Dancing Out of Step: A Case of Tuberculous Meningitis Presenting as Childhood Chorea.

Background: Acute to subacute pediatric movement disorders require prompt diagnosis to identify potentially treatable diseases. Case Report: We present a 6-year-old male with a three-week history of generalized chorea transitioning to predominantly right-sided hemichorea and then to left hemiplegia. Discussion: We review the mechanisms in tuberculous meningitis underlying his movement abnormalities.

A Rare Case of Streptococcus agalactiae Ventriculitis and Endocarditis.

Streptococcus agalactiae infection is typically seen in specific populations, including neonates, pregnant women, and the elderly. These patients have immature, lower, and waning immune systems, which makes them more susceptible to infections. Typical S. agalactiae infections manifest as cellulitis, bacteremia, endocarditis, meningitis, ventriculitis (a rare complication of meningitis), and osteomyelitis. In rare cases, a patient can present with two or more of these typical infection manifestations. The authors present a case of a 48-year-old female with a past medical history of hypothyroidism and chronic back pain who presented to the emergency department with altered mental status. The patient developed nausea and vomiting two days prior to presentation after a family gathering, followed by occipital headache and agitation. On arrival at the emergency department, the patient did not follow commands and was drowsy. The initial examination showed positive for Brudzinski and Kernig signs. The patient was tachycardic, tachypneic, and hypertensive. Initial computed tomography (CT) head without contrast was negative for any acute pathology. Neurology was consulted, and a bedside lumbar puncture was performed, which was significant for elevated opening pressure of 32 cm H2O. The patient was initially started on ceftriaxone, ampicillin, vancomycin, acyclovir, and dexamethasone. Magnetic resonance imaging (MRI) of the brain with and without contrast showed acute ventriculitis, mild leptomeningeal enhancement, and a right posterior corona radiata acute lacunar infarct. Meningitis panel, BioFire (BioFire Diagnostics, Salt Lake City, UT), was positive for S. agalactiae, and the patient was de-escalated to ceftriaxone. Cerebrospinal fluid and blood cultures returned positive for S. agalactiae. A transthoracic echocardiogram was negative for endocarditis, but a transesophageal echocardiogram was significant for a 0.7 × 0.4 cm mobile echodensity attached to the posterior leaflet of the mitral valve (P1/P2 scallop). Repeat blood cultures, additional cerebrospinal fluid analysis, and infectious workup remained negative. Cardiology was consulted and recommended medical treatment. The patient improved clinically, continued ceftriaxone, and was discharged to complete a total of six weeks of treatment with outpatient follow-up evaluations. This case depicts a rare presentation of endocarditis, meningitis, and ventriculitis S. agalactiae infection and the need for a definite treatment algorithm in the management of complicated conditions such as the one presented.

Migration of the anal distal end due to ventriculoperitoneal shunt placement: an atypical case report of a 9-month-old infant with tuberculous meningitis and review of the literature.

BACKGROUND: Ventriculoperitoneal shunt (VPS) represents one of the most classic and widely used treatments for hydrocephalus in pediatric patients. Migration and externalization of the distal end of the catheter through the rectum are extremely rare complications of intestinal perforation with devastating consequences such as meningitis or peritonitis due to enteric bacteria that are significantly life-threatening. Besides, one of the biggest topics with that is that it can happen without producing symptoms, like the patient we present in this case report, which further masks the condition and puts the patient's life more at risk. CASE PRESENTATION: We present a case of a 9-month-old infant patient, with a history of prematurity, tuberculous meningitis (TBM), and hydrocephalus, who came to ED with a functional VPS and the distal end of the catheter protruding outside the rectum for 7 days, without presenting neurological or intestinal symptoms accompanying. One of the parameters that guided the diagnosis and made us suspicious of asymptomatic intestinal perforation (IP) was the background of TMB. The patient was immediately transferred to the OR where both ends of the shunt were removed: in the first instance, the shunt tube was disconnected through the abdomen, thus withdrawing through the anus, and subsequently, the proximal end of the catheter was exteriorized. In turn, the intestinal fistula was successfully repaired laparoscopically, and prophylactic antibiotic treatment was early administered. On the 6th postop day, a shunt was internalized, and a child was discharged on postop day 15 without complications with alarm guidelines. CONCLUSIONS: The authors of this article strongly suggest that (1) anal extrusion of catheters is an uncommon complication but real: for this reason, its development should be considered in all patients with VPS, especially in infants. (2) The patients are often asymptomatic since false tracts can form around the catheter protecting it from spillage, and thus can be removed without complications. (3) Special care should be taken in patients with conditions that increase the risk of developing IP, such as TMB.

Brain Immune Cell Infiltration and Serum Metabolomic Characteristics Reveal that Lauric Acid Promotes Immune Cell Infiltration in Brain and Streptococcus suis Meningitis in Mice.

Although naturally Streptococcus suis serotype 2 (SS2) causes meningitis resulting in death or sequela of neurological symptoms in pigs and humans, severely threatening public health in the world, it has been difficult to build up and confirm experimental meningitis mouse models with obvious neurological syndrome for about two decades, which strongly hampers the in-depth study on the control measures and mechanisms of SS2-induced meningitis. In this study, a typical meningitis mouse model of SS2 was successfully established, as confirmed by the behavioral indicators of balance beam test, suspension test, and gait analysis. With bacteria gathering in the brain, distinguishable unique features including meningeal thickening, vacuolization of the Nissl body, brain barrier damage, glial cell activation, and more infiltration of T cells, macrophages, and DCs are observed in SS2 meningitis mice with typical neurological signs. Some meningitis mice were also accompanied by identical nephritis, ophthalmia, and cochlearitis. Investigation of the metabolic features demonstrated the downregulated cholic acid and upregulated 2-hydroxyvaleric acid, tetrahydrocortisone, nicotinic acid, and lauric acid in blood serum of mice and piglets with meningitis. And feeding trials show that lauric acid can promote meningitis by promoting the infiltration of immune cells into brain. These findings demonstrated that infection of ICR (improved castle road) mice with SS2 was able to induce typical meningitis accompanied by immune cell infiltration and lauric acid upregulation. These data provide a basis for the deep study of SS2 meningitis.

High-risk Escherichia coli clones that cause neonatal meningitis and association with recrudescent infection.

Neonatal meningitis is a devastating disease associated with high mortality and neurological sequelae. Escherichia coli is the second most common cause of neonatal meningitis in full-term infants (herein NMEC) and the most common cause of meningitis in preterm neonates. Here, we investigated the genomic relatedness of a collection of 58 NMEC isolates spanning 1974-2020 and isolated from seven different geographic regions. We show NMEC are comprised of diverse sequence types (STs), with ST95 (34.5%) and ST1193 (15.5%) the most common. No single virulence gene profile was conserved in all isolates; however, genes encoding fimbrial adhesins, iron acquisition systems, the K1 capsule, and O antigen types O18, O75, and O2 were most prevalent. Antibiotic resistance genes occurred infrequently in our collection. We also monitored the infection dynamics in three patients that suffered recrudescent invasive infection caused by the original infecting isolate despite appropriate antibiotic treatment based on antibiogram profile and resistance genotype. These patients exhibited severe gut dysbiosis. In one patient, the causative NMEC isolate was also detected in the fecal flora at the time of the second infection episode and after treatment. Thus, although antibiotics are the standard of care for NMEC treatment, our data suggest that failure to eliminate the causative NMEC that resides intestinally can lead to the existence of a refractory reservoir that may seed recrudescent infection.

The Evaluation of the BioFire FilmArray Meningitis/Encephalitis Panel for the Detection of Bacteria and Yeast in Cerebrospinal Fluid Specimens.

Background and objective Infectious meningitis and encephalitis are serious diseases that can have fatal consequences, especially in the case of bacterial meningitis. Molecular biology has made it possible to quickly introduce appropriate treatment. Our study aims to evaluate the FilmArray Meningitis/Encephalitis Polymerase Chain Reaction (PCR) Panel (BioFire Diagnostics, Salt Lake City, Utah) implemented in our department compared to traditional methods. Material and methods This was a retrospective single-center study conducted in the Department of Bacteriology of Mohammed V Military Training Hospital, Rabat, for a period of four years. All cerebrospinal fluid (CSF) samples from patients with symptoms of meningitis or meningoencephalitis submitted to the laboratory for cytobacteriological analysis were included in the study. Conventional analysis has been compared with molecular biology.  Results The overall agreement rate with FilmArray in our study was 86%. The sensitivity to Escherichia coli K1, Haemophilus influenzae, Neisseria meningitidis, Streptococcus agalactiae, and Streptococcus pneumoniae was 100%. And for Cryptococcus neoformans it was 83% in our study. Conclusion In summary, this technique can be used to diagnose bacterial meningitis more sensitively than with conventional techniques, while at the same time allowing a rapid and efficacious patient's treatment.

Cranial Nerve III Palsy as the First Sign of Carcinomatous Meningitis From Non-Hodgkin's Lymphoma.

Carcinomatous meningitis (CM) is characterized by the multifocal dissemination of malignant cells into the cerebrospinal fluid (CSF), pia mater, and subarachnoid space. Involvement can occur in the advanced stage of malignancy, causing multifocal involvement and a wide array of symptoms. Diagnosis requires suspicions and a multimodal approach that includes imaging, lumbar puncture, and diagnostic laboratory evaluation. This case represents a female with a history of non-Hodgkin's lymphoma (NHL) and venous thromboembolism on chronic anticoagulation who presented due to acute encephalopathy, hallucinations, and right cranial nerve III palsy for 10 days before arrival. Computed tomography (CT) and angiography of the brain did not show any intracranial abnormalities. Subsequent magnetic resonance imaging (MRI) was without signs of infarction, hemorrhage, or abnormal enhancement, with the MRI of the orbits showing asymmetric linear enhancement anterior to the superior pons and midbrain on the right. Initial differential included a paraneoplastic syndrome, but there was no obvious evidence of pathological enhancement on MRI. Due to progressive bulbar symptoms, a lumbar puncture was performed with cerebrospinal fluid diagnostic workup with cytology showing monoclonal B-cell proliferation consistent with lymphoma. This case illustrates a rare but specific finding of CM as cranial nerve III palsy symptoms in this patient who did not have imaging findings that would reflect her symptoms on the initial MRI of the brain. Furthermore, diagnosing CM is complex and involves a combination of multiple diagnostic and treatment modalities. It is important to recognize the condition early to improve the patient's quality of life, prolong survival, and stabilize neurological deterioration.

Secondary normal pressure hydrocephalus following pituitary apoplexy: A case report.

Background: Although secondary normal pressure hydrocephalus (sNPH) can occur in various central nervous system diseases, there are no reports of sNPH caused by pituitary lesions. Herein, we present a unique case of sNPH caused by pituitary apoplexy. Case Description: A 70-year-old man was transferred to our hospital because of a sudden onset of headache and loss of consciousness. The cerebrospinal fluid (CSF) test showed slightly elevated cell counts and protein levels but a negative CSF culture test. Magnetic resonance imaging showed a dumbbell-like cystic lesion with hemorrhagic change at the sella turcica. From the above, the patient was diagnosed with aseptic meningitis caused by pituitary apoplexy. Pituitary hormone replacement therapy was undertaken, and his symptoms fully improved. However, two months later, he complained of a gait disturbance and incontinence that had gradually appeared. Brain imaging with computed tomography showed no ventricular enlargement compared with initial images, although the lateral ventricles were slightly enlarged. As a CSF drainage test improved his symptoms temporarily, sNPH with possible longstanding overt ventriculomegaly in adults (LOVA) background was suspected. We performed a lumboperitoneal shunt (LPS) placement, which improved his symptoms. Conclusion: This case suggests that sNPH can develop even after a small subarachnoid hemorrhage caused by a pituitary apoplexy in LOVA patients. If the aqueduct of Sylvius is open, sNPH with a LOVA background can be successfully treated with LPS placement.

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

CCR2+ monocytes replenish border-associated macrophages in the diseased mouse brain.

Border-associated macrophages (BAMs) are tissue-resident macrophages that reside at the border of the central nervous system (CNS). Since BAMs originate from yolk sac progenitors that do not persist after birth, the means by which this population of cells is maintained is not well understood. Using two-photon microscopy and multiple lineage-tracing strategies, we determine that CCR2+ monocytes are significant contributors to BAM populations following disruptions of CNS homeostasis in adult mice. After BAM depletion, while the residual BAMs possess partial self-repopulation capability, the CCR2+ monocytes are a critical source of the repopulated BAMs. In addition, we demonstrate the existence of CCR2+ monocyte-derived long-lived BAMs in a brain compression model and in a sepsis model after the initial disruption of homeostasis. Our study reveals that the short-lived CCR2+ monocytes transform into long-lived BAM-like cells at the CNS border and subsequently contribute to BAM populations.

Gold Nanoparticle-Based Drug Delivery System for the Diagnosis and Treatment of Bacterial Meningitis.

Managing bacterial pathogens in the central nervous system is an immense issue for researchers all around the globe. The problem of these infections remains throughout the population, regardless of the discovery of several possible medicines. The major obstacle to drug delivery is the BBB, but only a few medicines that fulfill demanding requirements can penetrate it. Considering inadequate antibiotic alternatives and the increasing development of resistance, it is more important than ever to find new approaches to address this worldwide problem. Medical nanotechnology has evolved as a cutting-edge and effective means of treating many of the most difficult CNS illnesses, including bacterial meningitis. Various metallic nanoparticles, such as gold, silver, and titanium oxide, have shown bactericidal potential. Gold nanoparticles have gotten a great deal of interest due to their excellent biocompatibility, simplicity of surface modification, and optical qualities. The current study described AuNP-based detection and therapy options against meningitis-- causing bacteria, including bacterial pathogens' mechanisms for crossing BBB and AuNPs' mode of Action against those bacteria. The current study looked into green synthesized bactericidal gold nanoparticles-based therapy techniques for diagnosing and intervening in bacterial meningitis. Nevertheless, more research is needed before these laboratory findings can be translated into therapeutic trials. Nonetheless, we can confidently assert that the knowledge acquired and addressed in this study will benefit neuro-nanotechnology researchers.

Cryptococcosis and Cryptococcal Meningitis: A Narrative Review and the Up-to-Date Management Approach.

Cryptococcosis is a fungal infectious disease that enormously impacts human health worldwide. Cryptococcal meningitis is the most severe disease caused by the fungus Cryptococcus, and can lead to death, if left untreated. Many patients develop resistance and progress to death even after treatment. It requires a prolonged treatment course in people with AIDS. This narrative review provides an evidence-based summary of the current treatment modalities and future trial options, including newer ones, namely, 18B7, T-2307, VT-1598, AR12, manogepix, and miltefosine. This review also evaluated the management and empiric treatment of cryptococcus meningitis. The disease can easily evade diagnosis with subacute presentation. Despite the severity of the disease, treatment options for cryptococcosis remain limited, and more research is needed.

A case report of Capnocytophaga canimorsus meningitis with failure of ceftriaxone therapy.

Background: Capnocytophaga canimorsus is a gram-negative zoonotic organism that has the potential to cause devastating human infection. Historically, treatment with beta-lactams including penicillin and ceftriaxone has been effective. Methods: We describe a complicated case of C. canimorsus meningitis in a 70-year-old female following a superficial puncture wound from her dog's teeth. Results: The case described here was complicated by seizures following treatment with ceftriaxone therapy. This case is also the first reported case of C. canimorsus meningitis associated with moyamoya disease and fibromuscular dysplasia. Conclusions: Physicians should be aware of the possibility of ceftriaxone-resistant C. canimorsus and have a low threshold to broaden antimicrobial coverage in the absence of clinical improvement. We also raise the possibility of an association between vasculopathies and unusual infections like C. canimorsus.

Historique: Le Capnocytophaga canimorsus est un organisme zoonotique à Gram négatif qui a le potentiel de causer une infection humaine dévastatrice. Par le passé, le traitement aux bêta-lactamines, y compris la pénicilline et la ceftriaxone, était efficace. Méthodologie: L'autrice décrit un cas compliqué de méningite à C. canimorsus chez une femme de 70 ans après une plaie punctiforme superficielle causée par la morsure de son chien. Résultats: Ce cas a été compliqué par des convulsions après un traitement à la ceftriaxone. C'est également le premier cas déclaré de méningite à C. canimorsus associée à une maladie de moyamoya et une dysplasie fibromusculaire. Conclusions: Les médecins devraient être au courant du risque de C. canimorsus résistant à la ceftriaxone et du faible seuil pour élargir la couverture antimicrobienne en l'absence d'amélioration clinique. Les auteurs soulèvent également la possibilité d'association entre les vasculopathies et des infections inhabituelles comme le C. canimorsus.

An umbrella review of the diagnostic value of next-generation sequencing in infectious diseases.

BACKGROUND: An increasing number of systematic reviews (SRs) have evaluated the diagnostic values of next-generation sequencing (NGS) in infectious diseases (IDs). AIM: This umbrella analysis aimed to assess the potential risk of bias in existing SRs and to summarize the published diagnostic values of NGS in different IDs. METHOD: We searched PubMed, Embase, and the Cochrane Library until September 2023 for SRs assessing the diagnostic validity of NGS for IDs. Two investigators independently determined review eligibility, extracted data, and evaluated reporting quality, risk of bias, methodological quality, and evidence certainty in the included SRs. RESULTS: Eleven SRs were analyzed. Most SRs exhibited a moderate level of reporting quality, while a serious risk of bias was observed in all SRs. The diagnostic performance of NGS in detecting pneumocystis pneumonia and periprosthetic/prosthetic joint infection was notably robust, showing excellent sensitivity (pneumocystis pneumonia: 0.96, 95% CI 0.90-0.99, very low certainty; periprosthetic/prosthetic joint infection: 0.93, 95% CI 0.83-0.97, very low certainty) and specificity (pneumocystis pneumonia: 0.96, 95% CI 0.92-0.98, very low certainty; periprosthetic/prosthetic joint infection: 0.95, 95% CI 0.92-0.97, very low certainty). NGS exhibited high specificity for central nervous system infection, bacterial meningoencephalitis, and tuberculous meningitis. The sensitivity to these infectious diseases was moderate. NGS demonstrated moderate sensitivity and specificity for multiple infections and pulmonary infections. CONCLUSION: This umbrella analysis indicates that NGS is a promising technique for diagnosing pneumocystis pneumonia and periprosthetic/prosthetic joint infection with excellent sensitivity and specificity. More high-quality original research and SRs are needed to verify the current findings.

Targeted Six-Week Intensive Physiotherapy for a Case of Tuberculous Meningitis With a Syndrome of Inappropriate Antidiuretic Hormone Secretion.

Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis (TB) characterized by the invasion of Mycobacterium tuberculosis into the meninges surrounding the brain and spinal cord. It triggers an intense inflammatory response, leading to neurological complications if not promptly and adequately managed. TBM often precipitates muscle weakness, neurological deficits, respiratory challenges, swallowing difficulties, joint contractures, and pain. Physiotherapy intervention is essential in treating these problems by personalized treatment strategies and treatment plans to enhance muscle strength, motor control, coordination, and overall mobility. This case report aims to highlight the significant role of physiotherapy in improving the quality of life (QOL) and functional abilities of patients with TBM. The current case report reviews the case of a 73-year-old male who presented with complaints of generalized weakness and difficulty in swallowing. The patient had a history of fever for the last six months. Magnetic resonance imaging (MRI) and high-resolution computed tomography (HRCT) diagnosed the case as TBM with miliary TB. Six weeks of targeted intensive rehabilitation program was designed according to the patient's impairments initiated from the intensive care unit (ICU) phase. The main goals of physiotherapy were to start early bed mobility, maintain joint integrity, improve postural strength and swallowing, and make the patient independent in transfer and activities of daily living (ADLs). After a six-week intensive physiotherapy (TIP-6) program, the patient exhibited significant improvements in muscle strength and independence in ADLs. This case highlights the critical role of physiotherapy in enhancing the QOL and functional abilities of patients with severe TB-related conditions.

Co-occurrence of Tuberculous Meningitis and Intestinal Perforation in Abdominal Tuberculosis (TB): A Report of a Rare Case From Pakistan.

Tuberculosis (TB) remains a significant global health concern, with millions affected worldwide each year. Extrapulmonary TB, particularly involving the digestive tract and central nervous system, poses distinctive difficulties in both diagnosis and treatment. We report a case involving a 15-year-old girl with a history of intestinal TB on anti-tuberculous therapy who presented with symptoms suggestive of meningitis, along with abdominal pain and distension. Our initial suspicion was tuberculous meningitis, considering the underlining abdominal TB, which was later supported by cerebrospinal fluid analysis showing lymphocytic-predominant pleocytosis and positive acid-fast bacilli staining. Concurrently, the patient developed hemodynamic instability and severe abdominal pain, which on repeat X-rays of the abdomen showed air under the diaphragms, prompting surgical exploration and revealing multiple ileal perforations. Histopathological examination confirmed TB as the cause of perforation. This case highlights the diagnostic and therapeutic complexities of concurrent tuberculous meningitis and intestinal TB perforation. Early recognition and interdisciplinary management are crucial for optimal patient outcomes.

Elderly Woman With No Autoimmune Disease With Aseptic Meningitis Caused by Celecoxib.

Nonsteroidal anti-inflammatory drug (NSAID)-induced aseptic meningitis (NIAM) is frequently reported in patients with autoimmune disease. Ibuprofen-induced NIAM is the most common case report of NIAM. We report a patient without autoimmune disease who developed NIAM following oral celecoxib administration. A literature review and survey of cases registered in the Japanese Adverse Drug Event Report (JADER) database is also provided. A 73-year-old woman with no autoimmune disease developed a headache the day after taking celecoxib, and NIAM was suspected. The headache resolved quickly following celecoxib discontinuation. Although lumbar puncture was not available in this case, bacterial or viral meningitis was negative, and NIAM could not be ruled out. This case involved an older adult patient without an autoimmune disease, with celecoxib as the causative NSAID. A literature review found numerous cases of autoimmune diseases in younger patients. To date, only one case of celecoxib-induced NIAM has been reported. Analysis of NIAM cases in JADER revealed an onset time of approximately three days. JADER analysis indicated that NIAM tended to occur immediately after administration, although the onset with cyclooxygenase-2 selective agents might be slower.

Urinary metabolic characterization of advanced tuberculous meningitis cases in a South African paediatric population.

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production-metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort.

Development of Mucoadhesive Microspheres for Intranasal Delivery of Fluconazole as an Alternative Treatment of Cryptococcal Meningitis Infection in Patients with Acquired Immunodeficiency.

Cryptococcal meningitis is a deadly disease with few treatment options. Its incidence is still high and closely linked to the HIV/AIDS epidemic. This study aimed to develop a mucoadhesive microsphere delivery system for fluconazole for the intranasal route. Microspheres of mucoadhesive fluconazole formulation variables, such as different amounts of drug concentration and polymer concentration, were prepared by a simple emulsion-crosslinking method. The prepared microspheres' surface was characterised by SEM (Scanning electron microscopy) and evaluated for particle size, entrapment efficiency, production yield, infrared spectroscopic study, in-vitro mucoadhesion, and in-vitro drug release. The results showed that formula 1 is the optimal mucoadhesive microsphere preparation, with a particle size of 56.375 m, a spherical surface shape, an entrapment efficiency of 99.96%, and a greater mucoadhesive capability during 6-hour evaluation. Furthermore, wash-off examination revealed that the mucoadhesive ability of this delivery system has a long duration and may release the active material at the right time, suggesting that it could be used to treat cryptococcal meningitis infection in HIV / AIDS patients.

Spatio-temporal brain invasion pattern of Streptococcus pneumoniae and dynamic changes in the cellular environment in bacteremia-derived meningitis.

Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by a neuroinflammatory response and the deleterious action of bacterial toxins in the brain. However, little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with the presence of pneumococci closely associated to the microvasculature. In the hippocampus, the invasion provoked microglial activation, while the neurogenic niche showed increased proliferation and migration of neuroblasts. Our results indicate that, even before the outbreak of symptoms, the bacterial load throughout the brain is high and causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.