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Annals of the Rheumatic Diseases Jan 2021Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease,... (Review)
Review
Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.
Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Autoantibodies; Azathioprine; Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Disease Management; Female; Glucocorticoids; Heart Valve Diseases; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Lupus Vasculitis, Central Nervous System; Macrophage Activation Syndrome; Methotrexate; Mycophenolic Acid; Myocarditis; Outcome Assessment, Health Care; Pericarditis; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Recurrence; Rituximab; Severity of Illness Index; Survival Rate; Uterine Cervical Neoplasms
PubMed: 33051219
DOI: 10.1136/annrheumdis-2020-218272 -
Annals of the Rheumatic Diseases May 2023Inflammatory mediators are detected in the cerebrospinal fluid of systemic lupus erythematosus patients with central nervous system involvement (NPSLE), yet the...
Microglia activation in the presence of intact blood-brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus.
INTRODUCTION
Inflammatory mediators are detected in the cerebrospinal fluid of systemic lupus erythematosus patients with central nervous system involvement (NPSLE), yet the underlying cellular and molecular mechanisms leading to neuropsychiatric disease remain elusive.
METHODS
We performed a comprehensive phenotyping of NZB/W-F1 lupus-prone mice including tests for depression, anxiety and cognition. Immunofluorescence, flow cytometry, RNA-sequencing, qPCR, cytokine quantification and blood-brain barrier (BBB) permeability assays were applied in hippocampal tissue obtained in both prenephritic (3-month-old) and nephritic (6-month-old) lupus mice and matched control strains. Healthy adult hippocampal neural stem cells (hiNSCs) were exposed to exogenous inflammatory cytokines to assess their effects on proliferation and apoptosis.
RESULTS
At the prenephritic stage, BBB is intact yet mice exhibit hippocampus-related behavioural deficits recapitulating the human diffuse neuropsychiatric disease. This phenotype is accounted by disrupted hippocampal neurogenesis with hiNSCs exhibiting increased proliferation combined with decreased differentiation and increased apoptosis in combination with microglia activation and increased secretion of proinflammatory cytokines and chemokines. Among these cytokines, IL-6 and IL-18 directly induce apoptosis of adult hiNSCs ex vivo. During the nephritic stage, BBB becomes disrupted which facilitates immune components of peripheral blood, particularly B-cells, to penetrate into the hippocampus further augmenting inflammation with locally increased levels of IL-6, IL-12, IL-18 and IL-23. Of note, an interferon gene signature was observed only at nephritic-stage.
CONCLUSION
An intact BBB with microglial activation disrupting the formation of new neurons within the hippocampus represent early events in NPSLE. Disturbances of the BBB and interferon signature are evident later in the course of the disease.
Topics: Adult; Humans; Mice; Animals; Infant; Blood-Brain Barrier; Lupus Vasculitis, Central Nervous System; Interleukin-6; Interleukin-18; Microglia; Lupus Erythematosus, Systemic; Cytokines; Neurogenesis; Interferons; Hippocampus
PubMed: 36898766
DOI: 10.1136/ard-2022-223506 -
Current Opinion in Rheumatology Mar 2020Diagnosing and treating neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging as the pathogenesis is still being debated. In this review, we discuss... (Review)
Review
PURPOSE OF REVIEW
Diagnosing and treating neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging as the pathogenesis is still being debated. In this review, we discuss studies evaluating recent advances in diagnostic methods, pathogenic mediators and potential treatments.
RECENT FINDINGS
Screening tools used for neurodegenerative diseases were found to be both sensitive and moderately specific for cognitive dysfunction in NPSLE. Neuroimaging can be used to distinguish systemic lupus erythematosus (SLE) patients from healthy controls, but further refinement is needed to differentiate between lupus patients with and without neuropsychiatric manifestations. Elevated levels of specific molecules in the cerebrospinal fluid and/or serum, as well as the presence of certain autoantibodies, have been identified as potential biomarkers in attempts to facilitate a more accurate and objective diagnosis. Among such autoantibodies, anti-NR2 and anti-ribosomal P autoantibodies also have a pathogenic role, although newer studies demonstrate that blood-brain barrier damage may not always be required as previously believed. These and other observations, together with new evidence for disease attenuation after microglial modulation, suggest direct involvement of the central nervous system in NPSLE pathogenesis.
SUMMARY
Neuropsychiatric involvement of SLE includes a variety of symptoms that impact quality of life and patient prognosis. There have been recent advances in improving the diagnosis of NPSLE as well as in dissecting the underlying pathogenesis. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for targeted therapies, which are based on a clearer understanding of the pathogenesis of NPSLE. Further assessment of these treatments is required in NPSLE patients, as well as the potential use of neuroimaging to distinguish between SLE patients with or without neuropsychiatric manifestations.
Topics: Adult; Animals; Autoantibodies; Biomarkers; Female; Humans; Lupus Vasculitis, Central Nervous System; Male; Mice; Prognosis; Quality of Life
PubMed: 31895125
DOI: 10.1097/BOR.0000000000000682 -
Neurological Sciences : Official... Nov 2019Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms... (Review)
Review
Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.
Topics: Autoimmune Diseases of the Nervous System; Basal Ganglia Diseases; Calcinosis; Cockayne Syndrome; Humans; Hypoparathyroidism; Lupus Vasculitis, Central Nervous System; Mitochondrial Diseases; Nervous System Malformations; Neurodegenerative Diseases; Neurotoxicity Syndromes; Pseudohypoparathyroidism; Xenotropic and Polytropic Retrovirus Receptor
PubMed: 31267306
DOI: 10.1007/s10072-019-03998-x -
Clinical Infectious Diseases : An... Oct 2022The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage,... (Review)
Review
The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage, including subarachnoid and intracerebral hemorrhage. Higher mortality than other forms of bacterial meningitis suggests that antimicrobials and cardiopulmonary support alone may be insufficient and that strategies targeting the hemorrhage might improve outcomes. In this review, we describe the toxic role of intracranial hemorrhage in anthrax meningoencephalitis. We first examine the high incidence of intracranial hemorrhage in patients with anthrax meningoencephalitis. We then review common diseases that present with intracranial hemorrhage, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, postulating applicability of established and potential neurointensive treatments to the multimodal management of hemorrhagic anthrax meningoencephalitis. Finally, we examine the therapeutic potential of minocycline, an antimicrobial that is effective against B. anthracis and that has been shown in preclinical studies to have neuroprotective properties, which thus might be repurposed for this historically fatal disease.
Topics: Anthrax; Bacillus anthracis; Cerebral Hemorrhage; Humans; Meningoencephalitis; Minocycline
PubMed: 36251558
DOI: 10.1093/cid/ciac521 -
Current Opinion in Infectious Diseases Jun 2023Free-living amebae (FLA) including Naegleria fowleri , Balamuthia mandrillaris , and Acanthamoeba species can cause rare, yet severe infections that are nearly always... (Review)
Review
PURPOSE OF REVIEW
Free-living amebae (FLA) including Naegleria fowleri , Balamuthia mandrillaris , and Acanthamoeba species can cause rare, yet severe infections that are nearly always fatal. This review describes recent developments in epidemiology, diagnosis, and treatment of amebic meningoencephalitis.
RECENT FINDINGS
Despite similarities among the three pathogenic FLA, there are notable variations in disease presentations, routes of transmission, populations at risk, and outcomes for each. Recently, molecular diagnostic tools have been used to diagnose a greater number of FLA infections. Treatment regimens for FLA have historically relied on survivor reports; more data is needed about novel treatments, including nitroxoline.
SUMMARY
Research to identify new drugs and guide treatment regimens for amebic meningoencephalitis is lacking. However, improved diagnostic capabilities may lead to earlier diagnoses, allowing earlier treatment initiation and improved outcomes. Public health practitioners should continue to prioritize increasing awareness and providing education to clinicians, laboratorians, and the public about amebic infections.
Topics: Humans; Central Nervous System Protozoal Infections; Amebiasis; Meningoencephalitis; Acanthamoeba; Infectious Encephalitis
PubMed: 37093056
DOI: 10.1097/QCO.0000000000000923 -
Pathogens (Basel, Switzerland) Oct 2023Cryptococcosis is an invasive fungal infection found worldwide that causes significant morbidity and mortality among a broad range of hosts. There are approximately... (Review)
Review
Cryptococcosis is an invasive fungal infection found worldwide that causes significant morbidity and mortality among a broad range of hosts. There are approximately 223,000 new cases of cryptococcosis annually throughout the world, and at least 180,000 deaths are attributed to this infection each year. Most of these are due to complications of cryptococcal meningoencephalitis among HIV-infected patients in resource-limited environments. The majority of individuals diagnosed with cryptococcosis have underlying conditions associated with immune dysfunction such as HIV, solid organ transplant, hematologic malignancy, organ failure syndromes, and/or the use of immunosuppressive agents such as glucocorticosteroids and biologic agents. In most clinical series, there is a small proportion of patients with cryptococcosis who are phenotypically normal; that is, they have no clinically obvious predisposition to disease. Cryptococcal meningoencephalitis (CME) presentation and management differ substantially between these normal individuals and their immunocompromised counterparts. In this review, we will focus on CME in the phenotypically normal host and underscore differences in the clinical presentation, management, outcome, and potential risk factors for these patients compared to immunocompromised persons who develop this potential devastating invasive fungal infection.
PubMed: 38003768
DOI: 10.3390/pathogens12111303 -
SA Journal of Radiology 2023Human parechovirus-3 (HPeV-3) infection is one of the differential diagnoses of neonatal meningoencephalitis. A 13-day-old full-term female neonate presented with a...
UNLABELLED
Human parechovirus-3 (HPeV-3) infection is one of the differential diagnoses of neonatal meningoencephalitis. A 13-day-old full-term female neonate presented with a seizure. Brain MRI showed classic imaging findings of the meningoencephalitis which was confirmed on cerebrospinal fluid analysis.
CONTRIBUTION
The HPeV-3 is an emerging pathogen for neonatal meningoencephalitis. The case in this study is unique with classic imaging findings, which are not routinely encountered in day-to-day practice. This case raises reader awareness.
PubMed: 36875173
DOI: 10.4102/sajr.v27i1.2589 -
Frontiers in Immunology 2023The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.
INTRODUCTION
The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.
METHODS
To identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s).
RESULTS
We enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients' sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients' sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies.
CONCLUSION
In conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.
Topics: Humans; Animals; Rats; Autoantibodies; HEK293 Cells; Lupus Vasculitis, Central Nervous System; Brain; Autoantigens; Immunoglobulin G
PubMed: 37383228
DOI: 10.3389/fimmu.2023.1157149