Hajo M. Hamer

Incidence of Status Epilepticus in Adults in Germany: A Prospective, Population‐Based Study

Summary:  Purpose: To determine the incidence and case‐fatality rate of status epilepticus (SE) in adults in Hessen, Germany, we performed a prospective, population‐based study from July 1997 through June 1999.

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Complications of invasive video-EEG monitoring with subdural grid electrodes

Objective: To evaluate the risk factors, type, and frequency of complications during video-EEG monitoring with subdural grid electrodes. Methods: The authors retrospectively reviewed the records of all patients who underwent invasive monitoring with subdural grid electrodes (n = 198 monitoring sessions on 187 patients; median age: 24 years; range: 1 to 50 years) at the Cleveland Clinic Foundation from 1980 to 1997. Results: From 1980 to 1997, the complication rate decreased (p = 0.003). In the last 5 years, 19/99 patients (19%) had complications, including two patients (2%) with permanent sequelae. In the last 3 years, the complication rate was 13.5% (n = 5/37) without permanent deficits. Overall, complications occurred during 52 monitoring sessions (26.3%): infection (n = 24; 12.1%), transient neurologic deficit (n = 22; 11.1%), epidural hematoma (n = 5; 2.5%), increased intracranial pressure (n = 5; 2.5%), and infarction (n = 3; 1.5%). One patient (0.5%) died during grid insertion. Complication occurrence was associated with greater number of grids/electrodes (p = 0.021/p = 0.052; especially >60 electrodes), longer duration of monitoring (p = 0.004; especially >10 days), older age of the patient (p = 0.005), left-sided grid insertion (p = 0.01), and burr holes in addition to the craniotomy (p = 0.022). No association with complications was found for number of seizures, IQ, anticonvulsants, or grid localization. Conclusions: Invasive monitoring with grid electrodes was associated with significant complications. Most of them were transient. Increased complication rates were related to left-sided grid insertion and longer monitoring with a greater number of electrodes (especially more than 60 electrodes). Improvements in grid technology, surgical technique, and postoperative care resulted in significant reductions in the complication rate.

Cost of Epilepsy: A Systematic Review

The objective of this review was to overview published cost-of-illness (COI) studies of epilepsy and their methodological approaches. Epilepsy imposes a substantial burden on individuals and society as a whole. The mean prevalence of epilepsy is estimated at 0.52% in Europe, 0.68% in the US, and peaks up to 1.5% in developing countries. Estimation of the economic burden of epilepsy is of pivotal relevance to enable a rational distribution of healthcare resources. This is especially so with the introduction of the newer antiepileptic drugs (AEDs), the marketing of vagal-nerve stimulators and the resurgence of new surgical treatment options, which have the potential to considerably increase the costs of treating epilepsy.A systematic literature review was performed to identify studies that evaluated direct and indirect costs of epilepsy. Using a standardized assessment form, information on the study design, methodological framework and data sources were extracted from each publication and systematically reported.We identified 22 studies worldwide on costs of epilepsy. The majority of the studies reflected the costs of epilepsy in Europe (three studies each for the UK and Italy, one study each for Germany, the Netherlands, Switzerland, France and the EU) and the US (four studies), but studies were also available from India (two), Hong Kong, Oman, Burundi, Chile and Mexico. The studies utilized different frameworks to evaluate costs. All used a bottom-up approach; however, only 12 studies (55%) evaluated direct as well as indirect costs. The range for the mean annual direct costs lay between 40 International Dollar purchasing power parities (PPP-

Cytokines and epilepsy

) in rural Burundi and PPP-

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients

4748 (adjusted to 2006 values) in a German epilepsy centre. Recent studies suggest AEDs are becoming the main contributor to direct costs. The mean indirect costs ranged between 12% and 85% of the total annual costs.Epilepsy is a cost-intensive disorder. A reliable comparison of the different COI studies in epilepsy is not easily feasible, as the evaluated studies show substantial methodological differences with respect to their patient selection criteria, diagnostic stratifications and evaluated costs. Therefore, there is an urgent need for studies that evaluate direct and indirect costs in a standardized fashion.

Men and women are different: Diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum

Epilepsy is a common chronic neurological disorder affecting approximately 8 out of 1000 people. Its pathophysiology, however, has remained elusive in many regards. Consequently, adequate seizure control is still lacking in about one third of patients. Cytokines are soluble mediators of cell communication that are critical in immune regulation. In recent years, studies have shown that epileptic seizures can induce the production of cytokines, which in turn influence the pathogenesis and course of epilepsies. At the time of this review, the focus is mostly on interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα). In this review, we summarize the current knowledge regarding these cytokines and their potential roles in epilepsy. The focus concentrates on their expression and influence on induced seizures in animal models of epilepsy, as well as findings in human studies. Both proconvulsive and anticonvulsive effects have been reported for each of these molecules. One possible explanation for this phenomenon is that cytokines play dichotomous roles through multiple pathways, each of which is dependent on free concentration and available receptors. Furthermore, the immune-mediated leakage in the blood-brain-barrier also plays an important role in epileptogenesis. Nonetheless, these observations demonstrate the multifarious nature of cytokine networks and the complex relationship between the immune system and epilepsy. Future studies are warranted to further clarify the influence of the immune system on epilepsy and vice versa.

The epidemiology of convulsive and nonconvulsive status epilepticus

OBJECTIVE To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Tiagabine-induced absence status in idiopathic generalized epilepsy

INTRODUCTION Numerous magnetic resonance imaging (MRI) studies have addressed the question of morphological differences of the brain of men and women, reporting conflicting results regarding brain size and the ratio of gray and white matter. In the present study, we used diffusion tensor imaging (DTI) to delineate sex differences of brain white matter. METHODS We investigated brain microstructure in 25 male and 25 female healthy subjects using a 3T MRI scanner. Whole-head DTI scans were analyzed without a-priori hypothesis using Tract-Based Spatial Statistics (TBSS) calculating maps of fractional anisotropy (FA), radial diffusivity (RD, a potential marker of glial alteration and changes in myelination) and axial diffusivity (AD, a potential marker of axonal changes). RESULTS DTI revealed regional microstructural differences between the brains of male and female subjects. Those were prominent in the thalamus, corpus callosum and cingulum. Men showed significantly (p<0.0001) higher values of fractional anisotropy and lower radial diffusivity in these areas, suggesting that the observed differences are mainly due to differences in myelination. DISCUSSION As a novel finding we showed widespread differences in thalamic microstructure that have not been described previously. Additionally, the present study confirmed earlier DTI studies focusing on sexual dimorphism in the corpus callosum and cingulum. All changes appear to be based on differences in myelination. The sex differences in thalamic microstructure call for further studies on the underlying cause and the behavioral correlates of this sexual dimorphism. Future DTI group studies may carefully control for gender to avoid confounding.

Direct and indirect costs of refractory epilepsy in a tertiary epilepsy center in Germany

Epidemiologic studies of status epilepticus (SE) depend on clear definitions of terms. Such a definition is available for convulsive generalized SE, but clear definitions of nonconvulsive SE (NCSE) are lacking. This as well as clinical difficulties to diagnose NCSE are one source of underascertainment. The minimal incidence of SE in the Caucasian population of industrialized countries is about 20/100,000/year. It depends on age, ethnic background and possibly gender. Case fatality rates lie between 1.9 and 40% depending on age, etiology and duration of the SE. Effective treatment can improve and focal SE itself may impair case fatality. Clearly increased rates of long term case fatality in patients with symptomatic SE suggest that these patients should be considered a population at high risk.