Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies.

Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (≥95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4/21, 19%) than those who did not develop AE (42/65, 65%, P = 0.0003) or the Spanish general population (2005/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (-0.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3/37 (8%) versus 2/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7-691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.

An alternative method of indexation in aortic stenosis: height-adjusted effective orifice area : An observational prospective study.

BACKGROUND: Although indexing effective orifice area (EOA) by body surface area (BSA) is recommended, this method has several disadvantages, since it corrects by acquired fatty tissue. Our aim was to analyze the value of EOA normalized by height for predicting cardiovascular outcome in patients with aortic stenosis (AS). METHODS: Patients with AS (peak velocity > 2 m/s) evaluated in our echocardiography laboratory between January 2015 and June 2018 were prospectively enrolled. EOA was indexed by BSA and height. A composite primary endpoint was defined as cardiac death or aortic valve replacement. A receiver operating characteristic curve was plotted to determine the best cutoff value of EOA/height for predicting cardiovascular events. RESULTS: Four-hundred and fifteen patients were included (52% women, mean age 74.8 ± 11.6 years). Area under the curve was similar for EOA/BSA (AUC 0.75, p < 0.001) and EOA/height (AUC 0.75, p < 0.001). A cutoff value of 0.60 cm2/m for EOA/height had a sensitivity of 84%, specificity of 61%, positive predictive value of 60% and negative predictive value of 84%. One-year survival from primary endpoint was significantly lower in patients with EOA/height ≤ 0.60 cm2/m (48 ± 5% vs 91 ± 4%, log-rank p < 0.001) than EOA/height > 0.60 cm2/m. The excess of risk of cardiovascular events seen in univariate analysis persists even after adjustment for other demonstrated adverse prognostic variables (HR 5.91, 95% CI 3.21-10.88, p < 0.001). In obese patients, there was an excess of risk in patients with EOA/height < 0.60 cm2/m (HR 10.2, 95% CI 3.5-29.5, p < 0.001), but not in EOA/BSA < 0.60 cm2/m2 (HR 0.14, 95% CI 0.14-1.4, p = 0.23). CONCLUSIONS: We could identify a subgroup of patients with AS at high risk of cardiovascular events. Consequently, we recommend using EOA/height as a method of indexation in AS, especially in obese patients, with a cutoff of 0.60 cm2/m for identifying patients with higher cardiovascular risk.

Effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on left ventricular remodelling and longitudinal strain: a prospective observational study.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower cardiovascular events in type 2 diabetes mellitus (T2DM) patients, although the mechanisms underlying these benefits are not clearly understood. Our aim was to study the effects of SGLT2i on left ventricular remodelling and longitudinal strain. METHODS: Between November 2019 and April 2020, we included 52 patients with T2DM ≥ 18 years old, with HbA1c between 6.5 and 10.0%, and estimated glomerular filtration ≥ 45 ml/min/1.73 m2. Patients were classified into SGLT2i group and control group, according to prescribed treatment by their referring physician. Conventional and speckle tracking echocardiography were performed by blinded sonographers, at baseline and after 6 months of treatment. RESULTS: Among the 52 included patients (44% females, mean age 66.8 ± 8.6 years, mean HbA1c was 7.40 ± 0.7%), 30 patients were prescribed SGLT2i and 22 patients were classified as control group. Mean change in indexed left ventricular mass (LVM) was - 0.85 ± 3.31 g/m2 (p = 0.003) in the SGLT2i group, and + 2.34 ± 4.13 g/m2 (p = 0.58) in the control group. Absolute value of Global Longitudinal Strain (GLS) increased by a mean of 1.29 ± 0.47 (p = 0.011) in the SGLT2i group, and 0.40 ± 0.62 (p = 0.34) in the control group. We did not find correlations between changes in LVM and GLS, and other variables like change in HbA1c. CONCLUSIONS: Among patients with T2DM, SGLT2i were associated with a significant reduction in indexed LVM and a significant increment in longitudinal strain measured by speckle tracking echocardiography, which may explain in part the clinical benefits found in clinical trials.

MOG Antibodies Restricted to CSF in Children With Inflammatory CNS Disorders.

OBJECTIVES: To assess the clinical significance of myelin oligodendrocyte glycoprotein antibodies (MOG-abs) restricted to CSF in children with inflammatory CNS disorders. METHODS: Patients included 760 children (younger than 18 years) from 3 multicenter prospective cohort studies: (A) acquired demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM); (B) non-ADEM encephalitis; and (C) noninflammatory neurologic disorders. For all cases, paired serum/CSF samples were systematically examined using brain immunohistochemistry and live cell-based assays. RESULTS: A total of 109 patients (14%) had MOG-abs in serum or CSF: 79 from cohort A, 30 from B, and none from C. Of these, 63 (58%) had antibodies in both samples, 37 (34%) only in serum, and 9 (8%) only in CSF. Children with MOG-abs only in CSF were older than those with MOG-abs only in serum or in both samples (median 12 vs 6 vs 5 years, p = 0.0002) and were more likely to have CSF oligoclonal bands (86% vs 12% vs 7%, p = 0.0001) and be diagnosed with multiple sclerosis (6/9 [67%] vs 0/37 [0%] vs 1/63 [2%], p < 0.0001). DISCUSSION: Detection of MOG-abs in serum or CSF is associated with CNS inflammatory disorders. Children with MOG-abs restricted to CSF are more likely to have CSF oligoclonal bands and multiple sclerosis than those with MOG-abs detectable in serum.

A naturalistic study on the effectiveness of long-acting antipsychotics in an early intervention program for patients with recent-onset psychosis.

AIM: To evaluate the impact of long-acting injectable antipsychotics (LAIs) on the risk of hospitalization and the length of hospitalization in the setting of an early intervention program for patients with recent-onset psychosis. METHODS: Observational, retrospective study conducted under routine clinical practice conditions. We included all patients admitted from July 2015 to April 2020 to the Early Intervention Program in Psychosis. We analysed the incidence of hospitalization and hospitalization days before and after treatment with LAIs and calculated the incidence rate ratio (IRR). We also compared the outcomes of patients treated with LAIs with those of the patients maintained on oral antipsychotics using a binomial negative regression analysis. RESULTS: A total of 170 patients were included in the program. Of them, 34 (20%) received LAIs (aripiprazole [n = 22], and paliperidone/risperidone [n = 12]). There was an 89% reduction in the incidence of hospitalizations after treatment with LAIs (IRR 0.11, 95%CI 0.05-0.21; p < .0001). The IRR for LAIs vs. oral antipsychotics was 0.87 (95%CI, 0.24-3.18; p = .829). The presence of a substance use disorder significantly increased the rate of hospitalizations by 123% (IRR 2.23, 95%CI 1.31-3.78). Analyses of hospitalization days showed similar results. CONCLUSIONS: Our results suggest that LAIs are useful for the management of patients with recent-onset psychosis who fail treatment with oral antipsychotics. Whether LAIs are superior to oral antipsychotics as first-line treatment of patients with early psychosis and/or could play a special role in managing patients with early psychosis and comorbid substance use disorders should be further evaluated.

mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.

Cardio-Onco-Hematology in Clinical Practice. Position Paper and Recommendations.

Improvements in early detection and treatment have markedly reduced cancer-related mortality. However survival not only depends on effectively cure cancer, but prevention, diagnosis and treatment of cancer-related complications is also needed. Cardiovascular toxicity is a widespread problem across many classes of therapeutic schemes, however scientific evidence in the management of cardiovascular complications of onco-hematological patients is scarce, as these patients have been systematically excluded from clinical trials and current recommendations are based on expert consensus. Multidisciplinary teams are mandatory to decrease morbidity and mortality from both cardiotoxicity and cancer itself. An excessive concern for the occurrence of cardiovascular toxicity, can avoid potentially curative therapies, while underestimating this risk, increases long-term mortality of cancer survivors. The objective of this consensus document, developed in collaboration of the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology and the Spanish Society of Hematology, is to update the necessary concepts and expertise on cardio-onco-hematology that enable its application in daily clinical practice and to promote the development of local multidisciplinary teams, to improve the cardiovascular health of patients with cancer.

[Functional assessment of patients with hypertrophic cardiomyopathy by maximal oxygen consumption]. / Evaluación funcional de los pacientes con miocardiopatía hipertrófica mediante análisis del consumo de oxígeno máximo.

INTRODUCTION AND OBJECTIVES: Differences between anatomical severity and clinical manifestations are frequent in patients with hypertrophic cardiomyopathy. Our objective was to assess functional capacity in a consecutive group of patients with hypertrophic cardiomyopathy measuring exercise aerobic parameters, as well as clinical and echocardiographic variables. PATIENTS AND METHOD: We studied 98 consecutive patients with hypertrophic cardiomyopathy. All patients underwent both echocardiographic and cardiopulmonary exercise testing. The control group consisted of 22 untrained persons. We studied exercise capacity by analyzing maximal oxygen consumption and aerobic functional capacity, among other variables. RESULTS: Patients with hypertrophic cardiomyopathy attained significantly lower maximal oxygen consumption values than controls (24.1 5.9 vs 36.4 5.9 ml/kg/min; p = 0.0001). Maximal aerobic capacity was significantly different among patients with NYHA functional capacity class I, II or III (78.9 13.5%; 71.9 14.7%; 63.9 15.7%; p = 0.009). However, considerable overlap was found between groups in maximal aerobic capacity. Functional impairment was greater in patients with left ventricular thickness > 20 mm, ejection fraction < 50%, left atrial dimension > 45 mm and pseudonormal or restrictive transmitral flow pattern. CONCLUSIONS: Patients with hypertrophic cardiomyopathy show significant functional impairment, which is difficult to detect from their clinical manifestations. Optimal assessment requires cardiopulmonary exercise testing.