Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany.

PURPOSE: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy. METHODS: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012. RESULTS: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years. CONCLUSIONS: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.

[Impact of early benefit assessment on patients with epilepsy in Germany: Current healthcare provision and therapeutic needs]. / Auswirkungen der frühen Nutzenbewertung auf Patienten mit Epilepsie in Deutschland : Aktuelle Versorgungsrealität und therapeutischer Bedarf.

Epilepsy is one of the most common chronic neurological diseases and represents a significant burden for patients, their families and society. In more than 75 % of patients anticonvulsant therapy consists of valproate, carbamazepine, lamotrigine or levetiracetam. There is a need for polytherapy in drug-refractory patients and they suffer from negative effects on quality of life and employment that is associated with high indirect costs. To allow a comprehensive treatment in this patient group, access to new anticonvulsants with novel modes of action is needed; however, all applications for new antiepileptic drugs failed to prove added benefits during the Pharmaceutical Market Restructuring Act (AMNOG) in Germany. One of the main reasons is the mandatory definition of a standard comparative therapy. It remains unclear whether there will be studies in the future which will fulfill the requirements of the current version of AMNOG. Observational studies after approval and marketing of new antiepileptic drugs could be better alternatives to prove added benefits for individual patients in the current German healthcare system.

[Invasive stimulation procedures and EEG diagnostics in epilepsy]. / Invasive Stimulationsverfahren und EEG-Diagnostik bei Epilepsien.

Stimulation has been performed experimentally and in small case series to treat epilepsy since the 1970s. Since the introduction of vagus nerve stimulation in 1997 and intracranial stimulation methods in 2011 into patient care, invasive stimulation has become a rapidly developing but infrequently used therapeutic option in Europe. Whereas vagus nerve stimulation is frequently used, particularly in the USA, intracranial stimulation differs in its regional availability. In order to improve the efficacy of stimulation, develop criteria for its use and assure low complication rates, a concentration on experienced centers and multicenter data acquisition and sharing are needed.Invasive electroencephalographic (EEG) monitoring with subdural electrodes and especially with stereotactically implanted depth electrodes have been used increasingly more often for presurgical evaluation in recent years. They are applied when non-invasive diagnostics show insufficient results to exactly identify the location and extent of the epileptogenic zone or cannot be adequately distinguished from eloquent cortex areas. Complications include intracranial hemorrhage, infections and increased intracranial pressure but lasting deficits or even death are rare (≤2 %). The outcome of invasive monitoring is inferior to non-invasive monitoring because of the higher degree of complexity of the cases; however, it is far superior to the seizure-free rates achieved by anticonvulsant drug treatment alone.

[New aspects in the field of epilepsy]. / Neues auf dem Gebiet der Epilepsien.

Regarding epilepsy several new developments can be reported. The International League Against Epilepsy (ILAE) has suggested a new definition of epilepsy, for the first time including a definition of epilepsy resolution. Progress in the diagnosis relates to new genetic findings, improvements in magnetic resonance imaging (MRI) and the increasing use of stereo electroencephalograms (sEEG). Regarding treatment there are new clinically relevant data on the pathophysiology and prevention of sudden unexpected death in epilepsy (SUDEP). Zonisamide has been approved by the European Medicines Agency (EMA) for monotherapy in adults with focal seizures and combination therapy in children aged ≥ 6 years. Retigabin and perampanel have been approved but are currently taken off the market in Germany (only) because the Gemeinsamer Bundesausschuss (GBA, Joint Federal Committee) did not find any additional therapeutic value as compared to lamotrigine due to a lack of data. A decision regarding a new application for perampanel is pending. Regarding surgical treatment novel ablation techniques (e.g. stereotactic radiofrequency and laser ablation as well as focussed ultrasound ablation) and brain stimulation paradigms are under investigation. Experimental studies, generously supported by the European Union (EU) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) are focusing on (opto-)genetic (e.g. using lentoviral transfection), epigenetic (e.g. micro-RNA-related) approaches and on the investigation of neuronal micronetworks.

[Neuropathology and etiology of focal epilepsy]. / Neuropathologie und Ätiologie fokaler Epilepsien.

In 2010 the International League against Epilepsy published a new classification of epilepsies. A major advance of this classification system is the acknowledgment of a genetic or pathologic-anatomic basis of epilepsy as important predictors of outcome (cause matters). This applies in particular to structural-metabolic lesions, which were frequently recognized in surgical specimens obtained from patients with drug-resistant focal epilepsy, i.e. hippocampal sclerosis, glioneuronal tumors, focal cortical dysplasias, vascular malformations, ischemia, intracerebral hemorrhage, glial scars or inflammation. A better understanding and classification of the etiopathology as well as the underlying molecular mechanisms will help to anticipate and appreciate the clinical course of a disease as well as to develop new and targeted drug treatment. Surgically available human brain tissue will be most helpful to support this approach but will also need careful neuropathological evaluation with accurate classification systems and use of terminology.

[Non-convulsive status epilepticus: temporary fad or reality in need of treatment?]. / Nonkonvulsiver Status epilepticus : Modeerscheinung oder behandlungspflichtige Realität?

The term non-convulsive status epilepticus (NCSE) refers to a heterogeneous group of diseases with different etiology, prognosis and treatment. The different forms of NCSE comprise about 25-50% of all status epilepticus cases. The most frequent form encountered in clinical practice is complex-partial SE but the rarer conditions of absence status, aura status and subtle SE are also included under this category. A diagnosis of NCSE should be considered in all patients with otherwise unexplained changes in consciousness or behavior and this diagnosis demands rapid further diagnostic work up including clinical examination, a detailed clinical history from the patient or an accompanying person, cranial computed tomography (CCT) and an electroencephalogram (EEG). If signs of an infectious or inflammatory disorder are present, a spinal tap is indicated. The EEG is of high relevance although interpretation can be challenging in NCSE.Absence status is usually treated by benzodiazepines and if necessary a broad spectrum anticonvulsive drug (ACD) such as valproic acid (VPA) can be added. The treatment of complex-partial SE follows the same scheme as that of generalized tonic-clonic SE and an initial benzodiazepine (i.v. lorazepam or intramuscular midazolam) followed by a bolus of one of the ACDs available as i.v. solution (e.g. VPA, phenytoin, phenobarbitol or levetiracetam). The third treatment step is general anesthesia if NCSE fails to be controlled. The aggressiveness of the applied therapy depends on the severity of the NCSE and the general condition of the patient. The prognosis is determined by the subtype of NCSE and the underlying etiology.

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

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.

Quality of life and employment status are correlated with antiepileptic monotherapy versus polytherapy and not with use of "newer" versus "classic" drugs: results of the "Compliant 2006" survey in 907 patients.

"Classic" and "newer" antiepileptic drugs (AEDs) were compared in an epidemiological survey regarding patient's acceptance of AEDs, quality of life (QoL), and employment. Data from 907 outpatients, 45.9% female (mean age: 44.8 ± 17.9 years), were evaluated by 90 neurologists in private practices, who were also involved in a non-interventional study by Sanofi-Aventis Deutschland GmbH, regarding medication, seizure type, illness duration, employment, patients' acceptance of AEDs (4-point scale where 1=very good), and QoL (6-point scale where 1=very good). Among the patients, 69.7% were on monotherapy, 25.4% were taking two AEDs, and 4.9% were taking more than two AEDs. Patient's acceptance of AEDs (mean ± SD=1.65 ± 0.62) and QoL (2.34 ± 0.89) were "good." Among patients aged 18-65 years, 68.6% were employed. QoL and acceptance were lower with polytherapy. Older age and polytherapy were associated with lower probability of employment. No differences emerged between "classic" and "newer" AED monotherapy. Polytherapy-associated lower QoL could be due to severity of illness or adverse effects of treatment.

[Primary brain tumors and brain metastases. Symptomatic epilepsy and driving ability - systematic review and expert opinion]. / Primäre Hirntumoren und Hirnmetastasen. Symptomatische Epilepsie und Fahreignung - Expertenumfrage und systematisches Review.

PURPOSE: Primary brain tumors and metastases are common causes of symptomatic epilepsy. Seizures, neurological and neuropsychological deficits can interfere with driving ability. The present paper aims to systematically review the incidence of epileptic seizures in brain tumor patients and to discuss driving ability in the context of the current German guidelines and expert opinions. METHODS: To evaluate the incidence of epileptic seizures which occur at the beginning and in the course of the disease, we performed a systematic literature research in PubMed from 1960 to 2007. Additionally on the basis of this data we performed a survey collecting expert opinions regarding the driving ability of brain tumor patients from members of the German working groups "Arbeitsgemeinschaft für prächirurgische Epilepsiediagnostik und operative Epilepsietherapie" (Working Group for Presurgical Epilepsy Diagnostics and Operative Epileptic Therapy) and "Neuroonkologische Arbeitsgemeinschaft" (Neuro-oncological Working Group). RESULTS: The incidence of epileptic seizures depends on the entity, dignity and localization of the tumor. The driving ability of brain tumor patients is not explicitly regulated in Germany. Of the interviewed experts 72% judged the guidelines to be precise enough and 44% did not want to deprive the patients of their driving ability without a first seizure, independent of the individual risk. DISCUSSION: The available studies are methodologically insufficient and show that a further evaluation is necessary to assess the driving ability. Possible restrictions of the driving ability in patients with a high risk of seizures in the course of the disease have to take into account the balance between individual rights and the interests of the general public.

[Seizures and epilepsies after stroke]. / Epileptische Anfälle und Epilepsien nach "Schlaganfall"

Epilepsies after stroke represent 20% of all adult-onset epilepsies and exhibit special characteristics with respect to diagnosis, treatment, and prognosis. Patients are frequently amnestic for their seizures the signs of which can be very subtle. Postictal pareses and confusional states can last for days, which further complicate diagnosis. Single seizures after stroke were reported in 2% to 10% of cases, and community-based studies found epilepsies in 3% to 4% of stroke patients. Analyses of subgroups identified epilepsy risks of 3% after ischemic infarction, 6% to 10% after intracerebral hemorrhage, and 9% after subarachnoid hemorrhage. Status epilepticus developed in less than 1% of stroke patients. Besides etiology, further risk factors for epilepsy comprise: remote seizures (latency >2 weeks, risk of recurrence >50%) more than early seizures (latency <2 weeks, risk of recurrence <50%), extent of stroke, cortical involvement, and degree of neurological deficit. The first appearance of seizures in patients older than 60 years represents a risk factor for future stroke with a hazard ratio of 2.89.There is currently no sufficient evidence for starting AED treatment before seizures occur. The benefit is still unclear of starting AED after a single early post-stroke seizure. Most authors recommend AED treatment after the second seizure but also after a first remote seizure because of the high risk of seizure recurrence in these situations. Possible pharmacokinetic interactions should be considered when choosing AED. Especially the first-generation AED carry the potential to interact with comedication, which is usually seen in stroke patients receiving substances such warfarin and salicylates. Only very few studies investigate specific AED exclusively in stroke patients. Lamotrigine and gabapentin have been successfully tested in these patients.

Topiramate, nutrition and weight change: a prospective study.

PURPOSE: To evaluate prospectively the relationship between appetite, food composition, nutritional habits and weight loss following administration of topiramate (TPM) and to identify predictors for TPM induced weight loss. METHODS: 22 patients with epilepsy who were started on TPM were prospectively followed for 6 months and contacted again after a mean follow-up time of 37.1 months. RESULTS: Body mass index (BMI) loss occurred in 59% of patients, with a mean weight loss of 9.5 kg after 6 months while receiving TPM without further weight loss at the long term follow-up. Weight loss was associated with reduction in appetite without affecting food composition. Predictors for BMI loss after 6 months were high initial BMI and body fat. After 3 weeks of treatment with TPM, the recorded parameters did not predict BMI loss but at 3 months, weight loss, reduction of appetite and amount of food intake were predictive for the amount of BMI loss after 6 months.

Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus.

In 2006, levetiracetam was approved as the first of the newer anticonvulsive drugs as an intravenous formulation (ivLEV) for patients with epileptic seizures who are unable to take oral medication. We report our experience with the use of ivLEV for the treatment of 18 episodes of benzodiazepine refractory focal status epilepticus (SE) in 16 patients, including four patients with secondary generalised SE. SE was controlled in all patients by the given combination of drugs; application of further antiepileptic medications after ivLEV was necessary in two episodes. No severe side effects occurred. Our data suggest that ivLEV may be an alternative for the treatment of SE in the future, even in patients that did not respond to benzodiazepines. A large prospective, randomised, controlled study is warranted to investigate the efficacy and safety of ivLEV for the treatment of SE.

The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Functional transcranial Doppler sonography and a spatial orientation paradigm identify the non-dominant hemisphere.

RATIONALE: Functional transcranial Doppler sonography (fTCD) during word generation is well established for language lateralization. In this study, we evaluated a fTCD paradigm to reliably identify the non-dominant hemisphere. METHODS: Twenty-nine right-handed healthy subjects (27.1+/-7.6 years) performed the 'cube perspective test' [Stumpf, H., & Fay, E. (1983). Schlauchfiguren: Ein Test zur Beurteilung des räumlichen Vorstellungsvermögens. Verlag für Psychologie Dr. C. J. Hogrefe, Göttingen, Toronto, Zürich] a spatial orientation task, while the cerebral blood flow velocity (CBFV) was simultaneously measured in both middle cerebral arteries (MCAs). In addition, the established word generation paradigm for language lateralization was performed. Subjects with atypical language representation were excluded. Data were analysed offline with the software Average, which performed a heart-cycle integration and a baseline-correction and calculated a lateralization index (LI) with its standard error of the mean increase in CBFV separately for both MCAs. RESULTS: Twenty-one of 29 subjects (72.4%) lateralized to the right hemisphere (chi2=5.828, p=0.016). The mean LI of the spatial orientation paradigm pointed to the right hemisphere (x =-1.9+/-3.2) and was different from the LI of word generation (x =3.9+/-2.2;p<0.001). There was no correlation between the LI of spatial orientation and word generation (R=0.095, p=0.624). Age of the subjects did not correlate with the LI during spatial orientation (p>0.05) but negatively with the LI during word generation (R=-0.468, p=0.010). The maximum increase of CBFV was greater in the spatial orientation (14.0%+/-3.6%) than in the word generation paradigm (9.4%+/-4.0%; p<0.001). CONCLUSIONS: In more than two thirds of the subjects with left-sided language dominance, the spatial orientation paradigm was able to identify the non-dominant hemisphere. The results suggest both paradigms to be independent of each other. The spatial orientation paradigm, therefore, appears to be a non-verbal fTCD paradigm with possible clinical relevance.

[Haemolysis: role of the direct antiglobulin test and eluate]. / Hemolyse: rol van directe antiglobulinetest en eluaat.

Haemolytic anaemia is the result of an abnormal breakdown of red blood cells. The direct antiglobulin test (DAT), also known as the direct Coombs test, can be used to determine the cause of the haemolysis. The DAT distinguishes between immune and non-immune causes of haemolysis. However, the DAT should not be used in screening for haemolysis. When the DAT is performed without an indication for in vivo haemolysis, there is a high risk of false-positive results. To increase the specificity of the DAT, the eluate can be tested to determine the specificity of the autoantibodies. In this article we present two cases of haemolytic anaemia in which the DAT gives further indication of the cause of haemolysis.

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

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.

Motor cortex excitability in focal epilepsies not including the primary motor area--a TMS study.

It is unclear whether focal epilepsies chronically influence the processing of cortex distant to the epileptogenic zone. Therefore, motor cortex excitability was analysed in patients with temporal and extratemporal epilepsies whose epileptogenic zones did not include the primary motor area. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to the primary motor cortex in 20 healthy controls and 23 patients with focal epilepsy (39.4 +/- 13.2 years; 12 left, 11 right; 14 temporal, nine extratemporal: six frontal, three parieto-occipital) ipsi- and contralateral to the epileptogenic zone. In all patients, the epileptogenic zone did not include the primary motor cortex. The resting motor threshold (RMT), the cortical silent period (CSP), the intracortical inhibition [ICI; combined interstimulus intervals (ISI) 2 and 3 ms] and the intracortical facilitation (ICF; combined ISI 10 and 15 ms) were determined. The measures obtained ipsilateral to the epileptogenic zone were compared with those elicited in contralateral hemispheres and, in exploratory analyses, with controls using non-parametric tests, including Hodges-Lehmann estimates of median differences (HLE) with 95% confidence intervals (CI). In the patient group, the CSP elicited in the ipsilateral motor cortex (median 162.3 ms) was shortened compared with the contralateral CSP (median 174.6 ms; HLE 15.9 ms; CI 6.2, 27.0 ms; P = 0.002). This interhemispheric difference was more pronounced in extratemporal epilepsies (HLE 23.4 ms; CI -3.2, 67.6 ms) compared with temporal epilepsies (HLE 14.3 ms; CI 4.7, 26.2 ms). Patients with parieto-occipital epilepsies showed the greatest interhemispheric differences in CSP (HLE 33.5 ms) and patients with mesial temporal epilepsies the smallest (HLE 9.9 ms). No significant differences were found between ipsi- and contralateral RMT, ICI or ICF. In analyses of subgroups, the CSP was shorter in epileptic hemispheres of patients with extratemporal epilepsies (141.4 ms) than in controls (173.4 ms; HLE 40.0 ms; CI 3.2, 83.4 ms; P = 0.029). ICF was increased in epileptic hemispheres of extratemporal epilepsies (147.6%) compared with temporal epilepsies (114.6%; HLE 33.0%; CI 4.1, 68.3%; P = 0.038). The results suggest that focal epilepsies influence chronically distant cortex, leading to decreased inhibition and increased facilitation in the ipsilateral motor cortex even when the epileptogenic zone is apart from it. This alteration may be due to synaptic reorganization and appears to be more pronounced in extratemporal and neocortical temporal than in mesial temporal epilepsies. This may have diagnostic implications.

Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

BACKGROUND: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. OBJECTIVE: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. METHODS: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. RESULTS: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related. CONCLUSIONS: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.

Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults.

OBJECTIVES: Delayed cerebral infarction (DCI) has a significant impact on mortality and morbidity of patients with subarachnoid hemorrhage (SAH). The aim of this study was to define quantitative EEG (qEEG) parameters for the early and reliable prediction of DCI and compare the validity and time course of qEEG to standard procedures. METHODS: 12 consecutive unselected SAH patients (8 female, mean age 52 years, Hunt-and-Hess grade I-IV) were prospectively examined. Continuous six channel EEG monitoring was started within 48 h after admission (mean duration 5.2 days; range: 2-12 days). All raw and unselected EEG signal underwent automated artifact rejection, Short Time Fast Fourier Transformation and a detrending procedure in order to analyze regional spectral power changes in different frequency bands. According to clinical standards, transcranial Doppler sonography (TCD) was performed at least on alternate days and repeat cerebral computer tomography (CCT) as needed. RESULTS: 6 patients (50%) developed vasospasm/DCI. Decrease of ⩾40% in power persisting over ⩾5h in the alpha band and ⩾6h in the theta band marked the optimal cut-off to detect DCI (sensitivity 89%, specificity 77% for alpha). EEG changes preceded detection of vasospasm/DCI in standard procedures by 2.3d ays. Changes in the beta and delta band as well as in the alpha/delta ratio demonstrated lower correlation with imminent DCI. CONCLUSIONS: Focal reduction in alpha power may represent a valid, observer independent, non-invasive and continuous marker for vasospasm/DCI in SAH patients. SIGNIFICANCE: qEEG indicates imminent ischemia earlier than established diagnostic tools, such as TCD.