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OBJECTIVE To ascertain factors that are related to the antiepileptic drug load in epilepsy. METHODS In this cross-sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n = 1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n = 91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic-clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). RESULTS Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%-10% of variance in drug load. Nearly the same variance (5%-8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. SIGNIFICANCE Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long-lasting epilepsies.

ZUSAMMENFASSUNGDer plötzliche, unerwartete Tod eines Menschen mit Epilepsie wird mit dem englischen Akronym SUDEP bezeichnet (sudden unexpected death in epilepsy). Etwa einer von 1000 Epilepsiepatienten stirbt hieran, vor allem jene mit häufigeren nächtlichen generalisierten konvulsiven Anfällen. Die Mehrzahl der SUDEP-Fälle ist durch postiktuale Störungen der Atem- und Kreislauffunktion mit primärer zentraler Apnoe und sekundärer Asystolie verursacht. Die beteiligten zellulären Pathomechanismen sind jedoch noch ungeklärt. Die Aufklärung aller Patienten und Angehörigen wird durch angloamerikanische Fachgesellschaften empfohlen und von den meisten auch gewünscht. Entscheidend für die Prävention ist eine konsequente Anfallskontrolle. Zudem kann eine nächtliche Supervision das Risiko für SUDEP relevant mindern, dafür stehen klinisch geprüfte alltagstaugliche Anfallsdetektionssysteme zur Verfügung.

Objective Tonic‐clonic seizures (TCS) lead to metabolic stress and changes in related blood markers. Such markers may indicate harmful conditions but can also help to identify TCS as a cause of transient loss of consciousness. In this study, we hypothesized that the alterations of circulating markers of metabolic stress depend on the clinical features of TCS. Methods Ninety‐one adults undergoing video‐EEG monitoring participated in this prospective study. Electrolytes, renal parameters, creatine kinase (CK), prolactin (PRL), lactate, ammonia, glucose, and other parameters were measured at inclusion and different time points after TCS. Results A total of 39 TCS were recorded in 32 patients (six generalized onset tonic‐clonic seizures in 6 and 33 focal to bilateral tonic‐clonic seizures in 26 patients). Shortly after TCS, mean lactate, ammonia, and PRL levels were significantly increased 8.7‐fold, 2.6‐fold, and 5.1‐fold, respectively, with levels of more than twofold above the upper limits of the normal (ULN) in 90%, 71%, and 70% of the TCS and returned to baseline levels within 2 hours. Only postictal lactate levels were significantly correlated with the total duration of the tonic‐clonic phase. In contrast, CK elevations above the ULN were found in three TCS (~10%) only with a peak after 48 hours. Immediately after the TCS, hyperphosphatemia occurred in one third of the patients, whereas hypophosphatemia was observed in one third 2 hours later. TCS led to subtle but significant alterations of other electrolytes, creatinine, and uric acid, whereas glucose levels were moderately increased. Significance Lactate is a robust metabolic marker of TCS with elevations found in ~90% of cases within 30 minutes after seizure termination, whereas ammonia rises in ~ 70%, similarly to PRL. Phosphate levels show an early increase and a decrease 2 hours after TCS in a third of patients. CK elevations are rare after video‐EEG‐documented TCS, challenging its value as a diagnostic marker.

Background This observational study was done to develop a score based on clinical predictors that enables a guided decision for the necessity of cerebrospinal fluid (CSF) analysis after first unprovoked epileptic seizures and to validate this score in a retrospective patient cohort. Methods Clinical predictors were identified by two panels of epilepsy experts and selected according to content validity ratios. Based on these predictors a score was created and applied to a cohort of patients with first epileptic seizures. Results The “IDEAL score” consists of 9 items (fever, prolonged disturbance of consciousness, headache, imaging results, cognitive dysfunction, status epilepticus, malignancy, autoimmune encephalitis symptoms) that are collected at two different time points ( 3 h [B-score] after hospital admittance). A CSF analysis is recommended, if at least one clinical finding is present, either one of the items evaluated during the acute phase (A-score) or later in the diagnostic process (B-score). In 41 patients (13%) CSF analysis provided essential clues to the cause of the seizure. The combined IDEAL score reached a sensitivity of 98%, a specificity of 53%, a positive predictive value of 24% and a negative predictive value of 99% in this patient cohort. Conclusions A CSF analysis after first epileptic seizures provided decisive etiological findings in only 13% of all investigated patients. The IDEAL score offers clinicians a simple and easy-to-implement algorithm to assess the necessity of a CSF analysis, and to prevent unnecessary diagnostic procedures.

BACKGROUND AND PURPOSE Febrile-infection-related epilepsy syndrome (FIRES) is an exceedingly rare and devastating subtype of new-onset refractory status epilepticus, which causes refractory epilepsy and permanent neurocognitive impairment. METHODS This was a long-term follow-up of adult FIRES survivors treated between 2005 and 2018 as part of the EpiCARE initiative, a European Reference Network for rare and complex epilepsies. Clinical, electroencephalography, imaging and functional outcome measures are described using the Scores of Independence for Neurologic and Geriatric Rehabilitation, the modified Rankin Scale and the Global Assessment of Severity of Epilepsy Scale. RESULTS Six patients with refractory epilepsy following FIRES were evaluated. Despite general improvement after intensive care unit discharge, disease severity was still high at follow-up in all patients. The functional outcome, as assessed by the modified Rankin Scale, was moderately impaired in 2/6 patients. In contrast, the Scores of Independence for Neurologic and Geriatric Rehabilitation indicated a loss of independence in 5/6, serious problems in memory and planning/problem-solving in 4/6 and serious attentional problems in 3/6 patients. CONCLUSIONS Febrile-infection-related epilepsy syndrome survivors may regain vital functions and mobility but experience a significant loss of independence and participation due to recurring seizures, structural brain damage and neurocognitive decline. Minimization of disastrous outcomes through the systematic evaluation of rescue therapies within a network of specialized centres is crucial.

Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders.Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array.Results: We identified suitable samples from patients with AIE (n = 13) with different antibodies and compared them to HS (n = 13), GGE (n = 7), and PNES (n = 8). The NFL levels were significantly elevated in the serum (p = 0.0009) and CSF (p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere.Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.

It has been debated for decades whether single, self-limited seizures damage cerebral cells. Meanwhile, very sensitive measurements of biomarkers have become available, i.e. tau, neurofilament protein light (NFL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxyterminate hydrolase L1 (UCHL-1), which we explored in this study.Adult patients of the epilepsy monitoring unit were admitted to the study after written consent. Blood samples were drawn at baseline, immediately after a TCS and after two, six and 24 h. The markers were measured from frozen samples with a single-molecule array (SIMOA).20 patients and 20 seizures were included. All markers showed subtle but significant postictal increases and returned to normal within the next few hours (p 0.05). An increase of at least 100 % from baseline was noted in 30 % of patients for tau, 25 % for UCHL-1 and 15 % for GFAP, while NFL levels never increased above 100 %. Lactate was slightly correlated with the tau increase (r = 0.47, p = 0.037), leukocytes were correlated with postictal changes of GFAP (r = 0.68 p = 0.001).Our data supports the assumption that significant cerebral stress occurs in some but not all self-limited TCS. The postictal inflammatory response in particular seems to play an important role.

Objective Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. Methods Adult patients with refractory epilepsy who underwent video-electroencephalography (EEG) monitoring along with simultaneous one-lead electrocardiography (ECG) recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high-sensitive troponin T [hsTNT]; N-terminal prohormone of brain natriuretic peptide [NT-proBNP]; copeptin; suppression of tumorigenicity-2 [SST-2]; growth differentiation factor 15, [GDF-15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart-type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Periictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals(QTc). Results Thirty-six GCS (6 generalized-onset tonic-clonic seizures and 30 focal to bilateral tonic-clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than twofold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 of 30 patients (10%) and 6 of 23 patients (26%), respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST-2, HFABP, and GDF-15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. Significance The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. SuPAR may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS, but specificity needs to be tested.

Introduction: Sudden unexpected death in epilepsy (SUDEP) affects about 1 in 1000 people with epilepsy, and even more in medically refractory epilepsy. As most people are between 20 and 40 years when dying suddenly, SUDEP leads to a considerable loss of potential life years. The most important risk factors are nocturnal and tonic-clonic seizures, underscoring that supervision and effective seizure control are key elements for SUDEP prevention. The question of whether specific antiepileptic drugs are linked to SUDEP is still controversially discussed. Knowledge and education about SUDEP among health-care professionals, patients, and relatives are of outstanding importance for preventive measures to be taken, but still poor and widely neglected. Areas covered: This article reviews epidemiology, pathophysiology, risk factors, assessment of individual SUDEP risk and available measures for SUDEP prevention. Literature search was done using Medline and Pubmed in October 2019. Expert opinion: Significant advances in the understanding of SUDEP were made in the last decade which allow testing of novel strategies to prevent SUDEP. Promising current strategies target neuronal mechanisms of brain stem dysfunction, cardiac susceptibility for fatal arrhythmias, and reliable detection of tonic-clonic seizures using mobile health technologies. Abbreviations: AED, antiepileptic drug; CBZ, carbamazepine; cLQTS, congenital long QT syndrome; EMU, epilepsy monitoring unit; FBTCS, focal to bilateral tonic-clonic seizures; GTCS, generalized tonic-clonic seizures; ICA, ictal central apnea; LTG, lamotrigine; PCCA, postconvulsive central apnea; PGES, postictal generalized EEG suppression; SRI, serotonin reuptake inhibitor; SUDEP, sudden unexpected death in epilepsy; TCS, tonic-clonic seizures.

Kardiovaskulare Risikofaktoren sind bei Epilepsiepatienten weit verbreitet und pradisponieren zu zerebrovaskularen Erkrankungen und vaskular bedingten Epilepsien. Umgekehrt konnen Epilepsien und Antikonvulsiva einen negativen Einfluss auf das kardiovaskulare Risiko haben. Insbesondere der Einsatz enzyminduzierender Antikonvulsiva kann Dyslipidamien, Ubergewicht oder Hyperhomozysteinamien verursachen oder verstarken. Kardiovaskulare Erkrankungen konnen Epilepsien oder akut-symptomatische Anfalle bedingen, z. B. durch Hirninfarkte, Hirnblutungen, zerebrale Hypoxien und hypertensive Krisen. Die allgemeine und kardiovaskulare Mortalitat ist bei Menschen mit Epilepsie erhoht. Sie erleiden im Vergleich zur Allgemeinbevolkerung haufiger und fruher Schlaganfalle, Herzinfarkte und einen plotzlichen Herztod. Epileptische Anfalle konnen zu Storungen der koronaren Durchblutung, Herzmuskelmechanik und des Herzrhythmus fuhren. Die kardiale Belastung durch Anfalle findet ihren Ausdruck in EKG-Veranderungen und Troponin-Erhohungen. Herzrhythmusstorungen sind eine haufige Folge epileptischer Anfalle. Iktale und postiktale Tachykardien sind haufig, diagnostisch nutzlich und nur selten gefahrlich. Iktale Bradykardien und Asystolien konnen typischerweise selbstlimitierende Synkopen auslosen, postiktale Asystolien enden hingegen unbehandelt nicht selten todlich. Synkopen sind die haufigste Differenzialdiagnose zu epileptischen Anfallen. Antikonvulsiva und in sehr seltenen Fallen auch die Vagusnervstimulation konnen arrhythmogene Wirkungen entfalten, hier ist daher insbesondere bei herzkranken Patienten Vorsicht geboten.

Neuroinflammation and disruption of blood brain barrier (BBB) are important players in epileptogenesis, ictogenesis and pharmacoresistance. In this context, we investigated blood levels of HMGB1 and other inflammatory and BBB markers after generalized and focal to bilateral tonic-clonic seizures in serum, summarized under the term generalized convulsive seizures (GCS).We included consenting adults who were admitted to the epilepsy monitoring unit. Blood samples were drawn at baseline and immediately after a GCS as well as after 2, 6 and 24 h. We measured leukocytes, c-reactive protein (CRP), the danger-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and S100, receptor of advanced glycation end products (RAGE) alongside the BBB markers intercellular adhesion molecule-1 (ICAM1) and matrix metalloproteinase 9 (MMP9). Noradrenaline and lactate measurements were available from a previous study. P-levels0.05 were regarded as significant.Twenty-eight patients with 28 GCS were included. Leukocytosis occurred immediately after GCS and normalized within two hours (p0.001). S100 and HMGB1 both increased by ∼80 % (p0.001). MMP9 peaked after six hours with levels at 48.6 % above baseline. RAGE decreased by 17.6 % with a nadir at 24 h. CRP increased by 118 % with a peak at 24 h. ICAM1 remained stable (p = 0.068). Postictal HMGB1 correlated with postictal leukocytosis (r = 0.42; p = 0.025) and with MMP9 levels six hours later (r = 0.374; p = 0.05). Postictal lactate levels correlated with MMP9 at 6 h (r = 0.48; p = 0.01) and CRP at 24 h (r = 0.39; p = 0.04). Postictal noradrenaline correlated with lactate (r = 0.57; p = 0.02) and leukocytes (r = 0.39; p = 0.047).The serum level of the DAMPs HMGB1 and S100 increase immediately after GCS. The hypothetical mechanism includes central nervous processes, such as glutamate toxicity and ROS release from seizing neurons but also muscular tissues. BBB breakdown is marked by the release of MMP9. Further research is needed to understand the complex interactions between electrical and metabolic stress, neuroinflammation and BBB mechanics in seizures and epilepsy.Our study reveals signs of inflammation, neuronal damage and transitory disruption of BBB following single GCS, underscoring the widespread and possibily detrimental effects of recurrent seizures on brain properties. The long term impact on the disease course, however, is unclear.

Epilepsien zahlen weltweit zu den haufigsten neurologischen Erkrankungen. Je nach Schweregrad der Epilepsie konnen Betroffene ein nahezu unbeschwertes Leben fuhren oder grose Einschrankungen ihrer Autonomie erleben. Charakteristisches Symptom sind wiederkehrende epileptische Anfalle, die aufgrund der Unvorhersehbarkeit des Zeitpunkts, an dem Anfalle auftreten, als auch der Bewusstseinsstorungen und des Kontrollverlustes uber verschiedene Korperfunktionen fur Betroffene, Angehorige und Pflegende sehr belastend sein konnen. Die fruhzeitige Erkennung von Anfallen kann ggf. das Ergreifen entsprechender Sicherheitsmasnahmen fur den Betroffenen beschleunigen. Neben einer solchen Fruherkennung hilft eine akkurate Aufzeichnung der Anfalle zudem bei der individuellen Abstimmung der Therapie. Im Rahmen des hier vorgestellten Projekts werden technische Innovationen fur die Unterstutzung epilepsieerkrankter Menschen durch sensorische Anfallsdetektion und -dokumentation sowie den Aufbau einer interoperablen Gesundheitsinfrastruktur und von Gesundheitsanwendungen entwickelt.

In this narrative review, we summarize the current knowledge of neurally mediated blood pressure (BP) control and discuss how recently described epilepsy- and seizure-related BP alterations may contribute to premature mortality and sudden unexpected death in epilepsy (SUDEP). Although people with epilepsy display disturbed interictal autonomic function with a shift toward predominant sympathetic activity, prevalence of arterial hypertension is similar in people with and without epilepsy. BP is transiently increased in association with most types of epileptic seizures but may also decrease in some, illustrating that seizure activity can cause both a decrease and increase of BP, probably because of stimulation or inhibition of distinct central autonomic function by epileptic activity that propagates into different neuronal networks of the central autonomic nervous system. The principal regulatory neural loop for short-term BP control is termed baroreflex, mainly involving peripheral sensors and brain stem nuclei. The baroreflex sensitivity (BRS, expressed as change of interbeat interval per change in BP) is intact after focal seizures, whereas BRS is markedly impaired in the early postictal period following generalized convulsive seizures (GCS), possibly due to metabolically mediated muscular hyperemia in skeletal muscles, a massive release of catecholamines and compromised brain stem function. Whilst most SUDEP cases are probably caused by a cardiorespiratory failure during the early postictal period following GCS, a profoundly disturbed BRS may allow a life-threatening drop of systemic BP in the aftermath of GCS, as recently reported in a patient as a plausible cause of SUDEP in a few patients.

Epilepsy has been associated with a dysfunction of the blood-brain barrier. While there is ample evidence that a dysfunction of the blood-brain barrier contributes to epileptogenesis, blood-brain barrier dysfunction as a consequence of single epileptic seizures has not been systematically investigated. We hypothesized that blood-brain barrier dysfunction is temporally and anatomically associated with epileptic seizures in patients and used a newly-established quantitative MRI protocol to test our hypothesis. Twenty-three patients with epilepsy undergoing inpatient monitoring as part of their presurgical evaluation were included in this study (10 females, mean age ± standard deviation: 28.78 ± 8.45). For each patient, we acquired quantitative T1 relaxation time maps (qT1) after both ictal and interictal injection of gadolinium-based contrast agent. The postictal enhancement of contrast agent was quantified by subtracting postictal qT1 from interictal qT1 and the resulting ΔqT1 was used as a surrogate imaging marker of peri-ictal blood-brain barrier dysfunction. Additionally, the serum concentrations of MMP9 and S100, both considered biomarkers of blood-brain barrier dysfunction, were assessed in serum samples obtained prior to and after the index seizure. Fifteen patients exhibited secondarily generalized tonic-clonic seizures and eight patients exhibited focal seizures at ictal injection of contrast agent. By comparing ΔqT1 of the generalized tonic-clonic seizures and focal seizures groups, the anatomical association between ictal epileptic activity and postictal enhancement of contrast agent could be probed. The generalized tonic-clonic seizures group showed significantly higher ΔqT1 in the whole brain as compared to the focal seizures group. Specific analysis of scans acquired later than 3 h after the onset of the seizure revealed higher ΔqT1 in the generalized tonic-clonic seizures group as compared to the focal seizures group, which was strictly lateralized to the hemisphere of seizure onset. Both MMP9 and S100 showed a significantly increased postictal concentration. The current study provides evidence for the occurrence of a blood-brain barrier dysfunction, which is temporally and anatomically associated with epileptic seizures. qT1 after ictal contrast agent injection is rendered as valuable imaging marker of seizure-associated blood-brain barrier dysfunction and may be measured hours after the seizure. The observation of the strong anatomical association of peri-ictal blood-brain barrier dysfunction may spark the development of new functional imaging modalities for the post hoc visualization of brain areas affected by the seizure.

Purpose We here evaluated (1) the differential characteristics of status epilepticus (SE) in older (≥60 years) compared to younger adults (18–59 years). In particular, we were interested in (2) the proportion and characteristics of new onset SE in patients with no history of epilepsy (NOSE) in older compared to younger adults, and (3) predictive parameters for clinical outcome in older subjects with NOSE. Methods We performed a monocentric retrospective analysis of all adult patients (≥18years) admitted with SE to our tertiary care centre over a period of 10 years (2006–2015) to evaluate clinical characteristics and short-time outcome at discharge. Results One-hundred-thirty-five patients with SE were included in the study. Mean age at onset was 64 years (range 21–90), eighty-seven of the patients (64%) were older than 60 years. In 76 patients (56%), SE occurred as NOSE, sixty-seven percent of them were aged ≥60 years. There was no age-dependent predominance for NOSE. NOSE was not a relevant outcome predictor, especially regarding age-related subgroups. Older patients with NOSE had less frequently general tonic clonic SE (GTCSE; p=0.001) and were more often female (p=0.01). Regarding outcome parameters and risk factors in older patients with NOSE, unfavourable outcome was associated with infections during in-hospital treatment (0.04), extended stay in ICU (p=0.001), and generally in hospital (p Conclusion In our cohort, older patients represented the predominant subgroup in patients with SE. Older patients suffered more often from non-convulsive semiology and had a less favourable short-time outcome. NOSE was not a predictive outcome parameter in older patients. Data suggest that avoiding infections should have a priority because higher infection rates were associated with unfavourable outcome.

Objective Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. Methods We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. Results There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 μmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. Conclusions Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

Electroencephalography (EEG) is a core element in the diagnosis of epilepsy syndromes and can help to monitor antiseizure treatment. Mobile EEG (mEEG) devices are increasingly available on the consumer market and may offer easier access to EEG recordings especially in rural or resource-poor areas. The usefulness of consumer-grade devices for clinical purposes is still underinvestigated. Here, we compared EEG traces of a commercially available mEEG device (Emotiv EPOC) to a simultaneously recorded clinical video EEG (vEEG). Twenty-two adult patients (11 female, mean age 40.2 years) undergoing noninvasive vEEG monitoring for clinical purposes were prospectively enrolled. The EEG recordings were evaluated by 10 independent raters with unmodifiable view settings. The individual evaluations were compared with respect to the presence of abnormal EEG findings (regional slowing, epileptiform potentials, seizure pattern). Video EEG yielded a sensitivity of 56% and specificity of 88% for abnormal EEG findings, whereas mEEG reached 39% and 85%, respectively. Interrater reliability coefficients were better in vEEG as compared to mEEG (ϰ = 0.50 vs. 0.30), corresponding to a moderate and fair agreement. Intrarater reliability between mEEG and vEEG evaluations of simultaneous recordings of a given participant was moderate (ϰ = 0.48). Given the limitations of our exploratory pilot study, our results suggest that vEEG is superior to mEEG, but that mEEG can be helpful for diagnostic purposes. We present the first quantitative comparison of simultaneously acquired clinical and mobile consumer-grade EEG for a clinical use-case.

Das Auftreten kognitiver Einschrankungen bei der amyotrophen Lateralsklerose (ALS), vor allem in Form einer frontotemporalen Demenz (FTD), ist seit langerer Zeit bekannt. Molekularbiologische und histopathologische Erkenntnisse der letzten Jahre ergeben Hinweise darauf, dass ALS und FTD gemeinsame pathologische Mechanismen haben und verschiedene Phanotypen derselben Proteinopathie darstellen konnten. Der zugrunde liegende Pathomechanismus konnte eine fehlerhafte RNA- und DNA-Modulation sein, vermittelt unter anderem durch die Proteine TDP43 und FUS. Diese Ergebnisse haben zur Beschreibung der neuen Kategorie der TDP43-Proteinopathien gefuhrt, zu welcher neben der ALS und der FTD auch kombinierte Krankheitsbilder zahlen. Wahrend knapp die Halfte der FTD-Falle mit TDP43-Ablagerungen assoziiert ist, finden sich bei der anderen Halfte Tau-Ablagerungen. Auch hier bestehen klinische Uberlappungen zu anderen Tauopathien, z. B. dem corticobasalen Syndrom. Ausgehend von einem Fallbeispiel geben wir einen Uberblick uber das klinische Spektrum und die aktuellen pathogenetischen Konzepte der FTD.

Convulsions following traumatic brain injury (TBI) represent a diagnostic and therapeutic challenge. They can be differentiated into late (> 7 days after TBI), early (1 - 7 days after TBI), immediate (within the first 24 h after TBI), and impact seizures (within seconds after TBI). Some authors suggest that most impact seizures are non-epileptic in origin and hence coined the term "concussive convulsions" for benign impact seizures. Early and late post-traumatic seizures frequently indicate structural brain damage and transition to chronic, post-traumatic epilepsy. The data for impact seizures or concussive convulsions is less clear: only a small percentage of impact seizures is associated with structural brain damage and the development of post-traumatic epilepsy, rather the majority of cases are benign and associated with an excellent prognosis. Here, we present a case report as a starting point for pathophysiological and clinical considerations regarding convulsions that start within seconds after TBI.

Chronically elevated levels of oxidative stress resulting from increased production and/or impaired scavenging of reactive oxygen species are a hallmark of mitochondrial dysfunction in left ventricular hypertrophy. Recently, oscillations of the mitochondrial membrane potential (DeltaPsi(m)) were mechanistically linked to changes in cellular excitability under conditions of acute oxidative stress produced by laser-induced photooxidation of cardiac myocytes in vitro. Here, we investigate the spatiotemporal dynamics of DeltaPsi(m) within the intact heart during ischemia-reperfusion injury. We hypothesize that altered metabolic properties in left ventricular hypertrophy modulate DeltaPsi(m) spatiotemporal properties and arrhythmia propensity.

Parkinson's disease is a common motor disorder that not only leads to motor symptoms but also autonomic dysregulation, mental changes, sensory disturbances, and sleep disorders such as increased daytime sleepiness and sleep fragmentation. The aim of this study was to find out how the daytime and night-time motor activity levels in individuals without motor disorders differ from patients with Parkinson's disease. Daytime and night-time motor activity levels in 17 PD patients and 69 controls were measured for three consecutive days and nights via actigraphy, a method of continuous long-term assessment of activity levels. A ratio between night-time and daytime motor activity was calculated. PD patients had a 1.5-2-fold lower daytime motor activity but also showed 1.5-2-fold higher motor activity at night time. Older controls showed a lower daytime but similar night-time motor activity when compared to younger controls. A ratio of night-time to daytime motor activity could clearly distinguish controls and patients. The possibility to distinguish patients and controls by the ratio of night-time to daytime motor activity is worth further investigation.

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.

Calcium channels are crucially involved in brain development and neuronal function. Mutations in the pore-forming Cav subunits of high- and low-voltage dependent calcium channels (VDCC) have been found in patients with autistic syndromes (Splawski et al., Cell 2004;119:19-31; Splawski et al., PNAS 2005;102:8089-96; Splawski et al., JBC 2006;281:22085-91). In Timothy syndrome, the G406R mutation of Cav1.2 results in a reduction of inactivation rate. Such biophysical effects can likewise be induced by the influence of auxiliary VDCC β subunits. For instance, we demonstrated a novel mechanism of β subunit modulation: the inactivation of VDCC is under length-dependent control of the β2 subunit N terminus (Herzig et al., FASEB J 2007;21:1527-38). A similar mechanism operates with the β1 subunit (Jangsangthong et al., Pflugers Arch 2009, in press).Therefore, the β2-subunit gene was screened for mutations in 155 patients with Autistic Spectrum Disorder (ASD). We detected several new variations and compared the genotypes with 375 matching controls. (Male to female ratio for both groups is 1:4.). Statistical analysis of preselected variations showed two significant SNPs in functional intronic regions (χ2 p = 5x10−6 and χ2 p =9x10−3).Furthermore, we also identified several rare ASD-specific missense mutations at the gene locus of the β2 subunit. These mutations occur in highly conserved domains and may lead to alterations in the β2 subunit function, e.g. by interfering with subunit phosphorylation. The affected amino acids are highly conserved among species, suggesting an importance for topology and function of the subunit. We will clone these variations into expression vectors and characterize their functional effects by electrophysiological studies. These studies may provide new insights into molecular mechanisms leading to ASD.

Polarization of the mitochondrial membrane potential (DeltaPsi(m)) is critical for normal mitochondrial function and cellular energetics. Mitochondrial dysfunction, manifesting as disrupted DeltaPsi(m) polarization (i.e. depolarization or hyperpolarization), underlies several important and highly prevalent diseases, including a variety of cardiac and neurological disorders. As such, DeltaPsi(m) instability might form a unifying mechanism for a class of metabolic disorders affecting excitable tissues. Here, we measured the spatio-temporal kinetics of DeltaPsi(m) changes across the intact heart using high-resolution optical DeltaPsi(m) imaging and uncovered surprisingly complex spatial patterns and dynamically fluctuating changes in DeltaPsi(m) that developed into actively propagating waves of mitochondrial depolarization during global ischemia. Our data further indicated that the recovery of DeltaPsi(m) upon reperfusion is dictated by the duration of the preceding ischemic insult. Post-ischemic electrical and functional recovery was dependent on early DeltaPsi(m) recovery but independent of overall cellular injury measured using a standard assay of lactate dehydrogenase release. These findings reveal a novel mechanism by which instabilities in cellular energetic properties that are independent of irreversible cellular injury can scale to the level of the intact organ via an organized process of active conduction involving the multi-cellular network. This highlights the importance of investigating cellular metabolic properties in the context of the intact organ.

In an attempt to compensate for compromised hemodynamics in heart failure, neurohumoral mechanisms are activated that trigger fundamental changes in gene expression and in protein processing, trafficking and post-translational regulation, resulting in myocyte hypertrophy. Unfortunately, over time these changes become maladaptive, predisposing to myocyte loss, chamber dilatation, interstitial hyperplasia and intercellular uncoupling. Intrinsic and peripheral responses to mechanical dysfunction alter the expression and function of key ion channels and calcium-handling proteins, thereby remodeling the cellular action potential and the intracellular calcium transient. This electrophysiological remodeling renders the heart more vulnerable to ventricular arrhythmias that underlie sudden cardiac death. In this Review, we consider key ventricular ionic changes that are associated with heart failure, with the intention of identifying molecular targets for antiarrhythmic therapy.

End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 (Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [left ventricular end-diastolic pressure (LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling (3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.