NORSE seasonality may vary geographically in adults.

The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008-2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C-reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non-NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies. PLAIN LANGUAGE SUMMARY: The study investigated the seasonal patterns of new-onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

Outcomes and Treatment Approaches for Super-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis.

Importance: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia. Current clinical knowledge of the disease and optimal treatment approach is sparse. Objective: To systematically assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with SRSE. Design, Setting, and Participants: In this systematic review and meta-analysis, all studies reporting adult patients (18 years or older) diagnosed with nonanoxic SRSE were considered for inclusion, irrespective of study design. The databases used were MEDLINE, Cochrane Library, EMBASE, and ClinicalTrials.org (database inception through May 5, 2022). Data extraction and synthesis: The study complied with the PRISMA guidelines for reporting, data extraction, and data synthesis. Different tools were used to assess risk of bias. All available data were extracted and missing data were neither imputed nor completed by contacting the study authors. Main outcome and measures: Successful treatment of SRSE, in-hospital mortality, and disability at discharge (estimated modified Rankin Scale). Results: The study team identified a total of 95 articles and 30 conference abstracts reporting 1200 patients with nonanoxic SRSE (266 individual patients were available for meta-analysis). They had a mean SRSE duration of 36.3 days, mean age of 40.8 years, and equal sex distribution. Patients with SRSE had a distinct pattern of etiologies where acute cerebral events and unknown etiologies accounted for 41.6% and 22.3% of all etiologies, respectively. Reports of SRSE caused by, eg, alcohol, drugs, or tumors were rare. At discharge, only 26.8% had none to slight disability (none, 16 [8.4%]; nonsignificant and slight disability, 35 [18.4%]). In-hospital mortality was 24.1%. Mortality stabilized after long-term treatment (more than 28 days) but with increased rates of seizure cessation and moderate to severe disability. Established prognostic factors, such as age and etiology, were not associated with in-hospital mortality. Reported treatment with ketamine, phenobarbital, other barbiturates, vagus nerve stimulator, and ketogenic diet were not associated with outcome. Conclusion and Relevance: Patients with SRSE are distinct due to their pattern of care (eg, long-term treatment to younger patients without negative prognostic factors and unknown/nonmalignant etiologies) and their natural course of SE. Very long-term treatment was associated with lower mortality and high odds of cessation of SRSE but increased risk of moderate to severe disability.

Feasibility and acceptability of a virtual diagnostic sleep disorders service: A qualitative study.

INTRODUCTION: The electronic collection of patient data is used for a large variety of conditions. The boundaries of its use in initial diagnostics and the extent to which it can replace specialist contact, however, remain vague. Our newly developed virtual diagnostic process for common sleep disorders involves digital questionnaire administration, neurophysiological diagnostic studies, and virtual consultation with a sleep specialist. In this study, we evaluated patients' virtual diagnostic process experiences as part of a full evaluation of this process. METHODS: Patients who completed the virtual diagnostic process participated in online semi-structured interviews based on the following criteria: age ≥ 18 years, no obvious cognitive deficits, and access to the internet. Patients who did not complete the virtual diagnostic process were contacted by telephone and given the opportunity to explain why. RESULTS: Of the 24 patients included, 14 completed the virtual diagnostic process. Most participants understood the concept of the virtual diagnostic process, could navigate the process, and felt that the combined use of a questionnaire and virtual consultation was meaningful. Although participants could provide information as free text, the simplified closed questions, required for diagnostic classification, triggered feelings of insecurity and the inability to sufficiently describe symptoms, thereby evoking concern. All patients deemed the complementary personal contact important. DISCUSSION: The findings demonstrate that the virtual diagnostic process is feasible and highly accepted by most patients. However, (virtual) personal (telephone or video) contact is mandatory to address patients' concerns. The virtual diagnostic process application evaluated here likely represents the outer limit of the use of electronic data collection in virtual diagnostic procedures.

Association of ictal imaging changes in status epilepticus and neurological deterioration.

OBJECTIVE: In patients with status epilepticus (SE), the clinical significance of ictal changes on magnetic resonance imaging (MRI) is insufficiently understood. We here studied whether the presence of ictal MRI changes was associated with neurological deterioration at discharge. METHODS: The retrospective cohort comprised all identifiable patients treated at Odense University Hospital in the period 2008-2017. All amenable MRIs were systemically screened for ictal changes. Patient demographics, electroencephalography, seizure characteristics, treatment, and SE duration were assessed. Neurological status was estimated before and after SE. The predefined endpoint was the association of neurological deterioration and ictal MRI changes. RESULTS: Of 261 eligible patients, 101 received at least one MRI during SE or within 7 days after cessation; 43.6% (44/101) had SE due to non- or less brain-damaging etiologies. Patients who received MRI had a longer duration of SE, less frequently had a history of epilepsy, and were more likely to have SE due to unknown causes. Basic characteristics (including electroencephalographic features defined by the Salzburg criteria) did not differ between patients with (n = 20) and without (n = 81) ictal MRI changes. Timing of MRI was important; postictal changes were rare within the first 24 h and hardly seen >5 days after cessation of SE. Ictal MRI changes were associated with a higher risk of neurological deterioration at discharge irrespective of etiology. Furthermore, they were associated with a longer duration of SE and higher long-term mortality that reached statistical significance in patients with non- or less brain-damaging etiologies. SIGNIFICANCE: In this retrospective cohort, ictal changes on MRI were associated with a higher risk of neurological deterioration at discharge and, possibly, with a longer duration of SE and poorer survival.

[Treatment of status epilepticus in children and adults].

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

Prediction of Long-term Survival After Status Epilepticus Using the ACD Score.

Importance: Early prediction of long-term mortality in status epilepticus is important given the high fatality rate in the years after diagnosis. Objective: To improve prognostication of long-term mortality after status epilepticus diagnosis. Design, Settings, and Participants: This retrospective, multicenter, multinational cohort study analyzed adult patients who were diagnosed with and treated for status epilepticus at university hospitals in Odense, Denmark, between January 1, 2008, and December 31, 2017, as well as in Oslo, Norway; Marburg, Germany; and Frankfurt, Germany. They were aged 18 years or older and had first-time, nonanoxic status epilepticus. A new scoring system, called the ACD score, for predicting 2-year (long-term) mortality after hospital discharge for status epilepticus was developed in the Danish cohort and validated in the German and Norwegian cohorts. The ACD score represents age at onset, level of consciousness at admission, and duration of status epilepticus. Data analysis was performed between September 1, 2019, and March 31, 2020. Exposures: Long-term follow-up using data from national and local civil registries in Denmark, Norway, and Germany. Main Outcomes and Measures: The predefined end point was 2-year survival for all patients and for a subgroup of patients with status epilepticus causes that were not damaging or were less damaging to the brain. Neurological deficits before and after onset, demographic characteristics, etiological categories of status epilepticus, comorbidities, survival, time points, treatments, and prognostic scores for different measures were assessed. Results: A total of 261 patients (mean [SD] age, 67.2 [14.8] years; 132 women [50.6%]) were included, of whom 145 patients (mean [SD] age, 66.3 [15.0] years; 78 women [53.8%]) had status epilepticus causes that were not damaging or were less damaging to the brain. The validation cohort comprised patients from Norway (n = 139) and Germany (n = 906). At hospital discharge, 29.8% of patients (n = 64 of 215) had new moderate to severe neurological deficits compared with baseline. New neurological deficits were a major predictor of 2-year survival after hospital discharge (odds ratio, 5.1; 95% CI, 2.2-11.8); this association was independent of etiological category. Nonconvulsive status epilepticus in coma and duration of status epilepticus were associated with development of new neurological deficits, and a simple 3-factor score (ACD score) combining these 2 risk factors with age at onset was developed to estimate survival after status epilepticus diagnosis. The ACD score had a linear correlation with 2-year survival (Pearson r2 = 0.848), especially in the subset of patients with a low likelihood of brain damage. Conclusions and Relevance: This study found that age, long duration, and nonconvulsive type of status epilepticus in coma were associated with the development of new neurological deficits, which were predictors of long-term mortality. Accounting for risk factors for new neurological deficits using the ACD score is a reliable method of prediction of long-term outcome in patients with status epilepticus causes that were not damaging or were less damaging to the brain.

Social outcome and psychiatric comorbidity of generalized epilepsies - A case-control study.

OBJECTIVE: To investigate social outcome and psychiatric comorbidity of patients with idiopathic/genetic generalized epilepsies (IGEs) and its subtypes (epilepsy with generalized tonic-clonic seizures alone [EGTCS], juvenile absence epilepsy [JAE], and juvenile myoclonic epilepsy [JME]). METHODS: A cohort of 402 adult patients with IGE from the Danish island Funen was matched with 4020 randomly selected geography-, age-, and sex-matched controls via the Danish Civil Registration System. Based on register data, we compared social status measured by cohabitant status, educational attainment, income, affiliation to labor market, and psychiatric comorbidity. RESULTS: As compared to controls, patients with IGE had similar cohabitant status but fewer children (no children: 59.0% vs 50.9%), and lower educational level (primary school only: 46.0% vs 37.3%), employment rate (outside of workforce: 56.7% vs 46.5%), and income (low income: 32.6% vs 24.9%) (P < 0.001 for all comparisons). Having IGE was associated with higher a proportion of psychiatric comorbidity (IGE, 22.6%; controls, 13.0%) (P < 0.001). Seizure-free patients did not differ from controls; patients with persistent seizures had lower incomes and employment rates. In the IGE subgroup analyses, JME was associated with worse social status in all parameters studied (eg, 65.9% of JME patients were outside the workforce vs 44.5% of matched controls; P < 0.001), whereas no adverse social status was identified in patients with EGTCS and JAE. SIGNIFICANCE: Patients with IGE in general and JME in particular have poorer social status and more psychiatric comorbidity than matched population controls without epilepsy. Poor seizure control was associated with social status and may contribute to negative socioeconomic consequences associated with IGE.

Risk factors of paradoxical reactions to anti-seizure medication in genetic generalized epilepsy.

This study aimed at providing valid estimates for the risk of clinically relevant seizure aggravation by recommended anti-seizure medications in patients with Genetic Generalized Epilepsy (GGE). To this aim, treatment response, side effects and paradoxical reactions to anti-seizure treatment were retrospectively assessed in a near-population based cohort comprising 471 adult GGE patients. A total of 1046 treatment attempts were analyzed (lamotrigine: 351, valproic acid: 295, levetiracetam: 249, primidone/phenobarbital: 94, zonisamide: 57). Under lamotrigine, seizure aggravation was observed in 15 patients (two patients during levetiracetam, one patient during zonisamide, none during phenobarbital and valproic acid). All but two patients with paradoxical reactions to lamotrigine were diagnosed with juvenile myoclonic epilepsy (JME), otherwise, the clinical and electroencephalographic characteristics of patients with paradoxical reactions did not differ. At treatment start, the estimated risk of a paradoxical reaction to lamotrigine was 7.9 % in JME patients (n = 190). For all GGE patients (incl. JME), the estimated risk of clinically relevant seizure aggravation under treatment with lamotrigine was 3.7 % (1.8 % for zonisamide and 0.8 % for levetiracetam). In conclusion, clinical significant aggravation of seizure frequency is common in lamotrigine-treated JME patients but rare in patients with other GGE subsyndromes or under treatment with other recommended anti-seizure medication.

Safety and feasibility of an intensive epilepsy nurse-based treatment course.

PURPOSE: To determine safety, feasibility and patient satisfaction of an epilepsy nurse-based treatment course with frequent contacts and changes of anti-epileptic treatment provided by supervised anti-epileptic drug (AED) prescribing epilepsy nurses. METHODS: Regular prescheduled clinical contacts with a neurologist to adjust AED treatment were largely substituted by on-demand contacts with epilepsy nurses with the delegated right to adapt AED within predefined limits. To secure safety, electronic medical files of patients with 6 or more contacts with epilepsy nurses were retrospectively analysed for clinical characteristics, safety measures and seizure frequency before/after the intensive treatment course and patients were asked to complete a questionnaire about treatment satisfaction. RESULTS: Between January 1st 2016 and 31st December 2018, 2721 patients were treated by epilepsy nurses (2561 ambulatory controls, 8690 phone contacts). 617 patients received an intensive treatment course (six or more contacts in the observation period, range: 6-65) with an average length of 24.3 months. The average number of AED tried was 3.4. In patients with ongoing seizures (n = 310), 165 (53.2 %) reported an improvement of seizure frequency by 50 % or more. Seizure frequency fell from 4.4 to 2.4 days with seizures/months (p < 0.001). The epilepsy-related hospitalization rate was 0.86/patient; 27 episodes with status epilepticus occurred in 21 patients, three hospitalizations were due to severe side effects. There were no fatal complications. No hospitalization was related to the intensive treatment course by prescribing epilepsy nurses. The overall patients' satisfaction was high. CONCLUSION: Intensive epilepsy treatment facilitated by epilepsy nurses was safe and associated with high patient accept and improvement of seizure frequency.

Transient epileptic amnesia diagnosed using long-term electroencephalography.

Transient epileptic amnesia (TEA) is a distinct syndrome affecting middle-aged persons without concurrent brain disease or disposition to epileptic seizures. Seizures are characterized by amnesia, usually lasting less than one hour, and interictal memory deficits that are common. Effective antiseizure treatment is usually rapid in patients with TEA, which underlines the need for prompt diagnosis. Here, we report a 58-year-old male patient with recurrent episodes of antero- and retrograde amnesia. MRI was normal and diagnosis was made using long-term EEG (27 hours), revealing 10 right-sided temporal lobe seizures with subtle clinical symptoms lasting up to 86 seconds. Details of the video-EEG are presented. Treatment with levetiracetam resulted in complete recovery and seizure freedom that was confirmed on a second long-term EEG. Given the favourable outcome with antiseizure treatment, our case study illustrates the role of long-term EEG monitoring in patients with recurrent transient amnesia to establish a correct diagnosis [Published with video sequence].

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation.

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance. METHODS: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132H doxycycline-inducible glioma cell line system. RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDHR132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT. CONCLUSION: ALT is the major telomere maintenance mechanism in IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.

Epidemiology-Based Mortality Score is Associated with Long-Term Mortality after Status Epilepticus.

BACKGROUND/OBJECTIVE: Status epilepticus (SE) is a life-threatening condition with a high long-term mortality. The correct prediction of the individual patient's outcome is crucial for stratifying treatment. Status epilepticus severity score (STESS) and the epidemiology-based mortality score (EMSE) are well established for predicting in-hospital mortality; however, scores indicating long-term mortality are lacking. We here studied the association of both scores with mortality after discharge and long-term mortality. METHODS: In this retrospective cohort study of adult patients with incident, non-anoxic, first-time SE (from 01/2008 to 12/2014), STESS, EMSE-EACE (etiology-age-comorbidity-EEG), demographic data, modified Rankin Scale at discharge, treatment, date of diagnosis, and date of death were determined based on electronic patients charts. RESULTS: A total of 129 patients with a median follow-up of 24.8 months were included. We found no significant difference between STESS and EMSE-EACE in predicting in-hospital and 3 months mortality. At end-of-study, EMSE-EACE with a cutoff of ≥ 64 showed the best association with overall survival. At last follow-up, only 15.7% (8 out of 51) of the patients with EMSE ≥ 64 were alive as compared to 32.4% (24 out of 74) of the patients with STESS ≥ 3. Median survival of patients with EMSE-EACE ≥ 64 and EMSE-EACE < 64 was 6.4 months (95% confidence interval (CI) 2.3-15.3 months) and 35.8 months (CI 32.8-37.9 months), respectively. In the subgroup of patients that were discharged alive from the hospital, EMSE-EACE was highly significantly associated with mortality (p < 0.001) after discharge. In the same patients, STESS with a cutoff of STESS ≥ 3 reached only borderline significance (p = 0.04), STESS with a cutoff of STESS ≥ 4 did not reach statistical significance (p = 0.23). Exploratory analyses of different EMSE components unveiled a strong association of etiology with in-house mortality but not with long-term survival. In patients discharged alive from the hospital, only comorbidity and age remained significantly associated with long-term mortality. CONCLUSIONS: In our cohort, EMSE-EACE was significantly associated with long-term survival after discharge.

Aberrant neuronal differentiation is common in glioma but is associated neither with epileptic seizures nor with better survival.

The mechanisms of glioma-associated seizures (GAS) have yet to be fully elucidated. Proneural subtype, isocitrate dehydrogenase 1 (IDH1) mutations, and epileptic seizures are closely associated suggesting that aberrant neuronal differentiation contributes to glioma-associated seizures. In a population-based cohort (n = 236), lack of stem cell marker expression (nestin, musashi) was significantly associated with IDH1 mutations and GAS at diagnosis. In vitro data suggested an association of IDH1 mutations and a more differentiated phenotype. Out of eight glioma stem cell (GSC) lines, seven revealed positivity for the synaptic marker protein synaptophysin. Three had synapse-like structures identified by electron microscopy and were either vGlut1 (glutamatergic) or GAD67 (GABAergic) positive. In vivo, >10% synaptophysin-positive tumour cells were present in >90% of all gliomas. Synaptophysin expression was associated with proneural subtype and vGlut1 expression, suggesting that most synapse-like structures in glioma are glutamatergic. However, we found null associations between vGlut1 protein/mRNA expression and survival, GAS at onset, development of GAS after resection, and refractory GAS. Synapse-like structures were neither functional nor activated by spontaneous action potentials or cellular networks. Thus, aberrant neuronal differentiation including glutamatergic synapse-like structures is detectable in glioma but is associated neither with epileptic seizures nor with better survival.

Hormonal contraception is not associated with increased risk for seizures in the general population: results from a cohort study using The Health Improvement Network.

PURPOSE: Endogenous human gonadal steroids and especially female sex hormones modulate the risk of developing epileptic seizures. In most circumstances, estrogens increase excitability, while progesterone bears substantial anticonvulsive properties. We questioned whether exogenous gonadal steroids used as hormonal contraception are associated with risk of seizures. METHODS: In a dynamic cohort ascertained within The Health Improvement Network database, we identified 2201 female patients aged 20-44 years with seizures during follow-up. In a nested case-control analysis, we matched these cases to 10,143 controls. Using logistic regression, we calculated the risk of seizure associated with use of contraceptives and adjusted for potential confounders. We performed same analyses among women with no prior hormonal contraception use ("new user" analyses) and in patients with a history of epilepsy. RESULTS: Unadjusted data suggested a lower risk for seizures in patients taking exogenous gonadal steroids irrespective of type of contraception used. After adjustment for potential confounders, neither use of combined oral contraceptives nor progestin-only oral contraceptives was associated with the risk for seizures overall. Analyses of "new users" of oral contraceptives produced similar risk estimates. CONCLUSIONS: We found no evidence supporting an effect of oral exogenous gonadal steroids used for hormonal contraception on the risk of seizures in the general female population.

High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma.

Epileptic seizures are an important cause of morbidity in glioma patients. Substantial lines of evidence support the concept of the excitatory neurotransmitter glutamate being a crucial mediator of glioma-associated seizures. In gliomas, non-vesicular secretion of glutamate via the cystine-glutamate exchanger (SLC7A11, xCT) constitutes the main mechanism contributing to high extracellular glutamate concentrations. However, a convincing "proof-of-relevance" of this mechanism in patient material is lacking. A cohort of 229 consecutive patients with newly diagnosed glioma was analyzed with respect to presence, time course, and severity of epileptic seizures. 14 patients were excluded due to previous epileptic seizures, insufficient clinical data or insufficient tumor material. The maximal immunohistochemical expression of xCT was determined in 1-3 independent samples from central tumor areas of each tumor using tissue microarrays. In addition to histological grading of the tumors, isocitrate dehydrogenase 1 (IDH1) R132H mutational status was determined by immunohistochemistry. 215 consecutive glioma patients were included in the study (7.4% grade II, 7.0% grade III, 85.6% grade IV). High xCT expression was significantly associated with seizures at onset (p = 0.05) but not with development of seizures or with refractory seizures. Low-grade gliomas (WHO II/III) had lower xCT expression than glioblastoma (p = 0.001), and tumors without IDH1 R132H mutation tended to have higher xCT levels (p = 0.07). In a multivariate analysis, high xCT expression and WHO tumor grade but not IDH1 R132H mutation, were significantly associated with epileptic seizures at diagnosis (odds ratio 2.2, p = 0.02). Further, xCT expression did not correlate with survival (p = 0.27, log-rank test). Thus, high xCT expression is an independent marker for glioma-associated seizures at diagnosis especially in high-grade glioma, but is not associated with worse survival in our cohort.

The Neuroradiological Spectra of Adult and Pediatric Medulloblastoma Differ : Results from a Literature-based Meta-analysis.

PURPOSE: Current knowledge on the spectrum of the neuroradiological appearance of adult medulloblastoma is sparse. Due to the rarity of the disease, adult patients were generally diagnosed and treated similar to children; however, pediatric and adult medulloblastomas display substantial molecular differences that may influence the neuroradiological phenotype. This study therefore aimed at assessment of the neuroradiological spectrum of adult medulloblastoma in comparison to pediatric tumors. METHODS: All available publications on adult medulloblastoma published until June 2013 were screened for imaging data on single patients. A total of 109 patients were identified and compared to 118 pediatric patients described in 4 cohorts. RESULTS: The average age of the adult patients was 34.3 years. Most adult medulloblastomas (57.6 %) were localized laterally (vs. 14.4 % in pediatric patients). On T1-weighted sequences, only 41.1 % of all adult medulloblastomas appeared hypointense (vs. 89.3 %) and 69.6 % were hyperintense on T2 sequences (vs. 83 %). In contrast to pediatric patients only 53.3 % showed strong contrast enhancement (pediatric patients 77.1 %), while the contrast uptake of the remainder was described as subtle, moderate or lacking. Contrast enhancement was more often described as inhomogeneous in adults (35.5 % as compared to 15.2 % in children) and 26.4 % had cysts. CONCLUSION: Although the neuroradiological spectrum of medulloblastoma in adults was similar to children, an atypical presentation with inhomogeneous contrast enhancement, more hyperintense signal on T1 and a more hypointense signal on T2-weighted sequences was common. Given the rarity of the tumor, awareness of these differences constitutes a prerequisite to avoid delays in diagnostics.

Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3.

Acidic microenvironment is commonly observed in tumour tissues, including glioblastoma (GBM), the most aggressive and lethal brain tumour in adults. Acid sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels, which are sensors of extracellular protons. Here we studied and functionally characterized ASICs in two primary glioblastoma stem cell lines as cell culture models. We detected transcripts of the ACCN2 and ACCN3 genes, coding for ASIC1 and ASIC3, respectively, but not transcripts of ACCN1 (coding for ASIC2). Available microarray data confirmed that ACCN1 is downregulated in glioma. Western blotting confirmed expression of ASIC1 and ASIC3, the most proton-sensitive ASICs, in both GBM cell lines. We characterized ASICs functionally using whole-cell patch clamp and detected different types of acid-sensitive currents. Some of these currents had kinetics typical for ASICs and were sensitive to specific toxin inhibitors of ASIC1a or ASIC3, demonstrating that the GBM cell lines express functional ASIC1a and ASIC3 that may enable GBM cells to sensitively detect extracellular pH in a tumour tissue. Microarray data revealed that expression of ACCN2 and ACCN3 is associated with improved survival of patients suffering from gliomas, suggesting that preserved susceptibility to extracellular pH may impair tumour growth.

Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies.

This study aimed at defining clinical predictors of drug resistance in adults with genetic generalized epilepsy (GGE) who were treated with a broad spectrum of antiepileptic drugs. Of a cohort of 137 unselected adult GGE patients with long-term follow up, clinical and demographic data, putative prognostic factors (e.g., psychiatric comorbidities, electroencephalography [EEG]), treatment response, and data indicative of social status were collected. Fifty-eight patients had seizures within the past year. Thirty-three patients met the definition of "drug-resistant epilepsy" according to the International League Against Epilepsy (ILAE) definition. Psychiatric comorbidities, age at first diagnosis, and absences were associated with worse seizure control, whereas focal changes in EEG remained without prognostic impact. Resistance to valproic acid was the most important prognostic factor for refractory seizures. Resistance to valproic acid had a specificity of 100% to identify patients with drug resistance and correlated strongly with bad social outcome and seizure burden. Conversely, 21.2% of all patients with refractory seizures according to the ILAE definition later became seizure free (mainly with valproic acid). Our data suggest that "drug resistant GGE" must not be declared unless patients were adequately treated with valproic acid, and advocate resistance to valproic acid as a new clinical biomarker for drug-resistant GGE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Predictive value of the Status Epilepticus Severity Score (STESS) and its components for long-term survival.

BACKGROUND: The "Status Epilepticus Severity Score" (STESS) is the most important clinical score to predict in-hospital mortality of patients with status epilepticus (SE), but its prognostic relevance for long-term survival is unknown. This study therefore examined if STESS and its components retain their prognostic relevance beyond acute treatment. METHODS: One hundred twenty-five non-anoxic patients with SE were retrospectively identified in two hospitals between 2008 and 2014 (39.2 % refractory SE). Patients' treatment, demographic data, date of death, aetiology of SE, and the components of the STESS (age, history of seizures, level of consciousness and worst seizure type) were determined based on the patients' records. RESULTS: In 94.4 % of patients, SE was treated successfully; in-hospital mortality rate was 12 %. The overall mortality was 42 % after median follow-up of 28.1 months. The survival plateaued after about 3 years, all patients with progressive brain diseases (n = 4) died within one year. In-hospital mortality correlated highly significantly with STESS, the optimal cut-off was 4. With respect to long-term outcome, STESS correlated significantly with overall mortality though with lower odds ratios. When looking only at patients that survived the acute phase of treatment, only the STESS components "level of consciousness" (at admission), "coma" as worst seizure type, and "age" reached a statistical significant association with mortality. In these patients, STESS with a cut-off of 4 was not significantly associated with survival/mortality. Aetiology of SE was insufficient to explain the weak association and the high mortality after discharge alone. CONCLUSION: STESS at onset of SE reliably assessed in-hospital mortality, and was indicative for overall survival. However, STESS did not allow correct estimation of mortality after discharge. The high mortality after discharge and high overall mortality of patients diagnosed with SE was not explained by progressive brain disorders alone. Further research is needed to understand the causes for high overall mortality after SE and putative prognostic factors.