Theodor W. May

Incidence of Epilepsies and Epileptic Syndromes in Children and Adolescents: A Population-Based Prospective Study in Germany

Summary:  Purpose: To estimate the incidence rate of epilepsies and epileptic syndromes in German children and adolescents aged 1 month to <15 years, and to provide data on their classification.

Psychometric Properties of the German Translation of the QOLIE-31

The purpose of this work was to assess the psychometric properties of the German Translation of the Quality of Life in Epilepsy Inventory, QOLIE-31. Internal consistency, construct and criterion validity, and responsiveness were tested in 509 patients with epilepsy who were administered the questionnaires at application or at admittance to the epilepsy center Bethel. Construct validity was tested in patients with different seizure frequencies and different degrees of tolerability of antiepileptic drug (AED) therapy (adverse effects). The scales Epilepsy-Related Fears und Restrictions in Daily Life due to Epilepsy were used as criterion measures. Test-retest reliability (long-term stability) and responsiveness of the questionnaire were analyzed in subgroups of patients who responded to the questionnaires a second time (n = 256). Cronbachs alpha of the QOLIE-31 was 0.94 and varied between 0.76 and 0.90 for the seven subscales. The correlations of the QOLIE with Epilepsy-Related Fears and Restrictions in Daily Life revealed high correlations between Epilepsy-Related Fears and the QOLIE subscale Seizure Worry (r = 0.81, P < 0.01) and the total score (r = 0.62, P < 0.01) and between Restrictions in Daily Life and the QOLIE subscale Social Functioning (r = 0.71) and the total score (r = 0.70, P < 0.01). Seizure frequency had a significant effect especially on the QOLIE subscales Social Functioning, Seizure Worry, and Overall QOL, whereas tolerability of AED therapy affected especially the subscales Medication Effects, Overall QOL, and Energy-Fatigue. The test-retest reliability (intraclass correlation coefficient) was 0.79 for the overall score and varied between 0.59 and 0.78 for the seven subscales. The German Translation of QOLIE-31 is a reliable and valid questionnaire with which to assess QOL in patients with epilepsy and is conceptually similar to the English version. It is a sensitive questionnaire with respect to seizure frequency and tolerability of antiepileptic drug treatment.

Prevalence of anxiety disorders in patients with refractory focal epilepsy—a prospective clinic based survey

Comorbid anxiety disorders severely affect daily living and quality of life in patients with epilepsy. We evaluated 97 consecutive outpatients (41.2% male, mean age=42.3+/-13.2 years, mean epilepsy duration=26.9+/-14.2 years) with refractory focal epilepsy using the German version of the anxiety section of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Nineteen patients (19.6%) were diagnosed with an anxiety disorder (social phobia, 7.2%; specific phobia, 6.2%; panic disorder, 5.1%; generalized anxiety disorder, 3.1%; anxiety disorder not further specified, 2.1%; obsessive-compulsive disorder, 1.0%; posttraumatic stress disorder, 1.0%). Four-week prevalence rates reported elsewhere for the general population in Germany are 1.24% for social phobia, 4.8% for specific phobia, 1.1% for panic disorder, 1.2% for generalized anxiety disorder, 1.3% for anxiety disorder not further specified, and 0.4% for obsessive-compulsive disorder. A trend for people with shorter epilepsy duration (P=0.084) and younger age (P=0.078) being more likely to have a diagnosis of anxiety disorder was revealed. No gender differences were found; however, this may be due to the small sample size. In conclusion, anxiety disorders are frequent in patients with refractory focal epilepsy, and clinicians should carefully examine their patients with this important comorbidity in mind.

Perioral Reflex Myoclonias: A Controlled Study in Patients with JME and Focal Epilepsies

Summary:  Purpose: Perioral reflex myoclonias (PORM) are obvious, frequent, but often unobserved focal seizures in different epileptic syndromes and the leading seizure type in reading epilepsy. PORMs remain often undiagnosed because the patients are not aware that these are epileptic seizures and fail to report them. Their semiology is not fundamentally different in various epileptic syndromes.

Postoperative routine EEG correlates with long-term seizure outcome after epilepsy surgery

We investigated the correlation of interictal epileptiform discharges (IED) in routine EEG 6 and 24 months after epilepsy surgery with regard to long-term seizure outcome. In 148 patients (74% temporal lobe epilepsy (TLE), 26% extratemporal epilepsy) EEG results (IED present or absent) were correlated with the postoperative outcome using the Engel classification 6 and 24 months after resection (PO6m and PO2y, respectively). Self-evaluation was conducted 3 and 5 years after resection (PO3y and PO5y, respectively). Ninety-one patients (62%) were seizure-free 5 years after resection; 88% of them showed no IED in PO6m. Twenty-eight patients (19%) displayed IED in routine EEG 6 months after resection; 61% of them had recurrent seizures at PO5y, whereas of 120 patients without IED only 33% had recurrent seizures at PO5y; p=0.01. Absence of IED in PO6m and PO2y correlated with good outcome: 71% without IED remained seizure-free, whereas only 25% with IED at PO6m and PO2y remained seizure-free; p=0.001. Seizure-free patients (Engel 1) and patients with less favourable outcome (Engel 3-4) at PO6m and PO2y rarely changed categories of outcome during the following years (p<0.001). Half of the patients with favourable seizure reduction (Engel 2) changed to seizure-free (Engel 1) or to a worse outcome category (Engel 3-4). Postoperative routine EEG is a good prognostic instrument for the prediction of long-term seizure outcome, especially for TLE. It predicts the running up and down of fits in patients with rare seizures (Engel 2).

Experience with generic drugs in epilepsy patients: an electronic survey of members of the German, Austrian and Swiss branches of the ILAE.

There has been a controversial discussion of the risks and benefits of generics in pharmacotherapy. While advocates point out that they are a reasonable means to limit the intensely growing healthcare costs, opponents expect negative effects on patient safety in at least some diseases and the efforts of research-based pharmaceutical companies. In 2002, an ad hoc committee of the German section of the International League against Epilepsy (German Society for Epileptology; DGfE) advised against including “traditional” antiepileptics such as carbamazepine and valproate in the so-called aut idem regulation, which would have resulted in prescribing generics becoming mandatory. One of the aspects emphasized was that physicians should generally refrain from switching seizure-free patients (Krämer, 2002). The German Pharmaceutical Society, too, expressly pointed out that antiepileptics are among the preparations or formulations, respectively, where substitution may be critical. The society generally recommended to refrain from substitution in cases where these “might raise the concern in the patient (e.g. antiepileptics) that he or she might experience a deterioration of his or her clinical picture as a result of preparations being switched,” adding that it is irrelevant “if the concerns are rationally founded or not” (Blume, 2002). In 2005, another ad hoc committee of the DGfE presented an updated statement on generic antiepileptics based on the licensing of generics for the first so-called new antiepileptics (gabapentin and lamotrigine). Consistent with the earlier paper, this statement set forth that generics can mostly be used without causing problems in newly diagnosed patients or in cases where a switch would have been required anyway. However, in cases of seizure freedom or side effects, again the society advised against any switches from branded preparations to generics, from one generic to another or from generics to branded preparations. Therefore, including the respective information on the prescription was recommended. Prior to a planned switch, patients who are free from seizures or side effects must be informed about the risks of a recurrence of seizures or new side effects and provide their consent in order to avoid the physicians becoming liable to damage claims (Krämer, 2005). The primary objective of the exploratory survey on hand was to collect experiences of physicians with generics in epilepsy patients in Germany, Austria, and Switzerland. Medical professional members of the three sections of the International League against Epilepsy as well as the German Society for Neurology (Deutsche Gesellschaft für Neurologie, DGN) were contacted by e-mail (November 2005) by the respective chairpersons or presidents (first three authors of this paper) to fill a web-based questionnaire. To increase participation, a raffle of 100 specialist books on epilepsy among all responders was announced. The study followed a similar survey that had been conducted in the United States in 2004 (Oles et al., 1992). To avoid manipulations of the data entered via the Internet as much as possible, various control mechanisms were introduced such as the recording of the individual IP no. (=no. of the respective personal computer). Data analysis was performed using descriptive and exploratorystatistical methods (chi-square test, Kruskal–Wallis test and t-test) differentiating by country, specialization (pediatricians, neurologists, psychiatrists), membership (DGN, epilepsy leagues), field of work (clinic, practice, other), and proportion of epilepsy patients among the total number of patients. A total of 2,800 e-mails were sent out. The response rate was 21.6% (606 responders). Twelve responses were excluded from the analysis because of duplicate e-mail addresses (n = 5), retirement of the physician (n = 4), lack of any treated epilepsy patient (n = 2), or response by a non-medical person (n = 1). Of the 594 questionnaires included in the analysis, 85.4% originated from Germany, 5.9% from Austria and 8.1% from Switzerland (in addition, three responses from Luxemburg and one from Belgium). A total of 61.8% of the responses were submitted by neurologists, 23.7% by (neuro-)pediatricians, and 13.1% by neuropsychiatrists. Most responding (neuro-)pediatricians were members of a division of the International League against Epilepsy, while most neurologists and neuropsychiatrists were members of the DGN. Most responding physicians worked in hospitals (70.9%), in addition to physicians working in private practice (26%). The mean number of patients treated per year was indicated as approx. 1,500 (median = 1,000), but showed considerable variation. Fig. 1 shows the frequency of the use of generics in general and with epilepsy patients in particular. For the following analysis, only those 480 physicians were considered who had stated that they used generic antiepileptics. About half of the physicians (49.2%) reported problems when switching from a branded

Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: A double-blinded, randomized, controlled trial (German HEAD Study)

OBJECTIVE To show non-inferiority of levetiracetam to sulthiame with respect to efficacy, tolerability and safety in benign epilepsy with centrotemporal spikes in a prospective, double-blinded randomized controlled trial. METHODS A sample size of 60 subjects (treatment group) was calculated to show reliable statistical results for non-inferiority. A total of 44 patients could be randomly allocated to either (LEV or STM) treatment group. Explorative data analysis was performed to investigate differences in the number of treatment failure events (occurrence of a seizure during the observation period of 6 months) and total dropouts. In addition, information of the occurrence of adverse events was collected. RESULTS 43 patients were analyzed. One patient had to be excluded due to protocol violation. Treatment failure events occurred in four patients (19.0%) in the LEV treatment group and in two patients (9.1%) in the STM treatment group, respectively, (p = 0.412). The number of dropouts due to adverse reactions was five in the LEV treatment group and one in STM treatment group (23.8% vs. 4.5%, respectively, p = 0.095). Severe adverse events occurred in patients treated with LEV (n = 2, 9.5%). The total number of dropouts due to either seizure recurrence or adverse events was significantly higher in the LEV group (n = 9, 42.9%) compared to the STM group (n = 3, 13.6%, p = 0.03). INTERPRETATION The study results concerning non-inferiority were not conclusive, as the calculated sample size was not reached to support sufficient statistical power due to limited recruitment in a 26 months period. The rates of seizure free patients were [relatively] high in both groups. However, the results indicate that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the LEV group compared to STM. Behavioral disturbances were the most common adverse event causing study termination.

Serum concentrations of rufinamide in children and adults with epilepsy: the influence of dose, age, and comedication.

Rufinamide (RUF) is an orphan drug for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in persons aged 4 years and older. Several studies have investigated the pharmaconkinetics of RUF, but information about interactions is still limited and the results are in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily RUF dose per body weight (mg/kg), valproic acid (VPA), and enzyme-inducing antiepileptic drugs (EIAEDs) on RUF concentration-to-dose ratio (RUF serum concentration/RUF dose per body weight), RUF clearance (RUF dose/RUF serum concentration), and RUF trough concentrations. Different statistical methods were used to evaluate 292 blood samples from 119 patients who fulfilled the inclusion criteria. In summary, the results using generalized estimating equation regression models confirm a moderate but statistically significant nonlinear RUF concentration-dose relationship. At steady state, the trough concentrations of RUF increase in a less than dose proportional manner. Children (younger than 12 years) had significantly lower RUF concentrations (19.0%, P < 0.001) than adults (18 years or older) on comparable RUF doses per body weight. VPA was the most frequent comedication (51%) in our patient group. Mean RUF concentrations were 86.6% higher when VPA concentrations were greater than 90 μg/mL (P < 0.001) and 45.4% higher when VPA concentrations were between 50 and 90 μg/mL (P < 0.001) but not significantly different at VPA concentrations less than 50 μg/mL (4.4%, P > 0.1) compared with combinations without VPA. In combination with EIAEDs, mean RUF concentrations were 21.8% lower (P = 0.002) compared with combinations without EIAEDs. However, the group of AEDs classified as EIAEDs was heterogeneous and the number of patients, especially of children with EIAEDs, was relatively small. Our data indicate that oxcarbazepine and, especially, methsuximide decrease RUF concentrations as well. Therapeutic drug monitoring might be helpful because RUF concentrations differ markedly in patients on comparable RUF doses.

Psychoeducational Programs for Patients with Epilepsy

Epilepsy is a common neurological disease, which affects people of all ages. Patients often have deficits regarding their knowledge of epilepsy. Many of them have recurrent seizures, psychosocial, and emotional problems and report restrictions in daily living as a result of their epilepsy. Meanwhile, a variety of psychoeducational programs have been developed with the intention to improve knowledge, coping with epilepsy, quality of life, compliance, and health status.This review article discusses the content and designs of formal patient educational programs for persons with epilepsy and reviews their role in improving patient outcomes. A systematic research of medical and psychological literature reveals that a sizeable amount of literature has been produced within the last decade that focuses on (psycho-) educational programs for adults, adolescents, and children with epilepsy as well as their families. These educational programs vary considerably in regard to content, didactic approach, and objectives. It is sometimes difficult to differentiate educational programs from psychological treatments or other interventions (e.g. by specialist epilepsy nurses). Information given about the theoretical frameworks guiding interventions, teaching strategies, and methodological approach of the programs is often sparse or lacking.The crucial point is that only very few educational programs have been evaluated in a randomized controlled trial. Furthermore, the methods of evaluation (e.g. questionnaires, inclusion and exclusion criteria, randomization, follow-up period) vary substantially and sometimes the number of subjects included in the study is too small for sufficient statistical evaluation.Overall, from the small number of evaluated programs it is evident that educational programs can improve epilepsy-related knowledge, improve the management of seizures, and reduce misinformation and misconceptions about epilepsy. They can support adults, adolescents, and children with epilepsy and their families and enable them to cope with the disease; they can sometimes also reduce seizure frequency and improve compliance with antiepileptic drugs. The effects on emotional disorders (e.g. depression) and quality of life are less obvious.Evaluated or standardized psychoeducational programs are available for specific target groups of patients with epilepsy. The review indicates that it is reasonable to perform or to adapt these educational programs for the benefit of the patients. Future research should focus on controlled evaluation studies of educational programs.

PESOS-Fragebogen für Menschen mit Epilepsie—

The PESOS questionnaire was developed at the Epilepsy Center Bethel in order to assess individual problems of patients with epilepsy in social and occupational surroundings (diagnostic function) and to investigate effects of treatment and counselling on quality of life (evaluative function). Clinical and demographic data, objective and subjective indicators of quality of life and modules (subscales) for specific patient groups (e. g. for students, employees) are included. The psychometric properties of the PESOS scales ‘Restrictions in daily life due to epilepsy’ ‘Epilepsy-related fear’, ‘Stigma’, and ‘Emotional adaptation’ were investigated in a multi-center study. The results indicate that the investigated subscales of the PESOS are reliable, valid and sensitive regarding effects of seizure frequency and tolerability of antiepileptic drugs.ZusammenfassungDer PESOS-Fragebogen wurde im Epilepsiezentrum Bethel entwickelt, um die individuellen Auswirkungen von Epilepsien auf soziale und berufliche Bereiche zu erfassen (diagnostische Funktion) und Effekte der Behandlung und Beratung auf die Lebensqualität der Betroffenen zu untersuchen (evaluierende Funktion). Erfasste Bereiche: medizinische und demographische Daten, objektive und subjektive Indikatoren der Lebensqualität sowie Module für spezielle Patientengruppen (z. B. Schüler/Studenten, Beschäftigte/Arbeitslose). Die psychometrischen Eigenschaften der PESOS-Skalen ‚Beeinträchtigungen im täglichen Leben durch die Epilepsie‘, ‚Epilepsiespezifische Angst‘, ‚Stigma‘ und ‚Emotionale Adaption an Epilepsie‘) wurden in einer multizentrischen Studie überprüft. Die Ergebnisse zeigen, dass die untersuchten Skalen des PESOS reliabel, valide und sensitiv hinsichtlich der Anfallsfrequenz sowie der Verträglichkeit der Antiepileptika-Therapie sind.