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Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
Objective: We sought to evaluate the efficacy and tolerability of intranasal midazolam (in‐MDZ) as first‐line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording.
Methods: Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in‐MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in‐MDZ and ß‐band effects were analyzed on EEG and with frequency analysis.
Results: In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in‐MDZ (range: 2.5–15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in‐MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in‐MDZ (median: 04:56; range: 00:29–14:53; SD:03:13). Frequency analysis showed an increased ß‐band on EEG after the application of in‐MDZ at 04:07 on average (median: 03:50; range: 02:20–05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient.
Conclusions: This pharmaco‐EEG–based study showed that in‐MDZ is effective and well‐tolerated for the acute treatment of SE. EEG and clinical effects of in‐MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first‐line treatment if an intravenous route is not available.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Background: Pulmonary nocardiosis (PN) is an uncommon but potentially life-threatening infection. Most of our knowledge is derived from case reports or smaller case series. Recently, increasing PN incidence rates have been reported. We aim to describe the clinical course of and risk factors for PN in four Western European countries and to estimate population-based annual hospitalization rates.
Methods: Retrospective evaluation (1995 to 2011) of the clinical course of and risk factors for PN in patients from 11 hospitals in four European countries (Germany, Austria, Switzerland and The Netherlands). Calculation of population-based estimates of hospitalization rates of PN in Germany (2005 to 2011) using official German nationwide diagnosis-related groups (DRG) hospital statistics.
Results: Forty-three patients fulfilled stringent criteria for proven (n = 8) and probable (n = 35) PN; seven with extrapulmonary dissemination. Within the 43 patients, major PN risk factors were immunocompromising (83.7%) and/or pulmonary (58.1%; in 27.9% as only comorbidity) comorbidities. Median duration of PN targeted therapy was 12 weeks. Distinguished patterns of resistance were observed (imipenem susceptibility: N. farcinica 33.3%; N. asteroides 66.7%). Overall mortality rate was 18.9%; in disseminated PN 50%. Over time, annual PN hospitalization rates remained unchanged at around 0.04/100′000 with the highest rate among men aged 75–84 years (0.24/100′000).
Conclusion: PN is rare, but potentially life-threatening, and mainly affects immunocompromised elder males. Overall annual hospitalization rates remained stable between 2005 and 2011.
EEG microstate periodicity explained by rotating phase patterns of resting-state alpha oscillations
(2020)
Spatio-temporal patterns in electroencephalography (EEG) can be described by microstate analysis, a discrete approximation of the continuous electric field patterns produced by the cerebral cortex. Resting-state EEG microstates are largely determined by alpha frequencies (8-12 Hz) and we recently demonstrated that microstates occur periodically with twice the alpha frequency.
To understand the origin of microstate periodicity, we analyzed the analytic amplitude and the analytic phase of resting-state alpha oscillations independently. In continuous EEG data we found rotating phase patterns organized around a small number of phase singularities which varied in number and location. The spatial rotation of phase patterns occurred with the underlying alpha frequency. Phase rotors coincided with periodic microstate motifs involving the four canonical microstate maps. The analytic amplitude showed no oscillatory behaviour and was almost static across time intervals of 1-2 alpha cycles, resulting in the global pattern of a standing wave.
In n=23 healthy adults, time-lagged mutual information analysis of microstate sequences derived from amplitude and phase signals of awake eyes-closed EEG records showed that only the phase component contributed to the periodicity of microstate sequences. Phase sequences showed mutual information peaks at multiples of 50 ms and the group average had a main peak at 100 ms (10 Hz), whereas amplitude sequences had a slow and monotonous information decay. This result was confirmed by an independent approach combining temporal principal component analysis (tPCA) and autocorrelation analysis.
We reproduced our observations in a generic model of EEG oscillations composed of coupled non-linear oscillators (Stuart-Landau model). Phase-amplitude dynamics similar to experimental EEG occurred when the oscillators underwent a supercritical Hopf bifurcation, a common feature of many computational models of the alpha rhythm.
These findings explain our previous description of periodic microstate recurrence and its relation to the time scale of alpha oscillations. Moreover, our results corroborate the predictions of computational models and connect experimentally observed EEG patterns to properties of critical oscillator networks.
Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.
Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.
Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3–74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2–3.4%) and 3.2% per patient (95% CI 1.8–5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5–2.2%) and 1.7% per patient (95% CI 0.8–3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.
Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.
There is a need for diagnostic biomarkers of epilepsy and status epilepticus to support clinical examination, electroencephalography and neuroimaging. Extracellular microRNAs may be potentially ideal biomarkers since some are expressed uniquely within specific brain regions and cell types. Cerebrospinal fluid offers a source of microRNA biomarkers with the advantage of being in close contact with the target tissue and sites of pathology. Here we profiled microRNA levels in cerebrospinal fluid from patients with temporal lobe epilepsy or status epilepticus, and compared findings to matched controls. Differential expression of 20 microRNAs was detected between patient groups and controls. A validation phase included an expanded cohort and samples from patients with other neurological diseases. This identified lower levels of miR-19b in temporal lobe epilepsy compared to controls, status epilepticus and other neurological diseases. Levels of miR-451a were higher in status epilepticus compared to other groups whereas miR-21-5p differed in status epilepticus compared to temporal lobe epilepsy but not to other neurological diseases. Targets of these microRNAs include proteins regulating neuronal death, tissue remodelling, gliosis and inflammation. The present study indicates cerebrospinal fluid contains microRNAs that can support differential diagnosis of temporal lobe epilepsy and status epilepticus from other neurological and non-neurological diseases.
Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy and is characterized by recurrent spontaneous seizures originating from the temporal lobe. The majority of mTLE patients develop pharmacoresistance to available anti-epileptic drugs (AEDs) while exhibiting severe pathological changes that can include hippocampal atrophy, neuronal death, gliosis and chronic seizures. The molecular mechanisms leading to mTLE remain incompletely understood, but are known to include defects in post-transcriptional gene expression regulation, including in non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a class of recently rediscovered ncRNAs with high levels of expression in the brain and proposed roles in diverse neuronal processes. To explore a potential role for circRNAs in epilepsy, RNA-sequencing (RNA-seq) was performed on hippocampal tissue from a rat perforant pathway stimulation (PPS) model of TLE at different post-stimulation time points. This analysis revealed 218 differentially expressed (DE) circRNAs. Remarkably, the majority of these circRNAs were changed at the time of the occurrence of the first spontaneous seizure (DOFS). The expression pattern of two circRNAs, circ_Arhgap4 and circ_Nav3, was further validated and linked to miR-6328 and miR-10b-3p target regulation, respectively. This is the first study to examine the regulation of circRNAs during the development of epilepsy. It reveals an intriguing link between circRNA deregulation and the transition of brain networks into the state of spontaneous seizure activity. Together, our results provide a molecular framework for further understanding the role and mechanism-of-action of circRNAs in TLE.
Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively. Objective: To investigate the influence of taVNS on gastric motility of healthy participants using rtMRI. Methods: We conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI. Results: After HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003). Conclusion: We provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.
Background: Refractory status epilepticus (RSE) represents a serious medical condition requiring early and targeted therapy. Given the increasing number of elderly or multimorbid patients with a limitation of life-sustaining therapy (LOT) or within a palliative care setting (PCS), guidelines-oriented therapy escalation options for RSE have to be omitted frequently. Objectives: This systematic review sought to summarize the evidence for fourth-line antiseizure drugs (ASDs) and other minimally or non-invasive therapeutic options beyond guideline recommendations in patients with RSE to elaborate on possible treatment options for patients undergoing LOT or in a PCS. Methods: A systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on fourth-line ASDs or other minimally or non-invasive therapeutic options was performed in February and June 2020 using the MEDLINE, EMBASE and Cochrane databases. The search terminology was constructed using the name of the specific ASD or therapy option and the term ‘status epilepticus’ with the use of Boolean operators, e.g. “(brivaracetam) AND (status epilepticus)”. The respective Medical Subject Headings (MeSH) and Emtree terms were used, if available. Results: There is currently no level 1, grade A evidence for the use of ASDs in RSE. The best evidence was found for the use of lacosamide and topiramate (level 3, grade C), followed by brivaracetam, perampanel (each level 4, grade D) and stiripentol, oxcarbazepine and zonisamide (each level 5, grade D). Regarding non-medicinal options, there is little evidence for the use of the ketogenic diet (level 4, grade D) and magnesium sulfate (level 5, grade D) in RSE. The broad use of immunomodulatory or immunosuppressive treatment options in the absence of a presumed autoimmune etiology cannot be recommended; however, if an autoimmune etiology is assumed, steroid pulse, intravenous immunoglobulins and plasma exchange/plasmapheresis should be considered (level 4, grade D). Even if several studies suggested that the use of neurosteroids (level 5, grade D) is beneficial in RSE, the current data situation indicates that there is formal evidence against it. Conclusions: RSE in patients undergoing LOT or in a PCS represents a challenge for modern clinicians and epileptologists. The evidence for the use of ASDs in RSE beyond that in current guidelines is low, but several effective and well-tolerated options are available that should be considered in this patient population. More so than in any other population, advance care planning, advance directives, and medical ethical aspects have to be considered carefully before and during therapy.
