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Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PKs), safety, and tolerability of daridorexant, a dual orexin receptor antagonist intended for the treatment of insomnia. A single‐center, open‐label study evaluated the PKs of daridorexant in patients with severe renal function impairment (SRFI; determined by creatinine clearance using the Cockcroft‐Gault equation; N = 8) not on dialysis, and in matched control subjects (based on sex, age, and body weight; N = 7). A single oral dose of daridorexant 25 mg was orally administered in the morning. Blood samples were collected up to 72 h postdose for PK assessments of daridorexant. In patients with SRFI, maximum plasma concentrations (Cmax; geometric mean ratio [GMR] and 90% confidence interval [CI]: 0.94 [0.60–1.46]), time to reach Cmax (T max; median difference [90% CI] of −0.25 h [−0.75 to 0.25]), and half‐life (GMR [90% CI] of 0.99 [0.66–1.48]), were virtually unchanged. Exposure (area under the plasma concentration‐time profile) to daridorexant was slightly higher in patients with SRFI than in control subjects with the GMR (90% CI) being 1.16 (0.63–2.12). No safety issue of concern was detected as all adverse events were transient and of mild or moderate intensity, and no treatment‐related effects on vital signs, clinical laboratory, or electrocardiogram variables were observed following daridorexant administration in patients with SRFI and control subjects. Based on these observations, PK alterations of daridorexant due to renal function impairment are not considered of clinical relevance and no dose adjustment is necessary in these patients.

Daridorexant is a dual orexin receptor antagonist in clinical development for insomnia. As daridorexant is cleared mainly via cytochrome P450 (CYP) 3A4, the effect of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of daridorexant was evaluated. Sleep disorders are common in patients with liver cirrhosis and, therefore, sleep-promoting drugs with a better tolerability than currently available would be preferable, a premise that dual orexin receptor antagonists may fulfill. This was a single-dose, open-label, phase I study. Subjects with mild (Child–Pugh A, N = 8) or moderate (Child–Pugh B, N = 8) liver cirrhosis and matched healthy control subjects (N = 8) received 25 mg of daridorexant orally. Blood samples were collected for 72 h post-dose for PK assessments of daridorexant and three major metabolites. Compared with healthy subjects, patients showed a decrease in total daridorexant area under the plasma concentration–time curve from zero to infinity (AUC0-inf) and maximum plasma concentration with a geometric mean ratio (GMR, 90% confidence interval [CI]) of 0.51 (0.28–0.92) and 0.50 (0.35–0.72) in Child–Pugh A and 0.74 (0.39–1.41) and 0.42 (0.29–0.60) in Child–Pugh B patients, respectively. Furthermore, the median time to reach maximum plasma concentration was slightly delayed (1.0 h [90% CI 0.0–2.0] in Child–Pugh A patients and 0.5 h [90% CI 0.0–1.5] in Child–Pugh B patients), while for Child–Pugh B patients, a doubling in half-life was observed (GMR [90% CI]: 2.09 [1.32–3.30]). Considering the high plasma protein binding (> 99%) and a 1.9-fold to 2.3-fold increase in the unbound fraction in patients, the PK of unbound daridorexant was also assessed. Compared with healthy subjects, Child–Pugh B patients had a higher AUC0-inf (GMR [90% CI] 1.60 [0.93–2.73]), a lower apparent plasma clearance (GMR [90% CI] 0.63 [0.37–1.07]), and the same doubling in the half-life observed for total daridorexant, whereas maximum plasma concentration and apparent volume of distribution were not different. Unbound daridorexant PK in Child–Pugh A patients did not differ from healthy subjects. In addition, the metabolic ratios (parent to metabolite), i.e., a marker of CYP 3A4 activity, of the two most abundant daridorexant metabolites were higher in patients with liver cirrhosis compared with healthy subjects. All treatment-emergent adverse events were transient and of mild or moderate intensity and no other treatment-related effects were apparent. No safety issue of concern was detected following administration of 25 mg of daridorexant in the study population. Moderate liver cirrhosis causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child–Pugh B patients. A dose adjustment is not required in Child–Pugh A patients, while avoidance of daridorexant in patients with Child–Pugh C cirrhosis is recommended. ClinicalTrials.gov ID: NCT03713242.

Introduction The role of immunological mechanisms in the pathophysiology of mental disorders has been discussed with increasing frequency. In this context, especially schizophrenia has become the focus of attention after the discovery of autoimmune encephalitis, which might present with psychotic symptoms. Furthermore, multiple studies have identified associations between infections or autoimmune diseases and schizophreniform disorders. Cerebrospinal fluid (CSF) analysis plays a central role in identifying potential inflammatory processes in the central nervous system. Therefore, the rationale of this retrospective study was the analysis of different cytokines, including interleukin-8 (IL-8) levels, in the CSF of patients with schizophrenia spectrum disorders. Methods The authors examined the CSF of 40 patients with schizophrenia spectrum disorders, in comparison to the CSF of a mentally healthy control group of 39 patients with idiopathic intracranial hypertension (IIH). Magnetic bead multiplexing immunoassay was used to retrospectively determine different cytokines in the participants' CSF. Results Participants with schizophrenia spectrum disorders had significantly higher IL-8 levels in their CSF than controls (mean ± SD: 41.83 ± 17.50 pg/ml versus 21.40 ± 7.96 pg/ml; p Conclusion The main finding of this study is the presence of significantly higher IL-8 concentrations in the CSF of patients with schizophrenia spectrum disorders when compared to the control group. This supports the hypothesis that immunological processes may be involved in the pathophysiology of a subgroup of patients with schizophrenia spectrum disorders. However, the study's results are limited by the retrospective design, methodological aspects, and the control group with IIH.

Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (tmax) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. Apart from a shift in tmax, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. NCT03609775 (ClinicalTrials.gov Identifier)

Glioblastoma multiforme might develop radiologically within a few days following unremarkable CT scan of the brain. Glioblastoma multiforme is the most frequent primary brain tumor. Initial presentations are diverse, including headache, seizures and transient or persistent neurological deficits. Cerebral imaging followed by histological examination of a tissue specimen is the mainstay of diagnosis. We report the case of a 79-year-old female patient whose computer tomography (CT) of the brain was unremarkable at first clinical presentation with a transient hemiparesis of the right side, but revealed a cerebral space-occupying lesion ultimately diagnosed as glioblastoma only 10 days later. According to our case presentation glioblastoma might develop radiologically within a few days following unremarkable CT scan of the brain. Since clinical manifestation with a transient ischemic attack (TIA)-like episode was preceding CT manifestation, this case indicates, that a magnetic resonance imaging (MRI) should be routinely performed in all patients presenting with TIA.

ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6β-hydroxycortisol/cortisol ratio (6β-CR), as the geometric mean ratio of the 6β-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6β-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.

Background: Myasthenic crisis (MC) requiring mechanical ventilation (MV) is a rare and serious complication of myasthenia gravis. Here we analyzed the frequency of performed tracheostomies, risk factors correlating with a tracheostomy, as well as the impact of an early tracheostomy on ventilation time and ICU length of stay (LOS) in MC. Methods: Retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015 to assess demographic/diagnostic data, rates and timing of tracheostomy and outcome. Results: In 107 out of 215 MC (49.8%), a tracheostomy was performed. Patients without tracheostomy were more likely to have an early-onset myasthenia gravis (27 [25.2%] vs 12 [11.5%], p = 0.01). Patients receiving a tracheostomy, however, were more frequently suffering from multiple comorbidities (20 [18.7%] vs 9 [8.3%], p = 0.03) and also the ventilation time (34.4 days ± 27.7 versus 7.9 ± 7.8, p < 0.0001) and ICU-LOS (34.8 days ± 25.5 versus 12.1 ± 8.0, p < 0.0001) was significantly longer than in non-tracheostomized patients. Demographics and characteristics of the course of the disease up to the crisis were not significantly different between patients with an early (within 10 days) compared to a late tracheostomy. However, an early tracheostomy correlated with a shorter duration of MV at ICU (26.2 days ± 18.1 versus 42.0 ± 33.1, p = 0.006), and ICU-LOS (26.2 days ± 14.6 versus 42.3 ± 33.0, p = 0.003). Conclusion: Half of the ventilated patients with MC required a tracheostomy. Poorer health condition before the crisis and late-onset MG were associated with a tracheostomy. An early tracheostomy (≤ day 10), however, was associated with a shorter duration of MV and ICU-LOS by 2 weeks.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Muscle-specific kinase-antibodies (MuSK-ABs) are detected in ~ 6% of MG, but data on outcome of MuSK-MCs are still lacking. We made a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody positive MG (AchR-MG) or MuSK-MG between 2006 and 2015 in a retrospective German multicenter study. We identified 19 MuSK-AB associated MCs in 15 patients and 161 MCs in 144 patients with AchR-ABs only. In contrast to patients with AchR-AB, MuSK-AB patients were more often female (p = 0.05, OR = 2.74) and classified as Myasthenia Gravis Foundation of America-class IV before crisis (p = 0.04, OR = 3.25). MuSK-AB patients suffer more often from multiple chronic disease (p = 0.016, OR = 4.87) and were treated more invasively in terms of plasma exchanging therapies (not significant). The number of days of mechanical ventilation (MV) (43.0 ± 53.1 vs. 17.4 ± 18; p p p

Objectives:Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context.Methods:Therefore, two patients with psychosis and anti-MOG antibodies – detected in fixed cell-based and live cell-based assays – are presented.Results:Patient 1 suffered from late-onset psychosis with singular white matter lesions in magnetic resonance imaging (MRI) and intermittent electroencephalography (EEG) slowing. Patient 2 suffered from a chronic paranoid–hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganised alpha rhythm on EEG, and elevated cerebrospinal fluid protein. Both patients had anti-MOG antibody titres of 1 : 320 in serum (reference < 1 : 20).Conclusions:The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titres, they may have caused a rather ‘subtle clinical picture’ consisting of psychosis instead of ‘classical’ MOG encephalomyelitis.

Regulatory review of new medicines is often viewed as a hindrance to innovation by increasing the hurdle to bring products to market. However, a more complete accounting of regulation must also account for its potential market expanding effects through quality certification. We combine data on FDA approvals for follow-on indications and patient-level data on utilization, and examine whether FDA approval of a follow-on indication increases the use of a drug for that indication. We find 5 facts for the market-expanding role of regulation: (1) follow-on approvals increase the share of patients taking a drug with that indication by 4.1 percentage points, or 40% increase over baseline use, at the time of approval; (2) there is little market learning prior to or following the approval of the follow-on indication, suggesting that such approvals fully certify the new use; (3) the effect of these approvals is larger for uses in a different disease area than previous indications, an increase equivalent to over 4 ½ years of market-learning; (4) it is FDA approval, not the initiation of clinical trials that generate the expansion in market size; (5) the market expansion is consistent with physicians prescribing the medicines more because of higher perceived benefits, not reduced administrative costs.

Background: Neuralgic amyotrophy (NA) has been described as a possible extrahepatic manifestation of hepatitis E virus (HEV) infection. Usually, HEV-associated NA occurs bilaterally. The clinical characteristics determining the course of HEV-associated NA have still not been defined. Methods: In this retrospective multicentric case series, 16 patients with HEV-associated NA were studied and compared to 176 HEV patients without NA in terms of their age, sex, and ALT levels. Results: Neither gender distribution (75% vs. 67% male) nor age (47 vs. 48 years median) differed significantly between the NA patients and controls. Eight NA patients (50%) presented with bilateral involvement—seven of these had right-side dominance and one had left-side dominance. Thirteen cases (81%) were hospitalized. Eight of these patients stayed in hospital for five to seven days, and five patients stayed for up to two weeks. The time from the onset of NA to the HEV diagnosis, as well as the diagnostic and therapeutic proceedings, showed a large variability. In total, 13 (81%) patients received treatment: 1/13 (8%) received intravenous immunoglobulins, 8/13 (62%) received glucocorticoids, 3/13 (23%) received ribavirin, and 6/13 (46%) received pregabalin/gabapentin. Patients with ages above the median (47 years) were more likely to be treated (p = 0.001). Conclusion: HEV-associated NA causes a relevant morbidity. In our case series neither the type of treatment nor the time of initiation of therapy had a significant effect on the duration of hospitalization or the course of the disease. The clinical presentation, the common diagnostic and therapeutic procedures, and the patients’ characteristics showed large variability, demonstrating the necessity of standardized protocols for this rare but relevant disease.

Background Central nervous system (CNS) infections can be caused by a variety of viruses, but in a significant number of patients no viral or other pathogen can be identified using routine diagnostic work-up. Interestingly, several case reports and series described Hepatitis E virus (HEV) as a potential pathogen. However, systematic studies have not been conducted so far. Methods We identified 243 patients from Southwestern Germany with acute CNS infections of unknown cause treated in our clinic between 2008 and 2018, of which serum and/or cerebrospinal fluid (CSF) samples were available. These patients were retrospectively tested for anti-HEV IgM and IgG antibodies. In addition, HEV PCR was performed in the majority of cases including IgM-negative patients with symptom onset Results Evidence of an acute HEV infection was found in four patients (1.7%). Three had recent HEV infection defined as positive anti-HEV IgM and IgG antibodies, one had current HEV infection defined as (additional) detection of HEV RNA in serum. However, anti-HEV IgM and IgG seroprevalence did not differ significantly from controls, though these had considerably lower IgM levels. Interestingly, anti-HEV IgG seroprevalence was unexpectedly high (30.7%) and revealed an age-dependent increase to more than 50% in patients older than 60 years. Conclusion This study supports previous findings that HEV could play a role in acute CNS infections. Therefore, we encourage testing for acute HEV infection if no other pathogen can be identified. However, further studies are necessary to prove a causal role.

Background and purpose: In 2017, eculizumab has been approved for treatment-refractory generalised myasthenia gravis (TRgMG). The German Myasthenia Foundation has published a consensus statement on the use of eculizumab, with a recent update. However, a treatment-refractory state is still ill-defined and the term warrants further clarification. We aimed at developing a sum score to operationalise the definition of a TRgMG status, which is easy- to-handle in clinical decision making. Methods: We established a structured consensus process according to the Delphi consensus methodology, with 12 members of the medical advisory board of the German Myasthenia Foundation. Accordingly, 4 consensus rounds were accomplished. Additionally, a literature survey covering the years 2004-2020 was done and relevant information offered to the consensus group. Consensus criteria were predefined. In the consensus process the relative importance of scoring items were to be consented, with a sum score of 20 and above indicating a TRgMG status. Results: The sum score considers the categories disease severity, inefficiency of antecedent therapies, cessation of therapies due to side effects, and long term stay on the intensive care unit. Categories were specified by a total of 13 scoring items. Eventually, the Delphi process developed an unanimous scoring consensus. Conclusion: We suggest a sum score to define treatment refractory state in generalised myasthenia gravis. Beyond clarifying the indication of eculizumab, this easy-to-handle score facilitates clinical decision making and offers new inclusion criteria for clinical studies that explore new therapeutic perspectives in myasthenia gravis treatment.

Background Myelin oligodendrocyte glycoprotein-IgG-associated encephalomyelitis (MOG-EM) and neuromyelitis optica spectrum disorders are challenging differential diagnoses of multiple sclerosis (MS). Hence, there is uncertainty, whether to test all MS patients for corresponding antibodies. Our objective was to provide a systematic study on the frequency of MOG and Aquaporin-4 (AQP4) autoantibodies in MS patients to evaluate a possible risk of misclassification. Methods Retrospective study in MS patients (including an unselected cohort of patients diagnosed with MS, a cohort of patients with PPMS and a healthy control group) for seroprevalence of MOG and AQP4 autoantibodies by cell-based assay. Results None of 241 patients with relapsing-remitting, 19 with secondary progressive and 82 with primary progressive MS revealed MOG or AQP4 autoantibodies. Conclusion General testing of MOG and AQP4 autoantibodies in MS patients seems not necessary, but should be limited to selected cases only.

Background: Most cases of COVID-19 are considered mild, but patients with immunosuppressant treatment might be prone to severe courses of disease. Expert panels advise to delay treatment with cell-depleting MS therapies during the COVID-19 pandemic. Methods: We report a case of a patient with relapsing-remitting multiple sclerosis who developed COVID-19 pneumonia 2 weeks after the first week of cladribine therapy. Results: Despite a severe lymphopenia (absolute lymphocyte count 240/µL), the patient had a moderate course of COVID-19. Conclusion: Apart from maximal supportive treatment, this could be due to cladribine reducing inflammatory response, which probably contributes considerably to severe courses of COVID-19 pneumonia.

Epileptic seizures associated with hyperglycemia have a rare but characteristic MR imaging pattern which however is frequently missed. It consists of a T2 hypointensity and an apparent diffusion coefficient (ADC) decrease of the white matter underlying the epileptic cortex; the cortex itself may be DWI hyperintense and show a blood-brain barrier disruption. Prompt diagnosis is relevant since treatment of the hyperglycemic state rather than treatment with anti-epileptic drugs frequently interrupts the seizures. Subcortical T2 hypointensity and ADC decrease may be completely reversible.

Objectives We evaluated whether dried blood spots (DBS) are suitable to monitor combined ART when samples are collected in rural Tanzania and transported over a long distance to a specialized bioanalytical laboratory. Methods Plasma and DBS samples were collected in Tanzania from study patients treated with nevirapine, efavirenz or lopinavir. In addition, plasma, whole blood and DBS samples were obtained from a cohort of HIV patients at the site of the bioanalytical laboratory in Switzerland. DBS samples were analysed using a fully automated LC-MS/MS method. Results Comparison of DBS versus plasma concentrations of samples obtained from the bridging study in Switzerland indicated an acceptable bias only for nevirapine (18.4%), whereas for efavirenz and lopinavir a pronounced difference of -47.4% and -48.1% was found, respectively. Adjusting the DBS concentrations by the haematocrit and the fraction of drug bound to plasma proteins removed this bias [efavirenz +9.4% (-6.9% to +25.7%), lopinavir +2.2% (-20.0% to +24.2%)]. Storage and transportation of samples from Tanzania to Switzerland did not affect the good agreement between plasma and DBS for nevirapine [-2.9% (-34.7% to +29.0%)] and efavirenz [-9.6% (-42.9% to +23.8%)]. For lopinavir, however, adjusted DBS concentrations remained considerably below [-32.8% (-70.4% to +4.8%)] corresponding plasma concentrations due to decay of lopinavir in DBS obtained under field conditions. Conclusions Our field study shows that the DBS technique is a suitable tool for therapeutic drug monitoring in resource-poor regions; however, sample stability remains an issue for certain analytes and therefore needs special consideration.

There is growing evidence that hepatitis E virus (HEV) infection can present with extrahepatic manifestations including neurological disorders. Among these, neuralgic amyotrophy (NA) has been reported to occur in some industrialized countries. We investigated 35 patients with NA and a control group for markers of HEV infection. Acute HEV infection was found in NA patients only and was associated with an inflammatory response in the central nervous system. Shedding of HEV RNA into the cerebrospinal fluid and intrathecal production of anti-HEV immunoglobulin M occurred in 1 patient, suggesting that HEV is neurotropic.

Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI ≥ 1.5 and 2.0) were applied, and MRZR was considered positive in cases with ≥ 2 positive AIs (MRZR-2). Using the common AI threshold of ≥ 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p

Power generation from biomass gasification through the use of spark ignition engines requires the cooling of the biomass syngas to avoid knock. This cooling leads to the condensation of tar impurities, which foul and clog up critical process components leading to significant maintenance issues and costs. Conventionally, tar related problems are addressed by optimizing the gasification process along with developing tar purification systems, both of which result in increased investment and maintenance costs. A novel method is being developed at the Université catholique de Louvain, where the entire process, from the exit of the biomass gasifier to the combustion of tar loaded impure syngas in an internal combustion engine, is carried out at a temperature of 250 ° C, thereby avoiding tar condensation and its consequent problems. A Homogeneous Charge Compression Ignition (HCCI) engine is utilized for such a high intake temperature operation. This paper describes the first experiments with an impure and hot biomass syngas, produced from a two-stage gasifier, which is burned in a HCCI engine without the intermediate cooling and tar purification steps. The objective of the experiment was to test the stability of the engine in response to the naturally occurring random variations in the syngas composition. The experiments were carried out over a continuous period of 24 h. Indicated efficiencies of 33%–39% and IMEP around 2.5 bar were observed while the emissions of NOx were relatively high, probably due to the presence of ammonia in the syngas. The implementation of a closed control loop, with the combustion phasing as the feedback parameter and the fueling rate as the controlled parameter, ensured a stable operation over the experimental duration.

Background Paraneoplastic neurological syndromes (PNS) might present as polyneuropathies (PNP). Because PNS are rare and PNP are frequent, it may be difficult to decide in patients with PNP of unclear or presumably idiopathic etiology whether to test for onconeural antibodies, which are highly predictive for PNS. In this regard, this is the largest study investigating the prevalence of onconeural antibodies in patients with PNP, in order to clarify whether such testing should be standard. Methods Of 1842 consecutive patients, 283 were suitable and had stored serum samples for screening for onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma2, and amphiphysin) by ELISA: 159 patients with PNP of – despite laborious work-up – unknown etiology without cancer, 67 with Guillain-Barre syndrome (GBS), 31 with chronic inflammatory demyelinating PNP (CIDP), and 26 with cancer and PNP. Results None of the 283 screening samples revealed high concentrations for any of the tested antibodies. Thirteen sera (4.6%) showing positive reactivity in the screening ELISA (11 with PNP of unknown etiology without cancer, one with GBS, and one with CIDP) most likely represented increased background activity, as confirmatory assays (immunoblotting and immunohistochemistry) were negative. Furthermore, none of these 13 patients had diagnosed cancer and 10 with sufficient follow-up data did not develop cancer during follow-up. Interestingly, none of the patients with known cancer and PNP was screened positive for any antibody reactivity. Conclusions Our data suggest that routine screening for onconeural antibodies in etiologically unclear and in presumably idiopathic (GBS and CIDP) PNP is not mandatory.

Objectives Anti-SOX1 antibodies are associated with small cell lung cancer (SCLC) and predict a paraneoplastic etiology in Lambert-Eaton myasthenic syndrome (LEMS). In 2010, a study described these antibodies in a small cohort of putative non-paraneoplastic, immune-mediated neuropathies. In this respect, we investigated the seroprevalence and specificity of anti-SOX1 antibodies in a large cohort of neurological disorders. Methods Overall, serum samples of 1493 consecutive patients were screened for anti-SOX1 reactivity by an ELISA: 471 with well-defined neurological disorders (multiple sclerosis, motor neuron disease, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy), 185 with polyneuropathy (PNP) of unknown origin, and 837 with neurological syndromes of suspicious paraneoplastic etiology. These were compared to eight positive controls with definite paraneoplastic neurological syndromes (PNS) and 92 healthy individuals. We also collected demographic and clinical data, including well-characterized onconeural antibodies in anti-SOX1–positive patients. Results Fifteen patients (1.0%) showed anti-SOX1 reactivity: two with multiple sclerosis, two with PNP of unknown origin, and 11 suspicious PNS cases. Remarkably, 9/15 anti-SOX1–positive patients had a PNP. However, antibody concentrations were significantly lower compared to positive controls, and none additionally harbored well-characterized onconeural antibodies. During a follow-up of at least four years, only five patients had cancer: one thyroid, one Hodgkin lymphoma, two breast, and one patient had multiple malignancies - prostate, penis, cecum, liver, and non–small cell lung cancer. However, none had SCLC, typically associated with SOX1 antibodies. Conclusions The seroprevalence of anti-SOX1 antibodies in patients with various neurological disorders is low. These patients predominantly have PNPs, which might represent a group of immune-mediated diseases.

Schizophreniform syndromes in combination with autoimmune thyroiditis and increased serum thyroid antibodies lead healthcare practitioners to consider a diagnosis of Hashimoto's encephalopathy. To detect specific biomarkers, the authors analyzed whether intrathecal antithyroid antibody synthesis occurred in a subgroup of schizophreniform patients. In doing so, the authors analyzed thyroid antibodies in paired cerebrospinal fluid and serum samples from 100 schizophreniform patients. Increased antibody indices (AIs) for antithyroid peroxidase or antithyroglobulin autoantibodies in 13 schizophreniform patients were found. AIs were increased in 68% of the seropositive patients. These findings support the hypothesis that autoimmune processes may contribute to the pathophysiology in these patients.

This publication is a contribution to basic research in image comparison using eigenvalue spectra as features. The differential-geometric approach of eigenvalue spectrum-based descriptors is naturally applicable to shape data, but so far little work has been done to transfer it to the setting of image data painted on a rectangle or general curved surface. We present a new semi-global feature descriptor that also contains information about geometry of shapes visible in the image. This may not only improve the performance of the resulting distance measures, but may even enable us to approach the partial matching problem using eigenvalue spectra, which were previously only considered as global feature descriptors. We introduce some concepts that are useful in designing and understanding the behaviour of similar fingerprinting algorithms for images (and surfaces) and discuss some preliminary results.

Purpose Because of the immune-suppressive effect of cerebral damage, stroke patients are at high risk for infections. These might result in sepsis, which is the major contributor to intensive care unit (ICU) mortality. Although there are numerous studies on infections in stroke patients, the role of sepsis as a poststroke complication is unknown. Methods We retrospectively analyzed incidence of and risk factors for sepsis acquisition as well as outcome parameters of 238 patients with ischemic or hemorrhagic strokes consecutively admitted to the neurologic ICU in a tertiary university hospital between January 1, 2009, and December 31, 2010. Basic demographic and clinical data including microbiological parameters as well as factors describing stroke severity (eg, lesion volume and National Institute of Health stroke scale score) were recorded and included into the analysis. The diagnosis of sepsis was based on the criteria of the German Sepsis Society. Results We identified 30 patients (12.6%) with sepsis within the first 7 days from stroke onset. The lungs were the most frequent source of infection (93.3%), and gram-positive organisms were dominating the microbiologic spectrum (52.4%). Comorbidities (chronic obstructive pulmonary disease and immunosuppressive disorders) and Simplified Acute Physiology Score II but none of the factors describing stroke severity were independent predictors of sepsis acquisition. Sepsis was associated with a significantly worse prognosis, leading to a 2-fold increased mortality rate during in-hospital care (36.7% vs 18.8%) and after 3 months (56.5% vs 28.5%), but only in the subgroup of supratentorial hemorrhages, it was an independent predictor of in-hospital and 3-month mortality. Other factors significantly associated with death in a multivariate analysis were chronic obstructive pulmonary disease, malignancies (in-hospital mortality only), and Simplified Acute Physiology Score II (3-month mortality only) for ischemia and heart failure (in-hospital mortality only), National Institute of Health stroke scale score (in-hospital mortality only), and stroke volume for hemorrhages, respectively. Conclusions Sepsis seems to be a frequent complication of stroke patients requiring neurologic ICU treatment. Predictors of sepsis acquisition in our study were comorbidities and severity of deterioration of physiological status, but not stroke severity. A better understanding of risk factors is important for prevention and early recognition, whereas knowledge of outcome may help in prognosis prediction. Further studies are needed to clarify the optimal preventive treatment for these patients.

Background and purpose Patients with severe acute stroke are at high risk for systemic infections which are associated with an increase in morbidity and mortality; nevertheless current guidelines do not recommend prophylactic antibiotic therapy. Sensitive detection of pathogens in the blood is desirable to guide early antibiotic therapy. We studied the yield of blood culture testing and microbiological PCR-based methods for early detection of post-stroke bacteremia. Methods Serial blood culture tests either during the first fever episode (> 38.5 °C) or 24 h after admission were performed every 12 h for up to 96 h after admission. Additionally, microbiological PCR-based techniques for the detection of microbiological pathogens were performed once during the first fever episode prior to initiating antibiotic treatment. Results 21 severely affected acute stroke patients deemed at high risk for systemic infections (median (interquartile range (IQR)) at admission NIHSSS 19 (15–30) were enrolled; 20 patients were intubated within 5 h after ICU admission. All patients developed clinical signs and laboratory constellations compatible with systemic infections within 36 h after admission. However, no patient had pathogenic bacteria either in serial blood culture analyses during the first 96 h after admission or by PCR-based techniques. Conclusions Very early bacteremia seems not to be a feature of severe stroke in patients despite signs of early immune system depression and frequent subsequent evidence of infection including pneumonia. Consequently our data suggests, that routine early blood-based standard or molecular microbiological assays do not reveal bacteremia, this finding questions the usefulness of their routine performance in this context.

A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing.We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence.In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies.In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.

Background Depression is the most prevalent psychiatric disease. In addition to primary, idiopathic depression, there are multiple secondary organic forms. However, distinguishing the two can be difficult, information about cerebrospinal fluid (CSF) basic findings in patients with depressive syndromes is sparse. Therefore, we investigated CSF alterations in so far the largest sample of patients with depressive syndromes. We hypothesized that increased prevalence of CSF pleocytosis, blood-brain-barrier (BBB) dysfunction, and oligoclonal bands (OCBs) would be observed as possible markers of underlying immunological processes. Methods From January 2006 until October 2013, we performed CSF basic diagnostics in 125 patients with depressive syndromes. We also performed serum and CSF autoantibody measurements, cerebral magnetic resonance imaging (cMRI) and electroencephalography (EEG). Results Four % of the patients displayed increased CSF white blood cell counts (WBC), 46.4% had increased protein concentrations, and 19.4% had pathological albumin quotients. OCBs in the CSF were detected in 6.5%. Overall, CSF basic diagnostics were abnormal in 56%. Including instrument-based diagnostics, we found alterations in 80.8% of patients. Suicidal tendencies correlated with an increased WBC count ( r =0.276, p =0.002). Limitations In this open, uncontrolled study, we investigated mainly CSF samples of depressive patients with signs of organic features. Therefore, the study cohort is not representative of idiopathic depression. Conclusions The main findings of this study are the high rates of pathological (although mainly unspecific) CSF findings. We discuss the findings regarding possible immunological mechanisms and the vascular depression hypothesis. If these findings are associated with low-level inflammation of the central nervous system, new treatment alternatives could be considered. More and better controlled research is necessary.

Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS.

Intrathecal baclofen (ITB) is an effective and well-tolerated treatment for patients with severe spasticity. Intoxications are rare and usually iatrogenic, with reported intrathecal boluses varying between 0.050 and 30 mg.We here report the case of a 47-year-old woman with severe spastic paraplegia due to multiple sclerosis who, during a routine filling procedure, accidentally received a bolus of 60 mg ITB because of injection into the side-port instead of the reservoir of her ITB pump (Archimedes(®), Codman, Germany).After a short period of dizziness, she lost consciousness and stopped breathing. She was immediately intubated, mechanically ventilated, and admitted to the intensive care unit. As specific treatment, she received cerebrospinal fluid drainage through a newly implanted lumbar catheter. A series of generalized and complex partial seizures were treated with levetiracetam and lacosamide. Acute autonomic dysfunction with episodic arterial hypo- and hypertensions was controlled by catecholamines and clonidine, respectively. Recurrent hyperthermia, however, responded neither to drugs nor to physical treatment. After 3 weeks, the patient was discharged without any relevant new neurologic signs or symptoms.This case demonstrates that even excessive doses of ITB can let the patients survive without sequelae if treated promptly and offensively. A pertinent problem during detoxification is the question of when to restart ITB to avoid drug withdrawal.

The performance of model-based engine calibration is highly dependent on the type of modelling which is used. A problem for state of the art algorithms for engine calibration arises, if outliers occur in the measurement data. Since outliers are not considered in recent types of modelling for engine calibration, they have to be removed before model training, in order to get a good model quality and a good prediction. This has serious drawbacks because either manual interaction is needed to identify the outliers, or automatic detection of outliers is not very robust if there are many outliers in the measurement data. In contrast to state of the art algorithms, a gaussian process modelling is presented, which is robust to outliers. After an introduction, the state of the art of modelling in engine calibration is presented and the drawbacks regarding outliers are shown. This is followed by a robust gaussian process formulation. At the end a simple theoretical example and an application on a diesel engine are given.

Introduction Antibodies against neurofascin, an axo-glial protein located around the node of Ranvier, have been shown to contribute to axonal pathology both in vitro and in experimental autoimmune encephalomyelitis models. Moreover, small case studies have reported anti-NF antibodies in samples from patients with progressive multiple sclerosis (MS). Patients and methods Building up on this observation, we compared the anti-NF reactivity in serum samples from 83 chronic progressive MS (PMS) patients to those with relapsing remitting MS (RRMS, n = 159) and 50 healthy controls. Anti-NF seroreactivity was quantified by enzyme-linked immunosorbent assay using recombinant rat neurofascin. In addition, to identify a potential intrathecal anti-NF antibody synthesis, we calculated the specific antibody index in paired cerebrospinal fluid and serum samples from MS patients with positive anti-NF seroreactivity. Results Prevalence of anti-NF seroreactivity in PMS patients (4.8%; all with primary progressive MS) was significantly higher than that detected in RRMS (0.6%; p = 0.030). However, we found no significant difference between PMS patients and healthy controls (2.0%; p = 0.408). MS patients with positive anti-NF reactivity experienced an above-average progression of disability compared to MS natural-history controls. Anti-NF-specific intrathecal antibody synthesis was not detected in MS patients with positive anti-NF seroreactivity. Conclusions Although present only in a minor subgroup, seroprevalence of anti-NF reactivity was significantly more frequent in patients with PMS than in those with RRMS, but was also occasionally found in healthy controls. Further prospective studies are warranted to investigate whether anti-NF antibodies anticipate disease progression.

Objectives Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into “classical” and “non-classical” syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. “Classical” PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. Methods We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. Results Of the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had “classical” PNS, and 22 (44.0%) “non-classical” PNS. Subacute cerebellar degeneration was the most frequent “classical” syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent “non-classical” syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between “classical” and “non-classical” syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with “classical” syndromes were females, there was no gender predominance in patients with “non-classical” PNS and the latter had significantly more frequent peripheral neurological syndromes. Conclusions The so-called “non-classical” PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.

Wilson’s disease is a rare autosomal recessive disorder of coper metabolism presenting preferentially with hepatic, neurologic r rarely psychiatric symptoms alone [1]. Without treatment it akes a fatal course whereas symptoms are potentially reversible ith early therapy. Therefore, the prognosis highly depends on arly diagnosis making the knowledge also of rare presentaions crucial [1]. As rapid decoppering therapy might result in eurological deterioration, careful dose titration is recommended 1]. Epileptic seizures have been described as a complication of ong-term treatment, but not during early stages of decoppering herapy [2].

Probabilistic conditionals are a powerful means for expressing uncertain knowledge. In this paper, we describe a system implemented in Java performing probabilistic reasoning at optimum entropy. It provides nonmonotonic belief change operations like revision and update and supports advanced querying facilities including diagnosis and what-if-analysis.