eligible patients were children and adults diagnosed before December 31, 2005, and followed for a minimum of 10 years. Two pairs of raters independently reviewed patients' records and classified each comorbidity. In case of disagreement, a third reviewer made the final decision. Comorbidities were classified according to type (organ/system) and underlying mechanism (causal, shared risk factors, chance association). Comorbidity types and mechanisms were described in the entire sample and according to epilepsy prognostic patterns (sustained remission, relapsing-remitting course, no remission). RESULTS: Of 1006 included patients, 266 (26.4%) had at least one comorbidity. The most common were developmental/perinatal (7.5% of cases), psychiatric (6.2%), cardiovascular (5.3%), and endocrine/metabolic (3.8%). Among 408 reported comorbidities, the underlying mechanisms were, in decreasing order, chance association (42.2%), shared risk factors (31.1%), and causal (26.7%). Psychiatric diseases were present in 13.3% of patients with no remission, 5.9% of patients with relapsing-remitting course, and 4.8% of patients with sustained remission (p = .016). The corresponding numbers for endocrine/metabolic diseases were respectively, 9.6%, 3.4%, and 2.9% (p = .013); for respiratory diseases were 3.6%, .3%, and .3% (p = .001), and for urogenital diseases were 3.6%, .7%, and 1.6% (p = .048). The association of endocrine/metabolic, psychiatric, and respiratory comorbidities with epilepsy prognosis was confirmed by multivariable analysis adjusted for the main demographic and clinical variables, with patients with these comorbidities showing a lower probability of achieving remission. SIGNIFICANCE: Comorbidities in epilepsy are not uncommon and reflect differing underlying mechanisms. Psychiatric, endocrine/metabolic, and respiratory disorders are associated with a worse long-term epileptological outcome.

Discontinuation of antiseizure medications in seizure-free patients with long-term follow-up: Patients' profile, seizure recurrence, and risk factors.

OBJECTIVE: To compare withdrawal of antiseizure medications (ASM) to continued treatment in newly diagnosed individuals achieving seizure freedom, and assess the risk of relapse and factors associated with relapse. METHODS: This is a multicenter retrospective cohort study with long-term follow-up. Patients with newly diagnosed epilepsy were identified from the medical records of 13 Italian epilepsy centers and followed up until the most recent visit or death. Seizure-free patients discontinuing treatment were compared to patients who maintained treatment for baseline characteristics. Treatment was stopped upon clinical judgment. The probability of relapse was calculated with the Kaplan-Meier method. Demographic, clinical, and instrumental variables associated with relapse were assessed with Cox proportional hazards models. RESULTS: One thousand and six patients aged 1 month to 72 years at diagnosis were enrolled and followed up for 17,892 person-years (median follow-up, 9.9 years). Three hundred and twenty patients (31.8%) underwent one or more treatment discontinuations. Factors associated with ASM withdrawal were younger age at remission and normal psychiatric examination. The probability of relapse after the first withdrawal was 16% at six months, 24% at 12 months, and 36%, 45%, and 53% at three, five, and ten years, respectively. The probability of remission after the first relapse was 59% at one month, 67%, 72, and 76% at three, six, and 12 months, respectively. Variables associated with relapse were age 14+ years, structural etiology, abnormal neuroimaging, ASM initiation after a single seizure, and symptomatic/cryptogenic epilepsy. CONCLUSIONS: About one half of seizure-free patients stopping ASM relapse in 10 years. However, the possibility of remission after relapse is high, particularly in children and patients with idiopathic/cryptogenic epilepsy. Treatment deprescription might be encouraged at least in these patients.

Prognostic patterns and predictors in epilepsy: a multicentre study (PRO-LONG).

OBJECTIVES: To describe the long-term prognosis of epilepsy and prognostic patterns in a large cohort of newly diagnosed patients and identify prognostic factors. METHODS: Study participants were 13 Italian epilepsy centres with accessible records dating back to 2005 or earlier, complete data on seizure outcome and treatments, precise epilepsy diagnosis, and follow-up of at least 10 years. Records were examined by trained neurology residents for demographics, seizure characteristics, neurological signs, psychiatric comorbidity, first electroencephalogram (EEG) and MRI/CT, epilepsy type and aetiology, antiepileptic drugs (AEDs), and 1-year, 2-year, 5-year and 10-year seizure remissions. Five predefined prognostic patterns were identified: early remission, late remission, relapsing-remitting course, worsening course and no remission. Prognostic factors were assessed using multinomial logistic regression models. RESULTS: 1006 children and adults were followed for 17 892 person-years (median 16 years; range 10-57). During follow-up, 923 patients (91.7%) experienced 1-year remission. 2-year, 5-year and 10-year remissions were present in 89.5%, 77.1% and 44.4% of cases. 5-year remission was associated with one to two seizures at diagnosis, generalised epilepsy, no psychiatric comorbidity, and treatment with one or two AEDs during follow-up. 10-year remission was associated with one or two AEDs. The most common prognostic pattern was relapsing-remitting (52.2%), followed by early remission (24.5%). 8.3% of cases experienced no remission. Predictors of a relapsing-remitting course were <6 seizures at diagnosis, (presumed) genetic aetiology and no psychiatric comorbidity. CONCLUSIONS: Few seizures at diagnosis, generalised epilepsy and no psychiatric comorbidity predict early or late seizure freedom in epilepsy. Achieving remission at any time after the diagnosis does not exclude further relapses.

Neurological outcome of postanoxic refractory status epilepticus after aggressive treatment.

Refractory status epilepticus (RSE) occurs in up to 30% of patients following resuscitation after cardiac arrest. The impact of aggressive treatment of postanoxic RSE on long-term neurological outcome remains uncertain. We investigated neurological outcome of cardiac arrest patients with RSE treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics, compared with patients with other electroencephalographic (EEG) patterns. A prospective cohort of 166 consecutive patients with cardiac arrest in coma was stratified according to four independent EEG patterns (benign; RSE; generalized periodic discharges (GPDs); malignant nonepileptiform) and multimodal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months. Refractory status epilepticus occurred in 36 patients (21.7%) and was treated with an aggressive standardized protocol as long as multimodal prognostic indicators were not unfavorable. Refractory status epilepticus started after 3 ±â€¯2.3 days after cardiac arrest and lasted 4.7 ±â€¯4.3 days. A benign electroencephalographic patterns was recorded in 76 patients (45.8%), a periodic pattern (GPDs) in 13 patients (7.8%), and a malignant nonepileptiform EEG pattern in 41 patients (24.7%). The four EEG patterns were highly associated with different prognostic indicators (low flow time, clinical motor seizures, N20 responses, neuron-specific enolase (NSE), neuroimaging). Survival and good neurological outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for RSE, 15.4% and 0% for GPDs, and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively. Aggressive and prolonged treatment of RSE may be justified in cardiac arrest patients with favorable multimodal prognostic indicators. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Long-term applicability of the new ILAE definition of epilepsy. Results from the PRO-LONG study.

OBJECTIVE: The new epilepsy definition adopted by the International League Against Epilepsy (ILAE) includes patients with one unprovoked seizure with a probability of further seizures, similar to the general recurrence risk after two unprovoked seizures, occurring in a 10-year period. Long-term follow-up of patients diagnosed after a single seizure is needed to assess the applicability of the new epilepsy definition in clinical practice. METHODS: Patients with newly diagnosed epilepsy were recruited retrospectively with a minimum follow-up of 10 years. Patients were stratified in two groups depending on the occurrence of one (new definition, ND) or two or more unprovoked seizures (traditional definition, TD) at the time of epilepsy diagnosis and compared for disease characteristics and factors predicting seizure recurrence. The primary outcome was the occurrence of a new unprovoked seizure during follow-up in the ND group. The secondary outcome was the achievement of an early remission in both groups. RESULTS: Among 1,006 patients with newly diagnosed epilepsy, 152 (15.1%) were diagnosed after a single seizure. Compared to patients diagnosed using the TD, patients diagnosed according to the ND showed a higher proportion of subjects with an abnormal neurologic examination (19.9% vs. 13.7%, p = 0.0504) and with focal seizures (69.3% vs. 60.4%, p = 0.0021). The two samples differed in the presence of at least one of the factors predicting seizure recurrence (focal seizures or abnormal findings in at least one among the following: neurologic examination, electroencephalography [EEG], and neuroimaging) (94.6% vs. 89.1%, p = 0.0376). Long-term recurrence in patients diagnosed with the new definition was 83.6% at 10 years and 89.1% at 15 years. The probability of early remission did not differ between the two groups. SIGNIFICANCE: Our results support the applicability of the new epilepsy definition in clinical practice. Individual patient characteristics and a personalized diagnostic approach can justify treatment after a single unprovoked seizure.

An international pilot study of an Internet-based platform to facilitate clinical research in epilepsy: the EpiNet project.

PURPOSE: We created an epilepsy patient database that can be accessed via the Internet by neurologists from anywhere in the world. The database was designed to enroll and follow large cohorts of patients with specific epilepsy syndromes, and to facilitate recruitment of patients for investigator-initiated clinical trials. METHODS: The EpiNet database records physician-derived information regarding seizure type and frequency, epilepsy syndrome, etiology, drug history, and investigations. It can be accessed from any country by approved investigators via a secure, password-protected Website. All data are encrypted. The database is for both research and clinical purposes. Investigators were invited to register any patient with epilepsy, but were particularly encouraged to register patients when uncertain of the optimal management. Participation required approval from investigators' ethics committees and institutional review boards, and all patients or their caregiver provided written informed consent. Patients were not enrolled in clinical trials in this pilot study. KEY FINDINGS: The international pilot study recruited patients from September 2010 to November 2011. Sixty-four investigators or research assistants from 25 centers in 13 countries registered 1,050 patients. Patients with a wide range of epilepsy syndromes and etiologies were registered. Patients' ages ranged from 2 weeks to 90 years. SIGNIFICANCE: The Website was successfully used by doctors working in different health systems. The pilot study confirmed that this low-cost, collaborative approach to research has great potential. Large, multicenter cohort studies will commence in 2012, and randomized clinical trials are being planned. All epileptologists are invited to join this project.

Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment.

OBJECTIVE: To investigate neurologic outcome of patients with cardiac arrest with refractory status epilepticus (RSE) treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics compared to patients with other EEG patterns. METHODS: In the prospective cohort study, 166 consecutive patients with cardiac arrest in coma were stratified according to 4 independent EEG patterns (benign, RSE, generalized periodic discharges [GPDs], malignant nonepileptiform) and multimodal prognostic indicators. Primary outcomes were survival and cerebral performance category (CPC) at 6 months. RESULTS: RSE occurred in 36 patients (21.7%) and was treated with an aggressive standardized protocol as long as multimodal prognostic indicators were not unfavorable. RSE started after 3 ± 2.3 days after cardiac arrest and lasted 4.7 ± 4.3 days. A benign EEG pattern was recorded in 76 patients (45.8%); a periodic pattern (GPDs) was seen in 13 patients (7.8%); and a malignant nonepileptiform EEG pattern was recorded in 41 patients (24.7%). The 4 EEG patterns were highly associated with different prognostic indicators (low-flow time, clinical motor seizures, N20 responses, neuron-specific enolase, neuroimaging). Survival and good neurologic outcome (CPC 1 or 2) at 6 months were 72.4% and 71.1% for benign EEG pattern, 54.3% and 44.4% for RSE, 15.4% and 0% for GPDs, and 2.4% and 0% for malignant nonepileptiform EEG pattern, respectively. CONCLUSIONS: Aggressive and prolonged treatment of RSE may be justified in patients with cardiac arrest with favorable multimodal prognostic indicators.

Cholinesterase inhibitor use is associated with increased plasma levels of anti-Aß 1-42 antibodies in Alzheimer's disease patients.

Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well as on behavioural and psychological symptoms of dementia and activities of daily living. The efficacy of AChEI may be ascribed not only to the activation of cholinergic transmission, but also to other mechanisms, among which a putative regulation of the immune response has already been hypothesized. In the present study, we evaluated, in a cross-sectional sample of 66AD patients and 48 healthy controls, the putative influence of AChEI on anti-Abeta 1-42 antibody plasma levels by ELISA assay. AD patients receiving AChEI therapy showed increased plasma levels of anti-Abeta 1-42 antibodies respect to untreated AD patients and antibodies levels similar to those of healthy controls, both before and after normalization by total IgG values. Our results support a potential role of AChEI in the modulation of the immune response against Abeta. We suggest that a strategy aimed at increasing the endogenous response against this peptide might represent an interesting therapeutic target to be further investigated.