Streptococcus bovis infection of the central nervous system in adults: Report of 4 cases and literature review.

OBJECTIVES: To describe the clinical features, history and association with intestinal disease in central nervous system (CNS) S. bovis infections. METHODS: Four cases of S. bovis CNS infections from our institution are presented. Additionally a systematic literature review of articles published between 1975 and 2021 in PubMed/MEDLINE was conducted. RESULTS: 52 studies with 65 cases were found; five were excluded because of incomplete data. In total 64 cases were analyzed including our four cases: 55 with meningitis and 9 with intracranial focal infections. Both infections were frequently associated with underlying conditions (70.3%) such as immunosuppression (32.8%) or cancer (10.9%). In 23 cases a biotype was identified, with biotype II being the most frequent (69.6%) and S. pasteurianus the most common within this subgroup. Intestinal diseases were found in 60.9% of cases, most commonly neoplasms (41.0%) and Strongyloides infestation (30.8%). Overall mortality was 17.1%, with a higher rate in focal infection (44.4% vs 12.7%; p=0.001). CONCLUSIONS: CNS infections due to S. bovis are infrequent and the most common clinical form is meningitis. Compared with focal infections, meningitis had a more acute course, was less associated with endocarditis and had a lower mortality. Immunosuppression and intestinal disease were frequent in both infections.

Brain MRI features of anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis secondary to central nervous system infection in adult patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis secondary to central nervous system (CNS) infection is a unique subtype of the autoimmune-mediated disease, of which the imaging features are unclear. PURPOSE: To compare the brain magnetic resonance imaging (MRI) features between the anti-NMDAR encephalitis secondary to CNS infection and that without initial infection. MATERIAL AND METHODS: A total of 70 adult patients with anti-NMDAR encephalitis were retrospectively enrolled (24 in the post-infection group, 46 in the non-infection-related group). Their clinical and imaging features (lesion distribution, lesion shape, enhancement pattern, brain atrophy) were reviewed and summarized. Lesion distributions were compared between the two groups on lesion probability maps. RESULTS: The patients with normal brain MRI scans in the post-infection group were less than those in the non-infection related group (29% vs. 63%; P = 0.0113). Among the 24 patients in the post-infection group, visible lesions were shown at the anti-NMDAR encephalitis onset in 17 patients; lesion distribution was more diffuse than the non-infection-related group, showing higher lesion peak probabilities in the bilateral hippocampus, frontal lobe, temporal lobe, insula, and cingulate. The lesions with contrast enhancement were also more common in the post-infection group than the non-infection-related group (7/13 vs. 2/10). Brain atrophy was observed in eight patients in the post-infection group and three in the non-infection-related group. CONCLUSION: Anti-NMDAR encephalitis secondary to CNS infection has its imaging features-extensive lesion distribution, leptomeningeal enhancement, early atrophy, and necrosis-that could deepen the understanding of the pathophysiology and manifestation of the autoimmune encephalitis besides the classic type.

Preformulation screening of lipids using solubility parameter concept in conjunction with experimental research to develop ceftriaxone loaded nanostructured lipid carriers

Abstract Development of ceftriaxone loaded nanostructured lipid carriers to increase permeability of ceftriaxone across uninflamed meninges after parenteral administration. Lipids were selected by theoretical and experimental techniques and optimization of NLCs done by response surface methodology using Box-Behnken design. The Δδt for glyceryl monostearate and Capryol90 were 4.39 and 2.92 respectively. The drug had maximum solubility of 0.175% (w/w) in glycerol monostearate and 2.56g of Capryol90 dissolved 10mg of drug. The binary mixture consisted of glyceryl monostearate and Capryol90 in a ratio of 70:30. The optimized NLCs particle size was 130.54nm, polydispersity index 0.28, % entrapment efficiency 44.32%, zeta potential -29.05mV, and % drug loading 8.10%. In vitro permeability of ceftriaxone loaded NLCs was 5.06x10-6 cm/s; evidently, the NLCs pervaded through uninflamed meninges, which, was further confirmed from in vivo biodistribution studies. The ratio of drug concentration between brain and plasma for ceftriaxone loaded NLCs was 0.29 and that for ceftriaxone solution was 0.02. With 44.32% entrapment of the drug in NLCs the biodistribution of ceftriaxone was enhanced 7.9 times compared with that of ceftriaxone solution. DSC and XRD studies revealed formation of imperfect crystalline NLCs. NLCs improved permeability of ceftriaxone through uninflamed meninges resulting in better management of CNS infections.

Understanding neuroinflammation through central nervous system infections.

Neuroinflammation is now recognized to compound many central nervous system (CNS) pathologies, from stroke to dementia. As immune responses evolved to handle infections, studying CNS infections can offer unique insights into the CNS immune response and address questions such as: What defenses and strategies do CNS parenchymal cells deploy in response to a dangerous pathogen? How do CNS cells interact with each other and infiltrating immune cells to control microbes? What pathways are beneficial for the host or for the pathogen? Here, we review recent studies that use CNS-tropic infections in combination with cutting-edge techniques to delve into the complex relationships between microbes, immune cells, and cells of the CNS.

Microglia in CNS infections: insights from Toxoplasma gondii and other pathogens.

Microglia, the resident immune cells of the central nervous system (CNS), are poised to respond to neuropathology. Microglia play multiple roles in maintaining homeostasis and promoting inflammation in numerous disease states. The study of microglial innate immune programs has largely focused on exploring neurodegenerative disease states with the use of genetic targeting approaches. Our understanding of how microglia participate in immune responses against pathogens is just beginning to take shape. Here, we review existing animal models of CNS infection, with a focus on how microglial physiology and inflammatory processes control protozoan and viral infections of the brain. We further discuss how microglial participation in over-exuberant immune responses can drive immunopathology that is detrimental to CNS health and homeostasis.

Neuroradiology of infectious diseases.

PURPOSE OF REVIEW: Early diagnosis of central nervous system (CNS) infections is crucial given high morbidity and mortality. Neuroimaging in CNS infections is widely used to aid in the diagnosis, treatment and to assess the response to antibiotic and neurosurgical interventions. RECENT FINDINGS: The Infectious Diseases Society of America (IDSA) guidelines have clear recommendations for obtaining a computerized tomography of the head (CTH) prior to lumbar puncture (LP) in suspected meningitis. In the absence of indications for imaging or in aseptic meningitis, cranial imaging is of low utility. In contrast, cranial imaging is of utmost importance in the setting of encephalitis, bacterial meningitis, ventriculitis, bacterial brain abscess, subdural empyema, epidural abscess, neurobrucellosis, neurocysticercosis, and CNS tuberculosis that can aid clinicians with the differential diagnosis, source of infection (e.g., otitis, sinusitis), assessing complications of meningitis (e.g., hydrocephalus, venous sinus thrombosis, strokes), need for neurosurgical interventions and to monitor for the response of therapy. Novel imaging techniques such as fast imaging employing steady-state acquisition (FIESTA), susceptibility-weighted imaging (SWI), and chemical exchange saturation transfer (CEST) contrast are briefly discussed. SUMMARY: Though the radiological findings in CNS infections are vast, certain patterns along with clinical clues from history and examination often pave the way to early diagnosis. This review reiterates the importance of obtaining cranial imaging when necessary, and the various radiological presentations of commonly encountered CNS infections.

Central nervous system infections after solid organ transplantation.

PURPOSE OF REVIEW: Significant advances to our understanding of several neuroinfectious complications after a solid organ transplant (SOT) have occurred in the last few years. Here, we review the central nervous system (CNS) infections that are relevant to SOT via a syndromic approach with a particular emphasis on recent updates in the field. RECENT FINDINGS: A few key studies have advanced our understanding of the epidemiology and clinical characteristics of several CNS infections in SOT recipients. Risk factors for poor prognosis and protective effects of standard posttransplant prophylactic strategies have been better elucidated. Newer diagnostic modalities which have broad clinical applications like metagenomic next-generation sequencing, as well as those that help us better understand esoteric concepts of disease pathogenesis have been studied. Finally, several studies have provided newer insights into the treatment of these diseases. SUMMARY: Recent findings reflect the steady progress in our understanding of CNS infections post SOT. They provide several avenues for improvement in the prevention, early recognition, and therapeutic outcomes of these diseases.

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases.

Under normal conditions, astrocytes perform a number of important physiological functions centered around neuronal support and synapse maintenance. In neurodegenerative diseases including Alzheimer's, Parkinson's and prion diseases, astrocytes acquire reactive phenotypes, which are sustained throughout the disease progression. It is not known whether in the reactive states associated with prion diseases, astrocytes lose their ability to perform physiological functions and whether the reactive states are neurotoxic or, on the contrary, neuroprotective. The current work addresses these questions by testing the effects of reactive astrocytes isolated from prion-infected C57BL/6J mice on primary neuronal cultures. We found that astrocytes isolated at the clinical stage of the disease exhibited reactive, pro-inflammatory phenotype, which also showed downregulation of genes involved in neurogenic and synaptogenic functions. In astrocyte-neuron co-cultures, astrocytes from prion-infected animals impaired neuronal growth, dendritic spine development and synapse maturation. Toward examining the role of factors secreted by reactive astrocytes, astrocyte-conditioned media was found to have detrimental effects on neuronal viability and synaptogenic functions via impairing synapse integrity, and by reducing spine size and density. Reactive microglia isolated from prion-infected animals were found to induce phenotypic changes in primary astrocytes reminiscent to those observed in prion-infected mice. In particular, astrocytes cultured with reactive microglia-conditioned media displayed hypertrophic morphology and a downregulation of genes involved in neurogenic and synaptogenic functions. In summary, the current study provided experimental support toward the non-cell autonomous mechanisms behind neurotoxicity in prion diseases and demonstrated that the astrocyte reactive phenotype associated with prion diseases is synaptotoxic.

Toxoplasma gondii infection and its implications within the central nervous system.

Toxoplasma gondii is a parasite that infects a wide range of animals and causes zoonotic infections in humans. Although it normally only results in mild illness in healthy individuals, toxoplasmosis is a common opportunistic infection with high mortality in individuals who are immunocompromised, most commonly due to reactivation of infection in the central nervous system. In the acute phase of infection, interferon-dependent immune responses control rapid parasite expansion and mitigate acute disease symptoms. However, after dissemination the parasite differentiates into semi-dormant cysts that form within muscle cells and neurons, where they persist for life in the infected host. Control of infection in the central nervous system, a compartment of immune privilege, relies on modified immune responses that aim to balance infection control while limiting potential damage due to inflammation. In response to the activation of interferon-mediated pathways, the parasite deploys an array of effector proteins to escape immune clearance and ensure latent survival. Although these pathways are best studied in the laboratory mouse, emerging evidence points to unique mechanisms of control in human toxoplasmosis. In this Review, we explore some of these recent findings that extend our understanding for proliferation, establishment and control of toxoplasmosis in humans.

Cerebral protothecosis mimicking high-grade glioma.

Prototheca wickerhamii is a common, indolent alga that seldom causes central nervous system infections in humans. We report the first UK case of cerebral protothecosis in an immunocompetent 56-year-old woman who presented with a 5-month history of intermittent fatigue followed by a 2-week history of symptoms, including right arm and leg weakness, a loss of fine motor coordination, worsening gait, right facial tingling, diplopia and a metallic oral taste. MRI scans revealed a multifocal abnormality suggestive of high-grade glioma. Given the clinical presentation, absence of immunodeficiency and characteristic MRI features, a diagnosis of high-grade glioma was deemed most likely by the multidisciplinary team. Surgical biopsy provided material for histopathological and microbiological diagnosis. She underwent a 2-year course of antimicrobials with surveillance MRI scans. The patient made a good functional recovery but still retains mild neurological sequelae.

Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.

Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a rat model of CSF catheter infection to C. acnes. We found elevated levels of interleukin-1ß (IL-1ß), IL-6, chemokine ligand 2, and IL-10 in the CSF and brain tissues of animals implanted with C. acnes-infected catheters compared to sterile controls at day 1 postinfection. This coincided with modest increases in neutrophils in the CSF and, to a greater extent, in the brain tissues of animals with C. acnes infection, which closely mirrors the clinical findings in patients with C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of disease, typified at day 1 postinfection by an acute-phase and pathogen neutralization response evolving to a response consistent with wound resolution at day 28 compared to a sterile catheter placement. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile postoperative inflammation and that CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases.

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction.

Single-Cell RNA Sequencing Reveals the Diversity of the Immunological Landscape following Central Nervous System Infection by a Murine Coronavirus.

Intracranial (i.c.) infection of susceptible C57BL/6 mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) (a member of the Coronaviridae family) results in acute encephalomyelitis and viral persistence associated with an immune-mediated demyelinating disease. The present study was undertaken to better understand the molecular pathways evoked during innate and adaptive immune responses as well as the chronic demyelinating stage of disease in response to JHMV infection of the central nervous system (CNS). Using single-cell RNA sequencing analysis (scRNAseq) on flow-sorted CD45-positive (CD45+) cells enriched from brains and spinal cords of experimental mice, we demonstrate the heterogeneity of the immune response as determined by the presence of unique molecular signatures and pathways involved in effective antiviral host defense. Furthermore, we identify potential genes involved in contributing to demyelination as well as remyelination being expressed by both microglia and macrophages. Collectively, these findings emphasize the diversity of the immune responses and molecular networks at defined stages following viral infection of the CNS.IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the molecular signatures of immune cells within the CNS at defined times following infection with a neuroadapted murine coronavirus using scRNAseq. This approach has revealed that the immunological landscape is diverse, with numerous immune cell subsets expressing distinct mRNA expression profiles that are, in part, dictated by the stage of infection. In addition, these findings reveal new insight into cellular pathways contributing to control of viral replication as well as to neurologic disease.

Molecular and Histologic Diagnosis of Central Nervous System Infections.

Infections of the central nervous system cause significant morbidity and mortality in immunocompetent and immunocompromised individuals. A wide variety of microorganisms can cause infections, including bacteria, mycobacteria, fungi, viruses, and parasites. Although less invasive testing is preferred, surgical biopsy may be necessary to collect diagnostic tissue. Histologic findings, including special stains and immunohistochemistry, can provide a morphologic diagnosis in many cases, which can be further classified by molecular testing. Correlation of molecular, culture, and other laboratory results with histologic findings is essential for an accurate diagnosis, and to minimize false positives from microbial contamination.

Primary Central Nervous System Infection by Histoplasma in an Immunocompetent Adult.

Central nervous system (CNS) infection by Histoplasma capsulatum is a rare disease in immunocompromised individuals in endemic areas. About one quarter of cases result from hematogenous dissemination. A 23-year-old upholsterer with chronic occipital headache had developed intracranial hypertension and dizziness, incoordination with ataxic gait, and acute confusion 5 months prior to admission. Laboratory examinations and chest roentgenogram were normal. Postcontrast T1-weighted MRI of the brain revealed a multiple ring-enhancing cerebellar, brain stem and parietal lobe lesions, and meningeal contrast enhancement. Cerebrospinal fluid culture was positive for H. capsulatum species complex, which was confirmed by phylogenetic analysis. Thirteen years after the diagnosis and treatment, there was no H. capsulatum recurrence; sequels related to complications due to the ventriculoperitoneal shunt. This case shows a primary neurological presentation of cerebral histoplasmosis, without meningitis or disseminated disease in nonimmune-compromised patient. The authors propose a categorization of the diagnosis of CNS histoplasmosis. Routine diagnostics of sibling species within the H. capsulatum complex proved to be difficult.

Prevalence and Risk Factors of White Matter Lesions in Tibetan Patients Without Acute Stroke.

Background and Purpose- Studies on the prevalence and risk factors of white matter lesions (WMLs) in Tibetans living at high altitudes are scarce. We conducted this study to determine the prevalence and risks of WMLs in Tibetan patients without or with nonacute stroke. Methods- We undertook a retrospective analysis of medical records of patients treated at the People's Hospital of Tibetan Autonomous Region and identified a total of 301 Tibetan patients without acute stroke. WML severity was graded by the Fazekas Scale. We assessed the overall and age-specific prevalence of WMLs and analyzed associations between WMLs and related factors with univariate and multivariate methods. Results- Of the 301 patients, 87 (28.9%) had peripheral vertigo, 83 (27.3%) had primary headache, 52 (17.3%) had a history of stroke, 36 (12.0%) had an anxiety disorder, 29 (9.6%) had epilepsy, 12 (4.0%) had infections of the central nervous system, and 3 (1.0%) had undetermined diseases. WMLs were present in 245 (81.4%) patients, and 54 (17.9%) were younger than 40 years. Univariate analysis showed that age, history of cerebral infarction, hypertension, the thickness of the common carotid artery intima, and plaque within the intracarotid artery were related risks for WMLs. Ordered logistic analysis showed that age, history of cerebral ischemic stroke, hypertension, male sex, and atrial fibrillation were associated with WML severity. Conclusions- Risk factors for WMLs appear similar for Tibetans residing at high altitudes and individuals living in the plains. Further investigations are needed to determine whether Tibetans residing at high altitudes have a higher burden of WMLs than inhabitants of the plains.

The Use of Large-Particle Aerosol Exposure to Nipah Virus to Mimic Human Neurological Disease Manifestations in the African Green Monkey.

Nipah virus (NiV) is an emerging virus associated with outbreaks of acute respiratory disease and encephalitis. To develop a neurological model for NiV infection, we exposed 6 adult African green monkeys to a large-particle (approximately 12 µm) aerosol containing NiV (Malaysian isolate). Brain magnetic resonance images were obtained at baseline, every 3 days after exposure for 2 weeks, and then weekly until week 8 after exposure. Four of six animals showed abnormalities reminiscent of human disease in brain magnetic resonance images. Abnormalities ranged from cytotoxic edema to vasogenic edema. The majority of lesions were small infarcts, and a few showed inflammatory or encephalitic changes. Resolution or decreased size in some lesions resembled findings reported in patients with NiV infection. Histological lesions in the brain included multifocal areas of encephalomalacia, corresponding to known ischemic foci. In other regions of the brain there was evidence of vasculitis, with perivascular infiltrates of inflammatory cells and rare intravascular fibrin thrombi. This animal model will help us better understand the acute neurological features of NiV infection and develop therapeutic approaches for managing disease caused by NiV infection.

Japanese Encephalitis Virus Infects the Thalamus Early Followed by Sensory-Associated Cortex and Other Parts of the Central and Peripheral Nervous Systems.

Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1-5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.