Patterns and Outcomes of Acute Central Nervous System Complications During Treatment of Childhood Acute Lymphoblastic Leukemia: A Single-center Experience.

Central nervous system (CNS) complications are considered adverse events during the treatment of pediatric acute lymphoblastic leukemia (ALL). This study aimed to assess the incidence, types, clinical and radiologic patterns, risk factors, and the fate of different CNS complications during the treatment of pediatric ALL. A retrospective study included 390 patients with pediatric ALL, treated according to St. Jude total XV protocol at the National Cancer Institute, Cairo University, from January 2012 to December 2017. Thirty-nine (10%) patients developed different types of CNS complications. Nineteen (4.9%) patients had cerebrovascular complications, 12 (3.1%) patients had posterior reversible encephalopathy syndrome (PRES), and 6 (1.5%) patients had leukoencephalopathy; both CNS infections and leukemic infiltrates were diagnosed in one patient each. CNS complications were significantly higher in patients older than 10 years old, patients with high-risk disease, and patients who were classified as CNS III status with a statistically significant P value of 0.040, 0.020, and 0.002, respectively. There were 31 (79.5%) cases that achieved complete recovery, 6 (15.4%) patients who died, and 2 (5.1%) patients who developed residual neurological deficits. In conclusion, pediatric patients with ALL, who presented with older age, high-risk disease initially, and had initial CNS III status, were at higher risk of developing acute CNS complications during their treatment period. Patients who developed visual disturbances were associated with unfavorable outcomes. Despite that, around 80% of patients showed complete recovery, but still, 15% of them died from these complications.

Characteristics of neonatal herpes simplex central nervous system disease in Australia (1997-2020).

BACKGROUND: Neonatal herpes simplex virus (HSV) central nervous system (CNS) disease can occur in isolation or as part of disseminated infection. We sought to describe neonatal HSV CNS disease in Australia over 24 years. METHODS: Neonates (≤28 days) with confirmed HSV infection, reported prospectively to the Australian Paediatric Surveillance Unit (1997-2020), were evaluated for HSV CNS disease (laboratory confirmation with clinical evidence of encephalitis, e.g., lethargy, seizures, focal signs; and/or abnormalities on neuroimaging or electroencephalogram), and compared with neonates without CNS disease. CNS-restricted disease was compared with CNS-disseminated disease. FINDINGS: Of 195 neonates with HSV disease; 87 (45%) had CNS disease (1.29 cases/100,000 live births per year, 95% CI: 1·04-1·59). Neonates with CNS disease were significantly more likely to be male than neonates without CNS disease (60% versus 39%, OR=2·32, 95% CI 1·29-4·18). Of the neonates with CNS disease, those with CNS-restricted disease (52/87, 60%) presented later than neonates with CNS-disseminated disease (35/87, 40%), (mean 12 versus 6 days). Twenty (23%) neonates with CNS disease died, the majority with CNS-disseminated disease (n = 19). Most neonates received aciclovir therapy (94·3%), however five neonates with unrecognised CNS disseminated disease (diagnosed at autopsy) had not been treated. Survivors of CNS disease were significantly more likely to have adverse neurological sequelae, compared with those without CNS disease (30% versus 4%, OR: 9·60, 95% CI: 2·6-35·0). INTERPRETATION: Male neonates have a higher burden of HSV CNS disease. Despite the use of antiviral agents, morbidity following neonatal HSV CNS disease remains high. Evaluation of adjunctive therapies to improve outcomes is needed.

[Retrospective Analysis of Pathological Diagnosis of Central Nervous System Diseases in Tibet].

Objective To analyze the disease spectrum and clinicopathological characteristics of central nervous system(CNS)diseases diagnosed based on pathological findings in Tibet. Methods We collected the data of all the cases with CNS lesions in Tibet Autonomous Region People's Hospital from January 2013 to December 2020.The clinicopathological features were analyzed via light microscopy,immunohistochemical staining,and special staining. Results A total of 383 CNS cases confirmed by pathological diagnosis were enrolled in this study,with a male-to-female ratio of 188∶195 and an average age of(40.03±17.39)years(0-74 years).Among them,127(33.2%)cases had non-neoplastic diseases,with a male-to-female ratio of 82∶45 and an average age of(31.99±19.29)years;256(66.8%)cases had neoplastic diseases,with a male-to-female ratio of 106∶150 and an average age of(44.01±14.87)years.The main non-neoplastic diseases were nervous system infectious diseases,cerebral vascular diseases,meningocele,cerebral cyst,and brain trauma.Among the infectious diseases,brain abscess,granulomatous inflammation,cysticercosis,and hydatidosis were common.The main neoplastic diseases included meningioma,pituitary adenoma,neuroepithelial tumor,schwannoma,metastatic tumor,and hemangioblastoma.The meningioma cases consisted of 95.4%(103/108)cases of grade Ⅰ,3.7%(4/108)cases of grade Ⅱ,and only 1(1/108,0.9%)case of grade Ⅲ.Among the neuroepithelial tumor cases,the top three were glioblastoma,grade Ⅲ diffuse glioma,and ependymoma. Conclusions There are diverse CNS diseases confirmed by pathological diagnosis in Tibet,among which non-neoplastic diseases account for 1/3 of all the cases.Infectious and vascular diseases are the most common non-neoplastic diseases in Tibet,and tuberculosis and parasitic infections are relatively common.The types and proportion of brain tumors in Tibet are different from those in other regions of China,and meningioma is the most common in Tibet,with higher proportion than neuroepithelial tumor.

Central nervous system disease in phase III studies for advanced HER2 positive breast cancer: A review.

IMPORTANCE: The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease. OBSERVATIONS: Using protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data. CONCLUSIONS: and Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies.

Neuroinflammatory diseases of the central nervous system of dogs: A retrospective study of 207 cases (2008-2019).

In this study we describe 207 cases of neuroinflammatory diseases of the central nervous system (CNS) in dogs autopsied at the Athens Veterinary Diagnostic Laboratory (University of Georgia, United States) from 2008 to 2019. Idiopathic and infectious diseases were diagnosed in 111 cases (53.6%) and 96 cases (46.4%), respectively. Idiopathic diseases consisted of granulomatous meningoencephalomyelitis (n = 42; 37.8% of idiopathic cases), nonspecific lymphoplasmacytic meningoencephalomyelitis (n = 39; 35.1%), necrotizing meningoencephalomyelitis (n = 22; 19.8%), presumed steroid-responsive meningitis-arteritis (n = 6; 5.4%), and necrotizing leukoencephalitis (n = 2; 1.8%). Infectious diseases consisted of bacterial infections (n = 49; 51% of infectious cases), viral infections (n = 39; 40.6%), fungal infections (n = 5; 5.2%), and parasitic infections (n = 3; 3.1%). Our study provides an overview of the most frequent neuroinflammatory diseases of the CNS of dogs in our diagnostic routine; indicates that a comprehensive diagnostic approach, including a thorough evaluation of the pathology findings and ancillary laboratory testing results, is important for an adequate diagnosis of neurologic diseases in dogs; and underscores the problems associated with the variability in tissue sample collection methods among cases. The great number of nonspecific lymphoplasmacytic meningoencephalitis also highlights the need for development of molecular laboratory tests to identify potential infectious agents in these cases.

Maladies neuro-inflammatoires du système nerveux central du chien : étude rétrospective de 207 cas (2008­2019). Dans cette étude, nous décrivons 207 cas de maladies neuro-inflammatoires du système nerveux central (SNC) chez des chiens autopsiés au Athens Veterinary Diagnostic Laboratory (University of Georgia, États-Unis) de 2008 à 2019. Des maladies idiopathiques et infectieuses ont été diagnostiquées dans 111 cas (53,6 %) et 96 cas (46,4 %), respectivement. Les maladies idiopathiques consistaient en : méningo-encéphalomyélite granulomateuse (n = 42; 37,8 % des cas idiopathiques), méningo-encéphalomyélite lymphoplasmocytaire non spécifique (n = 39; 35,1 %), méningo-encéphalomyélite nécrosante (n = 22; 19,8 %), méningite-artérite corticosensible présumée (n = 6; 5,4 %) et leucoencéphalite nécrosante (n = 2; 1,8 %). Les maladies infectieuses comprenaient des infections bactériennes (n = 49; 51 % des cas infectieux), des infections virales (n = 39; 40,6 %), des infections fongiques (n = 5; 5,2 %), et des infections parasitaires (n = 3; 3,1 %). Notre étude donne un aperçu des maladies neuro-inflammatoires du SNC des chiens les plus fréquentes dans notre routine de diagnostic; indique qu'une approche diagnostique complète, comprenant une évaluation approfondie des résultats de la pathologie et des résultats des tests de laboratoire auxiliaires, est importante pour un diagnostic adéquat des maladies neurologiques chez les chiens; et souligne les problèmes associés à la variabilité des méthodes de prélèvement d'échantillons de tissus entre les cas. Le grand nombre de méningo-encéphalites lymphoplasmocytaires non spécifiques souligne également la nécessité de développer des tests de laboratoire moléculaire pour identifier les agents infectieux potentiels dans ces cas.(Traduit par Dr Serge Messier).

Prognostic implications of the tumor immune microenvironment and immune checkpoint pathway in primary central nervous system diffuse large B-cell lymphoma in the North Indian population.

Primary central nervous system-diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare, extranodal malignant lymphoma carrying poor prognosis. The prognostic impact of tumor microenvironment (TME) composition and the PD-1/PD-L1 immune checkpoint pathway are still undetermined in PCNS-DLBCL. We aimed to quantify the tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and PD-L1 expression in the PCNSL and evaluated their prognostic significance. All patients with histopathologically diagnosed PCNS-DLBCL over a period of 7 years were recruited. Immunohistochemistry for CD3, CD4, CD8, FOXP3, CD68, CD163, PD-1, and PD-L1 was performed on the tissue microarray. Forty-four cases of PCNS-DLBCL, who satisfied the selection criteria, were included with mean age of 55 ± 12.3 years and male-to-female ratio of 0.91:1. The mean overall survival (OS) and disease-free survival (DFS) was 531.6 days and 409.8 days, respectively. Among TILs, an increased number of CD3+ T cells showed better OS and DFS, without achieving statistical significance. CD4 positive T-cells were significantly associated with the longer OS (p = 0.037) and DFS (p = 0.023). TAMs (68CD and CD163 positive) showed an inverse relationship with OS and DFS but did not reach statistical significance (p > 0.05). Increased PD-L1 expression in immune cells, but not in tumor cells, was associated with significantly better DFS (p = 0.037). The TME plays a significant role in the prognosis of PCNS-DLBCL. Increased number of CD4+ T cells and PD-L1-expressing immune cells is associated with better prognosis in PCNS-DLBCL. Further studies with larger sample size are required to evaluate the role of targeted therapy against the TME and immune check point inhibitors in this disease.

Analysis of anticholinergic adverse effects using two large databases: The US Food and Drug Administration Adverse Event Reporting System database and the Japanese Adverse Drug Event Report database.

INTRODUCTION: Anticholinergic adverse effects (AEs) are a problem for elderly people. This study aimed to answer the following questions. First, is an analysis of anticholinergic AEs using spontaneous adverse drug event databases possible? Second, what is the main drug suspected of inducing anticholinergic AEs in the databases? Third, do database differences yield different results? METHODS: We used two databases: the US Food and Drug Administration Adverse Event Reporting System database (FAERS) and the Japanese Adverse Drug Event Report database (JADER) recorded from 2004 to 2020. We defined three types of anticholinergic AEs: central nervous system (CNS) AEs, peripheral nervous system (PNS) AEs, and a combination of these AEs. We counted the number of cases and evaluated the ratio of drug-anticholinergic AE pairs between FAERS and JADER. We computed reporting odds ratios (RORs) and assessed the drugs using Beers Criteria®. RESULTS: Constipation was the most reported AE in FAERS. The ratio of drug-anticholinergic AE pairs was statistically significantly larger in FAERS than JADER. Overactive bladder agents were suspected drugs common to both databases. Other drugs differed between the two databases. CNS AEs were associated with antidementia drugs in FAERS and opioids in JADER. In the assessment using Beers Criteria®, signals were detected for almost all drugs. Between the two databases, a significantly higher positive correlation was observed for PNS AEs (correlation coefficient 0.85, P = 0.0001). The ROR was significantly greater in JADER. CONCLUSIONS: There are many methods to investigate AEs. This study shows that the analysis of anticholinergic AEs using spontaneous adverse drug event databases is possible. From this analysis, various suspected drugs were detected. In particular, FAERS had many cases. The differences in the results between the two databases may reflect differences in the reporting countries. Further study of the relationship between drugs and CNS AEs should be conducted.

A large-scale population-based epidemiological study on the prevalence of central sensitization syndromes in Japan.

A cross-sectional study of 21,665 Japanese residents was performed to investigate the prevalence of central sensitization syndromes (CSS). CSS were assessed using the Central Sensitization Inventory (CSI-A). CSS were defined as a CSI-A score of 40 or higher. Age, sex, district, 10 CSS-related diseases (CSI-B), lifestyle, and mental factors were rated in a self-reported survey. The prevalence of CSS and its relationship with potential factors were examined by sex using descriptive and logistic regression models. The prevalence of CSS was 4.2% in all participants and was significantly higher in women (4.9%) than in men (2.7%). Adjusted odds ratios correlated with CSS for an age of 80-97 years versus 60-79 years (2.07 and 2.89), one or more CSI-B diseases (3.58 and 3.51), few sleeping hours (2.18 and 1.98), high perceived stress (5.00 and 4.91), low (2.94 and 2.71) and high (0.45 and 0.66) resilience versus moderate resilience, and exercise habits (0.68 and 0.55) in men and women (all P < 0.05). The relationship between CSS and age 20 and 59 years, ex-smokers, coffee intake, and alcohol intake differed by sex. The prevalence of CSS was estimated to be low in the healthy population. CSS correlated with CSS-related diseases and some positive and negative factors.

Single Center Experience with Isolated Spinal Cord Neurosarcoidosis.

INTRODUCTION: Isolated spinal cord neurosarcoidosis is extremely rare. The potential implications of long-term immunosuppressant therapy make correct diagnosis imperative. However, there are challenges inherent in isolated spinal cord involvement that require a multidisciplinary approach. Here we present the largest series of definite and possible isolated spinal neurosarcoidosis and discuss our institutional experience in managing this rare but morbid condition. METHODS: A retrospective review was performed to identify all neurosarcoidosis cases starting from 2002 to 2020 at our institution. Patients were screened for cases of isolated spinal neurosarcoidosis. A descriptive analysis was performed for each case. RESULTS: A total of 64 cases of neurosarcoidosis were identified. The spine was involved in 26 (40.6%) patients. Only 4 (6.3%) cases had isolated spinal cord involvement. A full medical and imaging workup was performed in determining isolated spinal cord involvement. Three patients subsequently underwent surgical biopsy, and 1 did not undergo biopsy because of patient preference. One of the patients who underwent biopsy had an initial nondiagnostic biopsy and had a repeat biopsy. Corticosteroids were employed in all cases with additional immunosuppressive agents for maintenance therapy and refractory cases. All showed radiographic improvement and were clinically stable to improved. CONCLUSION: Isolated spinal cord involvement of neurosarcoidosis is rare and can present challenges in diagnosis. A biopsy can be performed when necessary. However, a biopsy of the spinal cord carries inherent risks and may not always be possible or result in a nondiagnostic sample. In the setting of high clinical suspicion, maximal medical therapy is still employed.

Inflammatory Diseases of the Central Nervous System.

Pediatric neuroinflammatory conditions are a complex group of disorders with a wide range of clinical presentations. Patients can present with a combination of focal neurologic deficits, encephalopathy, seizures, movement disorders, or psychiatric manifestations. There are several ways that pediatric neuroinflammatory conditions can be classified, including clinical presentation, pathophysiologic mechanism, and imaging and laboratory findings. In this article, we group these conditions into acquired demyelinating diseases, immune-mediated epilepsies/encephalopathies, primary rheumatologic conditions with central nervous system (CNS) manifestations, CNS vasculitis, and neurodegenerative/genetic conditions with immune-mediated pathophysiology and discuss epidemiology, pathophysiology, clinical presentation, treatment, and prognosis of each disorder.

[Neurological complications in haematopoietic stem cell transplant patients]. / Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.

INTRODUCTION: Neurological complications are some of the most important complications that can occur in a patient undergoing haematopoietic stem cell transplantation (HSCT), not only because of the high mortality rate, but also because of the sequelae that appear in survivors. The causes of such complications are manifold and very often coexist in the same patient: toxicity of the conditioning regimen, graft-versus-host disease and its treatment, infections and their treatment, platelets and coagulation disorders, liver failure or arterial hypertension with low platelet count. AIMS: The aim of the present study is to provide a clinical description and to describe the risk factors for complications involving the central nervous system that may occur during the course of HSCT, in order to assist in the early detection of these disorders that may have a negative influence on the morbidity and mortality of these patients. DEVELOPMENT: The following types of neurological complications are described: central nervous system infections, vascular complications, pharmacological toxicity, metabolic complications, immune-mediated disorders and post-HSCT carcinogenesis, and effects of graft-versus-host disease and thrombotic microangiopathy on the nervous system. CONCLUSIONS: The patient undergoing HSCT is at particular risk for the development of neurological complications. Early diagnosis and treatment are needed to try to reduce the high morbidity and mortality in these patients.

TITLE: Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.Introducción. Las complicaciones neurológicas son algunas de las más importantes que se pueden presentar en un paciente sometido a un trasplante de progenitores hematopoyéticos (TPH), no sólo porque conllevan una mortalidad elevada, sino también por las secuelas que aparecen en los supervivientes. Las causas de dichas complicaciones son múltiples y, muy frecuentemente, coexisten en el mismo paciente: toxicidad del régimen de acondicionamiento, enfermedad del injerto contra el hospedador y su tratamiento, infecciones y su tratamiento, plaquetopenia y trastornos de la coagulación, fallo hepático o hipertensión arterial con plaquetopenia. Objetivos. El objetivo del presente estudio es el de aportar una descripción clínica y de los factores de riesgo de las complicaciones sobre el sistema nervioso central que pueden presentarse en el curso de un TPH, para ayudar en la detección precoz de estos trastornos que pueden influir negativamente en la morbimortalidad de estos pacientes. Desarrollo. Se describen los siguientes tipos de complicaciones neurológicas: infecciones sobre el sistema nervioso central, complicaciones vasculares, toxicidad farmacológica, complicaciones metabólicas, trastornos inmunomediados y carcinogenia pos-TPH, y efectos de la enfermedad del injerto contra el hospedador y de la microangiopatía trombótica sobre el sistema nervioso. Conclusiones. El paciente sometido a TPH es de especial riesgo para el desarrollo de complicaciones neurológicas. Se precisan un diagnóstico y un tratamiento precoces para intentar disminuir la elevada morbimortalidad de estos pacientes.

Nutritional Disorders in a Group of Children and Adolescents with Syndromes or Diseases Involving Neurodysfunction.

A study of the literature shows the lack of data on a comprehensive analysis of eating disorders in children with neurodysfunction, which constitute a clinical subgroup with an increased risk of abnormalities in this area. Therefore, the aim of this study was to determine the relationship between the coexistence of nutritional disorders and diseases or syndromes associated with neurodysfunction based on data collected during hospitalization at a rehabilitation center for children and adolescents. A retrospective analysis was carried out in a group of 327 children and adolescents aged 4-18 years. The study group covered various types of diseases or syndromes involving damage to the central nervous system. A retrospective analysis of baseline data (age, sex, main and additional diagnosis and Body Mass Index-BMI) was performed. Two assessment criteria of nutritional status were taken into account (z-score BMI and other previously published normative values). In the study group, malnutrition was found more frequently (18.0% of the respondents) than obesity (11.3% of the subjects). Hypothyroidism coexisting with malnutrition was identified in the study group (N% = 43.8%, p = 0.011) and malnutrition with tetraplegia in the subgroup of spastic cerebral palsy (N% = 34.2 %, p = 0.029).

Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals.

To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.

Evaluation of the incidence, characteristics, and outcomes of pediatric chronic critical illness.

Our aim was to determine characteristics of children with chronic critical illness (CCI) admitted to the pediatric intensive care unit (PICU) of a tertiary care children's hospital in Turkey. The current study was a multicenter retrospective cohort study that was done from 2014 to 2017. It involved three university hospitals PICUs in which multiple criteria were set to identify pediatric CCIs. Pediatric patients staying in the ICU for at least 14 days and having at least one additional criterion, including prolonged mechanical ventilation, tracheostomy, sepsis, severe wound (burn) or trauma, encephalopathy, traumatic brain injury, status epilepticus, being postoperative, and neuromuscular disease, was accepted as CCI. In order to identify the newborn as a chronic critical patient, a stay in the intensive care unit for at least 30 days in addition to prematurity was required. Eight hundred eighty seven (11.14%) of the patients who were admitted to the PICU met the definition of CCI and 775 of them (87.3%) were discharged to their home. Of CCI patients, 289 (32.6%) were premature and 678 (76.4%) had prolonged mechanical ventilation. The total cost values for 2017 were statistically higher than the other years. As the length of ICU stay increased, the costs also increased. Interestingly, high incidence rates were observed for PCCI in our hospitals and these patients occupied 38.01% of the intensive care bed capacity. In conclusion, we observed that prematurity and prolonged mechanical ventilation increase the length of ICU stay, which also increased the costs. More work is needed to better understand PCCI.

Histoplasmosis of the Central Nervous System: A Case Series between 1990 and 2019 in French Guiana.

Disseminated histoplasmosis is the most frequent acquired immunodeficiency syndrome-defining illness in French Guiana. Paradoxically, central nervous system (CNS) involvement has been scarcely described. We aimed to identify CNS histoplasmosis in our territory. We conducted an observational, multicentric, descriptive, and retrospective study including patients with proven or probable CNS histoplasmosis according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MGS). The study population consisted of patients admitted in one of the hospitals of French Guiana between January 1, 1990 and December 31, 2019. During the study period, 390 cases of HIV-associated histoplasmosis were recorded, in which six of them had CNS infections with Histoplasma capsulatum. The male to female sex ratio was 0.25, and the median age at diagnosis was 37.5 years. The median CD4 count was 42 cells/mm3 ([IQR: 29-60]). All patients had disseminated histoplasmosis. Usual signs of meningitis were observed in three patients and focal signs in four patients. One patient had no neurological signs. The median time between the first cerebral symptoms and diagnosis was 22.4 days (IQR 9.5-36.2). Two patients died within a month after diagnosis. In conclusion, few proven CNS localizations of histoplasmosis were observed on 30-year study in French Guiana. This low proportion suggests that the documentation of CNS involvement is often not ascertained for lack of awareness of this particular presentation, and for lack of rapid and sensitive diagnostic tools.

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65 years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40 Gy with a median fraction of 2 Gy. The median number of administered doses of rituximab (375 mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5 years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6 years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Association between inflammatory central nervous system diseases and epilepsy: A retrospective cohort study of 4252 patients in Germany.

GOAL: The goal of this study was to analyze the association between inflammatory central nervous system (CNS) diseases and the incidence of epilepsy in patients followed up for up to 10 years in Germany. METHODS: This retrospective cohort study included adults aged ≥ 18 years who had an initial diagnosis of inflammatory CNS disease (i.e. encephalitis, meningitis or brain abscess) in one of 1229 general practices in Germany between 2005 and 2015 (index date). Patients without inflammatory CNS disease were matched (1:1) to those with inflammatory CNS disease by sex, age, follow-up time after index date, Charlson Comorbidity Index, and practice. The index date for patients without inflammatory CNS disease was a randomly selected visit date between 2005 and 2015. Kaplan-Meier curves and Cox regression analyses were used to assess the association between inflammatory CNS diseases and the incidence of epilepsy. RESULTS: This study included 2126 individuals with and 2126 patients without inflammatory CNS disease (56.4% women; mean [SD] age 50.0 [12.3] years). Within ten years of the index date, 4.2% of patients with and 1.5% of patients without inflammatory CNS disease had been diagnosed with epilepsy (p < 0.001). This finding was corroborated in the Cox regression analysis, and there was a positive and significant association between inflammatory CNS diseases and epilepsy (HR: 3.82, 95% CI: 2.24-6.52). CONCLUSIONS: Based on these results, preventive interventions are urgently warranted to reduce the incidence of epilepsy in individuals with a history of inflammatory CNS disease.

Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial.

BACKGROUND: R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial. METHODS: In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090. FINDINGS: Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. INTERPRETATION: Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. FUNDING: Deutsche Krebshilfe (German Cancer Aid).