Progress in the Treatment of Fungal Infections of the Central Nervous System

HThe incidence of fungal infections of the central nervous system(CNS) has gradually increased in recent years. Intracranial fungal infection can be classified as diffuse and focal infections. The clinical manifestations of these infections include fever and cranial pressure caused by meningitis or meningoencephalitis, and focal neurological defects caused by lesions in the intracranial space. Diagnosing fungal infections of the CNS requires the comprehensive analysis of the patient's medical history, epidemiology, underlying disease, clinical manifestation, imaging manifestations, and various laboratory test results. The identification of fungal bodies or structures in brain tissue or cerebrospinal fluid specimens is the golden standard of diagnosis. The principles for the treatment of the fungal infections of the CNS are the effective control of pathogenic risk factors, use of effective antifungal drugs, and the active implementation of surgical intervention for fungal abscesses and granuloma. In the meantime, new diagnoses and treatments should be actively explored to improve the prognosis of patients.

Pathogen Analysis of Central Nervous System Infections in a Chinese Teaching Hospital from 2012-2018: A Laboratory-based Retrospective Study

Central nervous system (CNS) infections are associated with high mortality rates. The clinical presentation of many CNS infections by different pathogens is difficult to distinguish, but the definite diagnosis of the etiology is critical for effective therapy and prognosis. The aim of this study was to explore the etiology of CNS infections with definite diagnoses based on data from a clinical microbiology laboratory in Tongji Hospital, a teaching hospital in China, obtained over a six-year period. We conducted a retrospective study on all cerebrospinal fluid (CSF) specimens submitted to our clinical microbiology laboratory from September, 2012 to December, 2018. The etiology of CNS infections caused by Cryptococcus neoformans, Mycobacterium tuberculosis and common bacteria was analyzed. Antimicrobial susceptibility testing was conducted on all isolates. The results showed that 1972 cases of CNS infections were identified from 18 300 CSF specimens. Common bacterial meningitis (BM), cryptococcal meningitis (CM) and tuberculous meningitis (TM) accounted for 86.3%(677/785), 9.4%(74/785) and 4.3%(34/785) respectively of cases over the six-year period. BM was the most common among the different age groups, followed by CM. Of the TM cases, 44.1%(15/34) were distributed within the age group of 15-34 years, whereas for CM cases, 52.7%(39/74) occurred within the 35-54-year age group, and the age distribution of BM cases was fairly even. Among the bacterial pathogens isolated, Staphylococcus epidermidis was the most common, accounting for 12.5%(98/785), followed by Acinetobacter baumannii (ABA) and Staphylococcus aureus (SAU), accounting for 11.8%(93/785) and 7.6%(60/785) respectively. The resistance rates to antibiotics were >75%, with the exception of the resistance rate of ABA to tegafycline, which was <3%. More than 60% of SAU strains displayed resistance to penicillin, oxacillin, ampicillin/sulbactam, cefazolin, cefuroxime, gentamycin, tobramycin, erythromycin and levofloxacin, whereas more than 90% of SAU strains showed susceptibility to trimethoprim/ sulfamethoxazole, tegafycline, vancomycin, teicoplanin and linezolid. For C. neoformans, the susceptibility rates to amphotericin B, 5-fluorocytosine, fluconazol and voriconazole were >95%. Analysis of samples from patients with CNS infection in a clinical microbiology laboratory at a teaching hospital in China over a six-year period indicated that the most common etiological agents were the bacteria ABA and SAU. The antibiotic resistance levels of ABA were found to be high and of concern, whereas isolates of C. neoformans were found to be sensitive to antifungal antibiotics.

MRI in central nervous system infections: A simplified patterned approach

Recognition and characterization of central nervous system infections poses a formidable challenge to the neuro-radiologist.Imaging plays a vital role,the lesions typically being relatively inaccessible to tisue sampling.The results of an accurate diagnosis are endlessly re-warding,given the availability of excellent pharmaco-logical regimen.The availability of numerous magnetic resonance(MR)sequences which provide functional and molecular information is a powerful tool in the hands of the radiologist.However,the plethora of se-quences and the possibilities on each sequence is also intimidating,and often confusing as well as time con-suming.While a large number of reviews have already described in detail the possible imaging findings in each infection,we intend to classify infections based on their imaging characteristics.In this review we describe an algorithm for first classifying the imaging findings into patterns based on basic MR sequences(T1,T2 and enhancement pattern with Gadolinium),and then sub-classify them based on more advanced molecular and functional sequences(Diffusion,Perfusion,Susceptibili-ty imaging,MR Spectroscopy).This patterned approachis intended as a guide to radiologists in-training and in-practice for quickly narrowing their list of differentials when faced with a clinical challenge.The entire content of the article has also been summarised in the form of flow-charts for the purpose of quick reference.

The choline pathway as a strategy to promote central nervous system(CNS) remyelination

Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinated axons and it is supposed to protect axons/neurons from degeneration and thus the patient from progressive disability （Franklin and Ffrench-Constant, 2008）. Current therapeutics for patients with multiple sclerosis are to some extent very effective in inhibiting neuroinflamma- tion and demyelination. However, to date there are no substanc- es available that can enhance remyelination. Remyelination is the result of recruitment/proliferation of new oligodendrocyte precursor cells （OPC） and differentiation into mature myelin producing oligodendrocytes （Franklin and Ffrench-Constant, 2008）. These processes are supported by many factors and signals and failure at any stage might lead to repair failure. Strategies to enhance myelin repair are either the promotion of endogenous repair mechanisms via modulation of OPC prolif- eration and oligodendrocyte differentiation or the transplantion of myelinating cells into lesions. Due to the multiloculated pro- cess in multiple sclerosis and the ethical problems with the cell source, the latter is less favoured. The endogenous promotion of remvelination could be achieved by several approaches such as：

Application of metagenomic next-generation sequencing in the diagnosis of infectious diseases of the central nervous system after empirical treatment

BACKGROUND The diagnostic value of metagenomic next-generation sequencing(mNGS)in central nervous system(CNS)infectious diseases after empirical treatment has not been reported.AIM To investigate the diagnostic value of mNGS of cerebrospinal fluid(CSF)in the empirically treated CNS infectious diseases.METHODS A total of 262 CSF samples from patients with suspected CNS infections were collected between August 2020 and December 2021.Both mNGS and conventional methods were used for testing.The conventional methods included microbial culture,smear,polymerase chain reaction,etc.RESULTS Among 262 suspected cases,183 cases(69.84%)were diagnosed as CNS infection,including 86 cases of virus infection(47.00%),70 cases of bacterial infection(38.25%)and 27 cases of fungal infection(14.76%).The sensitivity and specificity of mNGS were 65.6%(95%CI:58.2%-72.3%)and 89.6%(95%CI:79.1%-95.3%),respectively.The PPV of mNGS was 94.5%(95%CI:88.6%-97.6%),and the NPV was 48.8%(95%CI:39.7%–57.9%).The pathogen detective sensitivity and accuracy of mNGS were higher than those of conventional methods(Sensitivity:65.6%vs 37.2%;P<0.001;Accuracy:72.0%vs 50%,P<0.001).The results showed that compared with conventional methods,mNGS technology was a more sensitive method for the diagnosis of CNS infection after empirical treatment.CONCLUSION mNGS can be a better method applied in the diagnosis of CNS infection after empirical treatment.

Mesenchymal stem cell-derived exosomes regulate microglia phenotypes:a promising treatment for acute central nervous system injury

There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.

Self-healing hydrogel for tissue repair in the central nervous system

Neurological disorders are diseases of the central and peripheral nervous systems.These disorders include Alzheimer＇s disease,epilepsy,brain tumor,and cerebrovascular diseases（stroke,migraine and other headache disorders,multiple sclerosis,Parkinson＇s disease,and neuroinfections）.

The relationship between serum levels of uric acid and prognosis of infection in critically ill patients

Serum uric acid level is associated with some chronic diseases and prognosis of severe infection. This study aimed to investigate the relationship between serum uric acid （SUA） and prognosis of infection in critically ill patients. The data from 471 patients with infection admitted from January 2003 to April 2010 were analyzed retrospectively at Huashan Hospital Affiliated to Fudan University, Shanghai, China. The data of SUA, serum creatinine, blood urea nitrogen （BUN） and other relevant examinations within 24 hours after admission were recorded and the levels of SUA in those patients were described, then Student＇s t test was used to evaluate the relationship between SUA and pre-existing disorders. Different levels of SUA were graded for further analysis. The Chi-square test was used to examine the difference in the prognosis of infection. The mean initial level of SUA within 24 hours after admission was 0.232±0.131 mmol/L and the median was 0.199 mmol/L. Remarkable variations in the initial levels of SUA were observed in patients with pre-existing hypertension （t=-3.084, P=0.002）, diabetes mellitus （t=-2.487, P=0.013）, cerebral infarction （t=-3.061, P=0.002）, renal insufficiency （t=-4.547, P〈0.001）, central nervous system infection （t=5.096, P〈0.001） and trauma （t=2.875, P=0.004）. SUAwas linearly correlated with serum creatinine and BUN （F=159.470 and 165.059, respectively, P〈0.001）. No statistical correlation was found between the initial levels of SUA and prognosis of infection （X^2=60.892, P=0.100）. The current study found no direct correlation between the initial levels of SUA after admission and prognosis of infection in critically ill patients.

Innate host responses to West Nile virus: Implications for central nervous system immunopathology

West Nile virus(WNV) is an emerging neurotropic flavivirus that has recently spread to America and Southern Europe via an enzootic/epizootic bird-mosquito-bird transmission cycle. The virus can occasionally infect humans through mosquito bites, and man-to-man transmission has also been reported via infected blood or organ donation. In the human host, WNV causes asymptomatic infection in about 70%-80% of cases, while < 1% of clinical cases progress to severe neuroinvasive disease; long-term neurological sequelae are common in more than 50% of these severe cases. Thepathogenesis of the neuroinvasive form of WNV infection remains incompletely understood, and risk factors for developing severe clinical illness are largely unknown. The innate immune response plays a major role in the control of WNV replication, which is supported by the fact that the virus has developed numerous mechanisms to escape the control of antiviral interferons. However, exaggerated inflammatory responses lead to pathology, mainly involving the central nervous system. This brief review presents the salient features of innate host responses, WNV immunoevasion strategies, and WNV-induced immunopathology.

Clinical infections in neurosurgical oncology:An overview

Central nervous system(CNS)infections are urgent conditions with high morbidity and mortality.Bacteria,viruses,parasites or fungi can cause them.Intracranial infections after craniotomies are an important complication of treatment,especially in oncological patients that are already immunologically compromised due to the disease and treatment.The consequence of CNS infections in oncological patients includes longer treatment with antibiotics,additional surgical procedures,higher treatment costs and poorer treatment outcomes.Additionally,the management of primary pathology may be prolonged or postponed as a result of the active infection.By introducing new and improved protocols,tightening controls on their implementation,constantly educating the entire team involved in patient treatment and educating both patients and relatives,the incidence of infections can be reduced effectively.

Prevotella oris-caused meningitis and spinal canal infection:A case report

BACKGROUND Prevotella oris-induced meningitis and Prevotella oris-induced meningitis concomitant with spinal canal infection are extremely rare.To the best of our knowledge,only 1 case of Prevotella oris-induced central system infection has been reported.This is the second report on meningitis combined with spinal canal infection due to Prevotella oris.CASE SUMMARY We report a case of a 9-year-old boy suffering from meningitis and spinal canal infection.The patient presented to the neurosurgery department with lumbosacral pain for 1 mo and headache and vomiting for 1 d.He had been treated with cephalosporin and nonsteroidal anti-inflammatory drugs for fever,otalgia and pharyngalgia in a local hospital 2 mo prior to this admission.During hospitalization,magnetic resonance imaging suggested meningitis and L3-S1 lumbosacral dural sac infection.The cerebrospinal fluid and blood cultures were negative,but the cerebrospinal fluid specimen indicated the presence of Prevotella oris by metagenomic next-generation sequencing.Previous cases of Prevotella oris infection were retrieved from PubMed to characterize the clinicopathological features and identify the prognostic factors and related antimicrobial treatment of infection due to Prevotella oris.CONCLUSION This report shed light on the characteristics of Prevotella oris infection and highlighted the role of metagenomic next-generation sequencing in pathogen detection.

Magnetic Resonance Imaging of Central Nervous System Lesions in HIV/AIDS: About 35 Cases in Libreville (Gabon)

Background: Sub-Saharan Africa is the region most affected by the Human Immunodeficiency Virus (HIV) with an increasing prevalence of related cognitive impairments. Magnetic Resonance Imaging (MRI) plays an important role in the early detection of lesions. This work aimed to describe the MRI aspects of different brain lesions occurred in HIV positive patients in our practice. Methods: This was a descriptive cross-sectional study that took place from June 2014 to July 2016 in the medical imaging department of the EL RAPHA private Polyclinic in Libreville, Gabon. It included all patients referred for imaging for the exploration of a Central Nervous System (CNS) lesions at MRI, based on clinical and/or paraclinical arguments. Results: Among the 39 patients included, 19 (48.7%) had a previous brain CT scan, 11 of which were normal (28.2%). Thirty-five (89.74%) patients had a pathological MRI. The main etiologies found were toxoplasmosis (37.14%), tuberculosis (17.14%), cerebral atrophy (17.14%) and HIV encephalitis (14.28%). Among the eleven patients with a normal Computer Tomography scan, the MRI found 7 abnormalities including 1 case of toxoplasmosis, 3 cases of HIV encephalitis and 3 cases of Progressive Multifocal Leukoencephalopathy (PML). Conclusion: MRI played an important role in the diagnosis of CNS disorders in HIV-infected individuals. It can be used to differentiate and characterize various brain lesions. Improving its accessibility in sub-Saharan Africa should contribute to better care for people living with HIV.

Immunobiology of congenital cytomegalovirus infection of the central nervous system--the murine cytomegalovirus model

Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8＋ T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

Seizures and epilepsy secondary to viral infection in the central nervous system

Viral infection in the central nervous system(CNS)is a common cause of seizures and epilepsy.Acute symptomatic seizures can occur in the context of almost all types of acute CNS viral infection.However,late unprovoked seizures and epilepsy may not be frequent after viral infection of the CNS.The incidence of seizures and epilepsy after CNS viral infection is mainly dependent on the brain region of infection.It remains to be determined whether treatment of CNS viral infection using antiepileptic drugs(AEDs)can prevent seizures and subsequent epilepsy in patients,particularly with regard to the timing,drug choice and dosage,and duration of AEDs.The postoperative outcome of seizures in patients with intractable epilepsy caused by viral encephalitis primarily depends on the epileptogenic zone.In addition,neuroinflammation is known to be widely involved in the generation of seizures during CNS viral infection,and the effects of anti-inflammatory therapies in preventing seizures and epilepsy secondary to CNS viral infection require further studies.In this review,we discuss the incidence,mechanisms,clinical management and prognosis of seizures and epilepsy secondary to CNS viral infection,and summarize common CNS viral infections that cause seizures and epilepsy.

Long-term outcome of acute central nervous system infection in children

Importance:Central nervous system infection is a severe illness in children.Little is known about the long-term outcome in children with central nervous system infection of various etiologies.Objective:The aims of this study were to investigate the long-term outcomes of childhood acute central nervous system infection and to examine possible prognostic factors.Methods:Of 172 children who were treated for acute central nervous system infection from January 2009 through December 2009,139 were eligible for follow-up evaluations.A structured interview was conducted with the parents 3.8-4.7 years after hospital discharge.The global outcome was determined in all patients using the Pediatric Version of the Glasgow Outcome Scale-Extended.Clinical features of the acute episode were retrieved from medical records.Results:The outcome was favorable in 109 of 139 patients (78%),38 (27%) were mildly impaired,six (4%) were moderately impaired,14 (10%) were severely impaired and two (1%) were in a vegetative state.There were eight deaths.The most frequent symptoms were difficulty concentrating (16%),epilepsy (12%),limb paralysis (12%),memory impairment (10%),speech disorders (9%),irritability (9%).Significant risk factors for epilepsy included the presence of recurrent seizures or status epilepticus,the existence of pure spikes in the electroencephalogram,brain parenchyma abnormalities on neuroimaging and herpes simplex virus encephalitis (HSVE).A multivariate analysis identified three factors that were independently associated with poor outcome:coma,brain parenchyma abnormalities on neuroimaging and HSVE.Interpretation:Most children with acute central nervous system infection experienced a favorable outcome 3.8-4.7 years after discharge from the hospital.Minor to severe disability persists in a high proportion of cases.Coma,brain parenchymal abnormalities on neuroimaging and HSVE may predict poor long-term outcome.

The role of muscle LIM protein in the nervous system

Unlike the peripheral nervous system (PNS), the central nervous system (CNS) has a low intrinsic regenerative capacity and has mechanisms that actively suppress axon regrowth, for example, glial scarring and myelin inhibition (Fischer, 2012). Even in the PNS, which has the principle ability to regenerate injured axons, functional recovery remains limited, particularly in cases where the nerve target has become unreceptive to re-innervation over time due to an insufficient axonal growth rate (Diekmann and Fischer, 2015). Progress towards robust neuroregenerative therapies depends upon an understanding of the relevant signaling and cytoskeletal proteins that drive and control axon extension. Muscle LIM protein (MLP), also known as cysteine and glycine-rich protein 3, was recently discovered to be one such protein that is expressed in regenerating rat neurons and whose overexpression can promote the axon regeneration of adult central, and peripheral neurons of different species (Levin et al., 2019).

Low antioxidant status of patients with central nervous system infections

Aim:The pathogenesis of central nervous system infections(CNSI)has not been fully understood;some studies indicated that reactive oxygen species may induce brain damage.The aim of our study was to investigate serum antioxidant status in patients with CNSI.Methods:The serum levels of uric acid(UA),bilirubin and albumin of 548 individuals were enrolled in our study,comprising of 114 healthy controls(HC)and 434 patients with five different kinds of CNSI,which including viral meningitis and/or meningoencephalitis,cysticercosis of brain,tuberculous meningitis and/or meningoencephalitis,cryptococcus meningitis and/or meningoencephalitis,and bacterial meningitis and/or meningoencephalitis.Results:The data suggested that there were reducing levels of oxidation state(serum UA,bilirubin and albumin)in CNSI patients when compared with HC.Likewise,similar results were observed when cohorts were divided into male and female subgroups.Conclusion:The authors demonstrated that serum antioxidant status in patients with CNSI was lower;the reason may be due to exhaustion of antioxidant capacity.Therefore,enhancing antioxidant power and keeping oxidative stress and antioxidants in balance may be beneficial to the patients with CNSI.

Neurodevelopment in HIV Infected Children at Roosevelt’s Hospital Infectious Diseases Clinic, in Guatemala

Background: The infection with HIV has been related to neurological disorders that are very frequent, since this virus crosses the blood-brain barrier and enters the CNS, thus affecting its neurological development. About 50% - 90% of infected patients, with an average age of onset from 19 months to 3 years old may present some types of neurological alteration during the course of the disease. Currently in Guatemala, there are no researches that show changes in the neurodevelopment of patients infected with HIV. Objective: To identify neurodevelopment of pediatric patients infected with the HIV, taking into consideration clinical and epidemiological characteristics. Materials and Methods: Fifty-six patients, who were under 8 years and 6 months of age, that met the inclusion criteria (confirmed diagnosis of HIV), were evaluated through neurodevelopment test (Bayley Test and McCarthy’s Scale) during the months of May and June of 2016. Results: Within the neurodevelopment evaluation, it was discovered that between 36% and 54% of evaluated patients that were 3 years and 6 months to 8 years and 6 months old, presented alterations in more than one area of neurodevelopment, correlating it with studies performed in other countries with 30% - 70% of neurological affection. Conclusions-All infected patients have alterations in more than one area of neurodevelopment. The most affected areas of neurodevelopment were the verbal, numerical and cognitive areas.

Central and peripheral neurological involvement in monoclonal gammopathies of undetermined significance

Several studies have suggested a pathogenetic role of paraproteinaemias in PNS damage. Over the few last years, the presence of symptomatic or subclinical PNS lesions in CNS diseases like multiple sclerosis has been described. On the other hand, CNS demyelinating lesions and cervical atrophy have been re- ported in patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Very few cases of MGUS associated with CNS disease alone or with both CNS and PNS disease have been re- ported. Since 1999, we have been studying 16 patients (8 M, 8 F), with a mean age 60.2 ± 13.4, affected by MGUS associated with symptomatic neurological central and/or peripheral diseases. Patients affected with lymphomas, lupus erithematosus and other immunological diseases were excluded. Involvement of both PNS and CNS was not associated to a particular type of paraproteinemia: monoclonal IgM were found in 8 patients;monoclonal IgG in 6 patients and mono- clonal IgA in 1 patient and Igl in 1 patient. High anti- nervous system autoantibodies were found in 10/16 patients and antiMAG antibodies were detected in patients with paraproteinemic demyelinating neuropathy (PDN). High reactivity anti-nervous system might support the hypothesis of a pathogenetic role of MGUS in these neurological diseases. Nevertheless, at present, we cannot exclude that there is only a circumstantial association between MGUS and neurological damages, particularly concerning CNS.

Can the Glucose Central Control System Dysfunctions Induce Diabetes Mellitus?

We study afresh how the glucose control system anomalies impact the organicity of the glucose homeostasis and build up events of persistent hyperglycemia and diabetes mellitus. We have used critically the state of art literature related to the subject, in order to cross, to compare, and to organize the relevant contents to create a logical and consistent support to the finds. We show that it is consistent to assume that persistent hyperglycemia and diabetes mellitus can have precursors not only in pancreas, but also in brain, mainly induced by noxious dysfunctions of hypothalamus sensor neurons circuits and external noxious elements, causing pancreas overload, and the consequent exhaustion—overburden.