Efficacy, safety, and tolerability of nivasorexant in adults with binge-eating disorder: A randomized, Phase II proof of concept trial.

OBJECTIVE: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED). METHODS: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17). Key safety outcomes included treatment-emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue). RESULTS: Sixty-eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: -2.93) and nivasorexant (LSM: -2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): -.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo. DISCUSSION: In this proof-of-concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED. PUBLIC SIGNIFICANCE: The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin-1 receptor in BED.

Independent risk factors for myasthenic crisis and disease exacerbation in a retrospective cohort of myasthenia gravis patients.

BACKGROUND: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. METHODS: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. RESULTS: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. CONCLUSIONS: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.

Eculizumab versus rituximab in generalised myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies. METHODS: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model. RESULTS: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group. INTERPRETATION: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort.

Hepatitis E virus and Bell's palsy.

BACKGROUND AND PURPOSE: Acute hepatitis E virus (HEV) infections have been associated with various neurological disorders, including individual cases with Bell's palsy. Nonetheless, systematic studies in the latter are lacking. Therefore, this retrospective study systematically screened a cohort of patients with Bell's palsy for an acute HEV infection. METHODS: Overall, 104 patients with Bell's palsy treated in our clinic between 2008 and 2018 were identified. Serum samples were analyzed for anti-HEV immunoglobulin (Ig)M and IgG antibodies by enzyme-linked immunosorbent assay. Additionally, serum samples were tested for HEV RNA by polymerase chain reaction in 92 of these 104 patients presenting within the first 7 days from symptom onset. A large group of 263 healthy individuals served as controls. RESULTS: None of the patients with Bell's palsy but two healthy controls (0.8%) had an acute HEV infection. Anti-HEV IgG seroprevalence indicating previous infection was unexpectedly high in patients with Bell's palsy (34%) and revealed an age-dependent increase. CONCLUSIONS: In this first systematic study, no cases of Bell's palsy in association with an acute HEV infection were identified. However, based on previous case descriptions, rare associations cannot be excluded. Therefore, large prospective multicenter studies will be necessary for conclusions that are more definitive.

Early Tracheostomy Is Associated With Shorter Ventilation Time and Duration of ICU Stay in Patients With Myasthenic Crisis-A Multicenter Analysis.

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.

Anti-MOG autoantibody-associated schizophreniform psychosis.

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.

Hepatitis E virus as a trigger for Guillain-Barré syndrome.

BACKGROUND: Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An association with neuralgic amyotrophy and Guillain-Barré syndrome (GBS) was previously described. Concerning GBS, studies from other countries found an acute HEV infection in 5-11% of cases. However, HEV prevalence shows considerable regional variations. Therefore, we retrospectively analyzed the frequency of HEV infections in association with GBS in a monocentric cohort in Southwestern Germany. METHODS: Overall, 163 patients with GBS treated in our clinic between 2008 and 2018 of whom serum and/or cerebrospinal fluid (CSF) samples were available, were identified. Serum samples were analyzed for anti-HEV immunoglobulin (Ig)M and IgG antibodies by ELISA. Additionally, both serum and cerebrospinal fluid (CSF) samples were tested for HEV RNA by PCR if IgM was positive or patients presented within the first 7 days from GBS symptom onset. A group of 167 healthy volunteers and 96 healthy blood donors served as controls. RESULTS: An acute HEV infection was found in two GBS patients (1.2%) with anti-HEV IgM and IgG antibodies. HEV PCR in serum and CSF was negative in these two patients as well as in all other tested cases. Seroprevalences indicated that acute infection did not differ significantly from controls (0.8%). Anti-HEV IgG seroprevalence indicating previous infection was unexpectedly high (41%) and revealed an age-dependent increase to more than 50% in patients older than 60 years. CONCLUSION: In this study, serological evidence of an acute HEV infection in patients with GBS was rare and not different from controls. Comparing our data with previous studies, incidence rates show considerable regional variations.

Glioblastoma evolving within 10 days following unremarkable computer tomography of the brain: a case report.

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.

COVID-19 pneumonia in a multiple sclerosis patient with severe lymphopenia due to recent cladribine treatment.

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.

Pharmacokinetics and phenotyping properties of the Basel phenotyping cocktail combination capsule in healthy male adults.

AIMS: We compared the phenotyping metrics of a combination capsule formulation to its individual components of the newly composed Basel phenotyping cocktail. Moreover, we investigated a reduced sampling regimen for clinical applications. METHODS: We performed in vitro experiments and a crossover pharmacokinetic study in twelve healthy male subjects to compare the Basel phenotyping cocktail capsule containing 6 cytochrome P450 (CYP) probe drugs with individual administration of the same drugs. Parent compounds and selected metabolites were determined by liquid chromatography-tandem mass spectrometry. Metabolic ratios (MR) for are under the curve (AUC) and single time point measurements and their correlation were determined. RESULTS: Experiments with human liver microsomes and primary human hepatocytes in 3D co-culture confirmed that flurbiprofen is a suitable CYP2C9 substrate. Both cocktail formulations (capsule and individual probe drug administration) were well-tolerated and yielded reproducible MRs, which were almost identical. Correlations between single time point ratios and the corresponding AUC ratios depended on the sampling time point and the concentration time curve of the probe drugs. The MR of the capsule (Spearman rank correlation coefficient, Rs : 0.77-0.97) as well as the individual components (Rs : 0.69-0.99) correlated best at 6 h post-treatment considering all 6 CYPs. Moreover, the 2-h time points of the capsule agreed suitably with the AUC; however, the MR of omeprazole could not be determined for 10 out of 12 subjects. CONCLUSION: The capsule is easy to swallow, well tolerated and provides reliable estimates for CYP activity. The optimal sampling point for the capsule formulation is 6 h after intake.

"Negative T2 shine through" in patients with hyperglycemia and seizures: a frequently overlooked MRI pattern.

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.

Increased IL-8 concentrations in the cerebrospinal fluid of patients with unipolar depression.

INTRODUCTION: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. MATERIALS AND METHODS: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. RESULTS: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). LIMITATIONS: The significance of the results is limited by the retrospective design and methodological aspects. DISCUSSION: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.

Distinct conformations of GPCR-ß-arrestin complexes mediate desensitization, signaling, and endocytosis.

ß-Arrestins (ßarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-ßarr complexes: the "tail" conformation, with ßarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the "core" conformation, where, in addition to the phosphorylated C-terminal tail, ßarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of ßarrs is unknown. Here, we created a mutant form of ßarr lacking the "finger-loop" region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and ßarr signaling but not desensitization of G protein signaling. Thus, the two GPCR-ßarr conformations can carry out distinct functions.

Pathological Cerebrospinal Fluid Findings in Patients With Neuralgic Amyotrophy and Acute Hepatitis E Virus Infection.

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.

Using dried blood spots to facilitate therapeutic drug monitoring of antiretroviral drugs in resource-poor regions.

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.

The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis.

BACKGROUND: Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. METHODS: The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied. RESULTS: There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each). CONCLUSIONS: Considering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND.