Imaging panorama of pediatric central nervous system tuberculosis.

Central nervous system tuberculosis (CNS TB) is the most dreaded manifestation of systemic tuberculosis in the pediatric age group. It is associated with high morbidity and mortality due to severe neurological complications and sequelae. Knowledge about the imaging spectrum of CNS TB will help in early presumptive diagnosis and prompt treatment, reducing the development of complications. Imaging also plays a vital role in monitoring the progression of disease after the initiation of antituberculosis therapy. Advanced magnetic resonance imaging (MRI) techniques have recently improved the diagnostic efficacy manifold.In this review, we describe the imaging characteristics, the role of advanced imaging techniques, and follow-up imaging in various types of CNS TB in the pediatric population.

Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review.

BACKGROUND: Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1 month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids. METHODS: Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18 years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020. RESULTS: We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19-49 years old), developed a paradoxical manifestation within 4-14 weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response. CONCLUSIONS: This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.

Clinical Outcome of Tuberculous Meningitis with Hydrocephalus - A Retrospective Study.

BACKGROUND: To study the clinical outcome of tuberculous meningitis with hydrocephalus (TBMH) and the factors contributing to its poor clinical outcome. METHODS: Clinical data of 143 adult patients diagnosed with TBM over a 6-year period in two tertiary hospitals in Malaysia were retrospectively reviewed. Relevant clinical and radiological data were studied. Patients with TBMH were further analysed based on their clinical grade and rendered treatment to identify associated factors and outcome of this subgroup of patients. The functional outcome of patients was assessed at 12 months from treatment. RESULTS: The mean age of patients was 35.6 (12.4) years old, with a male gender predominance of 67.1%. Forty-four percent had TBMH, of which 42.9% had surgical intervention. In the good modified Vellore grade, 76.5% was managed medically with concurrent anti-tuberculosis treatment (ATT), steroids and osmotic agents. Four patients had surgery early in the disease as they did not respond to medical therapy and reported a good outcome subsequently. Poor outcome (65.2%) was seen in the poor modified Vellore grade despite medical and surgical intervention. Multivariate model multiple Cox regression showed significant results for seizure (adjusted hazard ratio [aHR]: 15.05; 95% CI: 3.73, 60.78), Glasgow coma scale (GCS) (aHR: 0.79; 95% CI: 0.70, 0.89) and cerebrospinal fluid (CSF) cell count (aHR: 1.11; 95% CI: 1.05, 1.17). CONCLUSION: Hydrocephalus was seen in 44% of patients in this study. GCS score, seizure and high CSF cell count were factors associated with a poor prognosis in TBM. Patients with TBMH treated medically (TBMHM) had better survival function compared to TBMH patients undergoing surgical intervention (TBMHS) (P-value < 0.001). This retrospective study emphasises that TBMH is still a serious illness as 47.6% of the patients had poor outcome despite adequate treatment.

Tuberculosis: Cliché or Outsider?

Tuberculosis is an infectious disease with the potential for multisystemic dissemination, including the central nervous system (CNS). It is difficult to diagnose when the central nervous system is involved. Brain biopsy is the diagnostic method par excellence for diagnostic confirmation; however, as it is an invasive method and therefore not free from risks, before carrying it out, extra-CNS sites should be privileged, whenever available, through mycobacteriological culture. Here, we present a case of a 34-year-old female with chronic onset of neurologic semiology, whose diagnostic evolution culminated in the diagnosis of cerebral tuberculomas and miliary tuberculosis. Rapid commencement of antibacillaty therapy led to the resolution of the neurologic deficits. Although we face a cliché clinical presentation, in the sense that is very common, the authors consider it outsider because such a presentation is rarely seen in Portugal.

Revisiting the tubercular zone: A poor prognostic finding on neuroimaging.

Central nervous system tuberculosis accounts for approximately 1-2% of cases but with a high morbidity and mortality burden. A 37-year-old female presented with fever and headache for 15 days followed by altered sensorium with associated dystonic posturing of both upper limbs and lower limbs (left>right side). The patient's condition deteriorated despite optimal antitubercular treatment and other supportive measures for two weeks. An MRI brain was suggestive of areas of diffusion restriction in the right caudate nucleus, anterior limb of internal capsule, genu, and anteromedial thalamus. The patient ultimately succumbed to death. Tubercular zone infarctions carry an ominous prognosis and can be considered an indicator of morbidity and mortality in patients with tuberculous meningitis (TBM).

Persistence Pays: Diagnosing Tuberculous Meningitis after 11 Negative Polymerase Chain Reaction Evaluations.

Managing tuberculous meningitis (TBM) is challenging because of its poor prognosis and the difficulty in making an early diagnosis due to the low sensitivity of cerebrospinal fluid (CSF) polymerase chain reaction (PCR) evaluations. A 75-year-old woman presented with fatigue and multiple enlarged lymph nodes and was initially suspected of having metastatic cancer of unknown primary origin. Differential diagnoses included carcinomatous meningitis, neurosarcoidosis, and TBM, as suggested by the presence of multiple enhancing cerebral nodules. Despite 11 negative PCR evaluations, including nested PCR of CSF and biopsied lymph nodes within the first 3 days of empirical anti-tubercular treatment, TBM was eventually confirmed by CSF cultures 32 days later. This case highlights the need for repeated sampling.

Comprehensive Case Analysis of Tuberculous Meningitis in an Immunocompetent Patient: Diagnostic Challenges and Therapeutic Strategies.

Tuberculosis (TB) continues to be a significant global health concern, with India contributing substantially to the global burden. The management of TB is further complicated by HIV-associated immunodeficiency and the emergence of drug-resistant TB strains. Early diagnosis and treatment are critical, particularly for tubercular meningitis (TBM), which is among the most severe forms of extrapulmonary TB. We present the case of a 55-year-old male who arrived at our emergency department with a one-week history of fever, headache, incoherent speech, and slurred speech. The patient had no relevant medical history or known contact with TB patients. Neurological examination revealed ptosis of the right eye and a left extensor plantar response. Laboratory investigations revealed a miliary pattern on chest radiography, and cerebrospinal fluid analysis showed an adenosine deaminase (ADA) level of 14.4 U/L, a total cell count of 110/mm³, glucose of 6 mg/dL, and protein of 228.4 mg/dL, supporting the diagnosis of TBM. Magnetic resonance imaging (MRI) indicated brain lesions consistent with TBM. TBM represents the most devastating form of extrapulmonary TB if left untreated. Therefore, prompt initiation of antitubercular therapy and continued vigilance in endemic regions are essential for addressing this complex global health issue.

Outcomes of central nervous system tuberculosis in Saudi Arabia: a multi-center study.

OBJECTIVES: Central nervous system tuberculosis (TB) (CNS-TB) can occur in several forms, including intracranial tuberculoma, tuberculous brain abscess, TB meningitis (TBM), and spinal TB. Early treatment can save lives and prevent severe neurological complications. This study aimed to describe the characteristics and post-treatment outcomes of patients with CNS-TB and identify factors associated with poor outcomes. To the best of our knowledge, this is the largest CNS-TB study till date published in Saudi Arabia. METHODS: This retrospective cohort study included all patients diagnosed with CNS-TB in three tertiary centers in Saudi Arabia (King Abdulaziz Medical City in Jeddah, King Abdulaziz Medical City in Riyadh, and Al-Noor Specialist Hospital in Makkah) between 2009 and 2019. Data of patients' demographics, co-morbidities, presenting symptoms, type of CNS-TB, medical and surgical treatments, and outcome after completion of treatment were obtained from medical records. Treatment outcomes were categorized using the modified Rankin Scale for neurological disability. RESULTS: A total of 140 participants were included in this study from 2009 to 2019. Good outcomes were achieved in approximately 65% of cases, whereas 35% had poor outcomes based on the modified Rankin Scale. Glasgow Coma Scale score ≤10 at presentation and TBM/tuberculoma were significantly associated with poor outcomes. Moreover, the use of corticosteroids, more than three anti-TB medications, and surgical interventions were not significantly associated with good or poor outcomes. DISCUSSION: CNS-TB is associated with a high burden of long-term neurological morbidity. Early detection and treatment are crucial to prevent serious complications and decrease morbidity and mortality.

Cerebral Tuberculosis After Therapy With Adalimumab for Hidradenitis Suppurativa: A Rare Case.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited therapeutic options. Adalimumab, an anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody, was the first biological agent approved for the treatment of moderate to severe HS. Tuberculosis (TB) is a highly prevalent global public health problem, affecting individuals worldwide. Continuous immunosuppression from TNF-α treatment increases the risk of TB development. Isolated neurotuberculosis, in the absence of other symptoms, emerges as a rarely observed infection pattern in such patients. We present a case of a 23-year-old woman with severe HS undergoing treatment with adalimumab. After two years, she developed a pronounced occipital tension headache, constant nausea, and persistent fever. The patient's latent TB status was unknown without annual screening. Subsequent magnetic resonance imaging revealed a lesion in the cerebellar vermis. Immunosuppressive therapy was suspended and an etiological study was conducted; the only positive result was the interferon-gamma release assay. Empirically, antituberculosis treatment and prednisolone were initiated, leading to clinical and neurological improvement. After one year of treatment, symptoms resolved without neurological sequelae. This case highlights the importance of vigilant monitoring before, during, and after immunosuppressive treatment. Early recognition, discontinuation of anti-tumor necrosis factor medications, and appropriate management of TB are crucial to prevent complications.

Numerous Asymptomatic Brain Tuberculomas Complicated by Fatal Tuberculous Meningitis.

Tuberculosis (TB) is still one of the most challenging infectious diseases worldwide. Coinfection with HIV increases the likelihood of extrapulmonary involvement, including the tuberculosis of the central nervous system (CNS-TB). CNS-TB often presents as tuberculomas or tuberculous meningitis. Although tuberculomas can be single or multiple, asymptomatic carriage of numerous tuberculomas is seldom reported. We present a case of a 55-year-old man who carried at least 34 tuberculomas of different sizes asymptomatically before developing and succumbing to tuberculous meningitis. Furthermore, we highlight several possible public health challenges that might have complicated his clinical course, suggesting that future studies also focus on these variables alongside more traditional clinical issues.

Pediatric Neurotuberculosis: A cases series and review of the literature.

Neurotuberculosis or central nervous system tuberculosis is a form of tuberculous infection that affects any part of the nervous system. Although it is more frequent in adults, pediatric cases have been reported in endemic countries and it is potentially a deadly affection. Therefore, any unusual neurological manifestation in a formerly healthy child, independently of their vaccination status, must bring suspicion of CNS tuberculosis among other diagnoses. We report four cases of pediatric neurotuberculosis with various clinical presentations and outcome and a brief review of the litterature. We conclude that clinical manifestations of pediatric neurotuberculosis are extremely variable and could be misleading. Extra-neurological sites are a key element for diagnosis especially in the pediatric population. A diagnosis and clinical outcome score, especially designed for children might help personalize the therapeutic approach and outcome measures.

Nanoparticle delivery through the BBB in central nervous system tuberculosis.

Recent advances in Nanotechnology have revolutionized the production of materials for biomedical applications. Nowadays, there is a plethora of nanomaterials with potential for use towards improvement of human health. On the other hand, very little is known about how these materials interact with biological systems, especially at the nanoscale level, mainly because of the lack of specific methods to probe these interactions. In this review, we will analytically describe the journey of nanoparticles (NPs) through the brain, starting from the very first moment upon injection. We will preliminarily provide a brief overlook of the physicochemical properties of NPs. Then, we will discuss how these NPs interact with the body compartments and biological barriers, before reaching the blood-brain barrier (BBB), the last gate guarding the brain. Particular attention will be paid to the interaction with the biomolecular, the bio-mesoscopic, the (blood) cellular, and the tissue barriers, with a focus on the BBB. This will be framed in the context of brain infections, especially considering central nervous system tuberculosis (CNS-TB), which is one of the most devastating forms of human mycobacterial infections. The final aim of this review is not a collection, nor a list, of current literature data, as it provides the readers with the analytical tools and guidelines for the design of effective and rational NPs for delivery in the infected brain.

Angiopep-2 Modified Exosomes Load Rifampicin with Potential for Treating Central Nervous System Tuberculosis.

Background: Central nervous system tuberculosis (CNS-TB) is the most devastating form of extrapulmonary tuberculosis. Rifampin (RIF) is a first-line antimicrobial agent with potent bactericidal action. Nonetheless, the blood-brain barrier (BBB) limits the therapeutic effects on CNS-TB. Exosomes, however, can facilitate drug movements across the BBB. In addition, exosomes show high biocompatibility and drug-loading capacity. They can also be modified to increase drug delivery efficacy. In this study, we loaded RIF into exosomes and modified the exosomes with a brain-targeting peptide to improve BBB permeability of RIF; we named these exosomes ANG-Exo-RIF. Methods: Exosomes were isolated from the culture medium of BMSCs by differential ultracentrifugation and loaded RIF by electroporation and modified ANG by chemical reaction. To characterize ANG-Exo-RIF, Western blot (WB), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were performed. Bend.3 cells were incubated with DiI labeled ANG-Exo-RIF and then fluorescent microscopy and flow cytometry were used to evaluate the targeting ability of ANG-Exo-RIF in vitro. Fluorescence imaging and frozen section were used to evaluate the targeting ability of ANG-Exo-RIF in vivo. MIC and MBC were determined through microplate alamar blue assay (MABA). Results: A novel exosome-based nanoparticle was developed. Compared with untargeted exosomes, the targeted exosomes exhibited high targeting capacity and permeability in vitro and in vivo. The MIC and MBC of ANG-Exo-RIF were 0.25 µg/mL, which were sufficient to meet the clinical needs. Conclusion: In summary, excellent targeting ability, high antitubercular activity and biocompatibility endow ANG-Exo-RIF with potential for use in future translation-aimed research and provide hope for an effective CNS-TB treatment.

Paradoxical Reaction to Antitubercular Treatment in a Case of Tuberculous Meningitis.

Tuberculous meningitis (TBM) is a challenging disease to treat, as Mycobacterium tuberculosis infects the meninges, which are the outer membranes of the brain and the spinal cord. The majority of patients diagnosed with TBM acquire various other central nervous system complications, and as a result, treating the disease becomes a challenging task. A paradoxical reaction to the treatment may occur in the course of managing TBM. This case study describes a 20-year-old Southeast Asian female who was diagnosed and treated for TBM and subsequently developed a resurgence of the disease due to a paradoxical reaction.

Central Nervous System Tuberculosis in a Murine Model: Neurotropic Strains or a New Pathway of Infection?

Tuberculosis (TB) of the central nervous system (CNS) is a lethal and incapacitating disease. Several studies have been performed to understand the mechanism of bacterial arrival to CNS, however, it remains unclear. Although the interaction of the host, the pathogen, and the environment trigger the course of the disease, in TB the characteristics of these factors seem to be more relevant in the genesis of the clinical features of each patient. We previously tested three mycobacterial clinical isolates with distinctive genotypes obtained from the cerebrospinal fluid of patients with meningeal TB and showed that these strains disseminated extensively to the brain after intratracheal inoculation and pulmonary infection in BALB/c mice. In this present study, BALB/c mice were infected through the intranasal route. One of these strains reaches the olfactory bulb at the early stage of the infection and infects the brain before the lungs, but the histological study of the nasal mucosa did not show any alteration. This observation suggests that some mycobacteria strains can arrive directly at the brain, apparently toward the olfactory nerve after infecting the nasal mucosa, and guides us to study in more detail during mycobacteria infection the nasal mucosa, the associated connective tissue, and nervous structures of the cribriform plate, which connect the nasal cavity with the olfactory bulb.

A Rare Diagnosis of Aseptic Hypertrophic Pachymeningitis: A Case of Mycobacterial Tuberculosis Origin.

Tubercular meningitis is a rare yet devastating type of extrapulmonary tuberculosis (TB) posing great diagnostic challenges due to the nonspecific clinical presentation of the patients. Here, we present a rare diagnosis of hypertrophic pachymeningitis due to Mycobacterium tuberculosis. A 36-year-old male presented with a history of headaches and giddiness for one month. Neurological examination revealed hypo-reflexive triceps and ankle reflexes. Routine blood tests and autoimmune workup were normal. Brain MRI with contrast revealed diffuse dural thickening, focal leptomeningeal enhancement in the right temporal sulci, and enhancement in both the frontal and parietal convexity and the falx cerebri and along the tentorium cerebelli. Cerebrospinal fluid (CSF) analysis revealed elevated proteins, suggestive of aseptic meningitis. Meningeal biopsy revealed a chronic ill-formed granulomatous inflammatory lesion with occasional acid-fast bacilli, consistent with tubercular pachymeningitis. The patient was administered intravenous (IV) methylprednisolone for five days, following which the symptoms subsided. He was advised tablet prednisolone on discharge, and immunomodulation with rituximab was recommended as outpatient treatment. Hypertrophic pachymeningitis is a rare diagnosis characterized by the inflammation and fibrosis of the dura matter due to a diverse etiology. Tubercular etiology must be considered when the routine laboratory tests are negative, and the diagnosis should be confirmed by meningeal biopsy. The treatment of the underlying cause and corticosteroids remain the mainstay management of hypertrophic pachymeningitis. Hence, mycobacterial tuberculosis should be considered as a possible differential diagnosis while evaluating hypertrophic pachymeningitis, especially when the routine laboratory tests and immunological workup are negative.

Central Nervous System Tuberculosis: Risk Factors for Mortality in a Propensity Score-Matched Case-Control Study.

Background: Despite advancements in tuberculosis (TB) control and treatment in the United States (US), patients with central nervous system TB (CNS-TB) continue to experience significantly higher mortality rates than those without CNS-TB. This raises concerns regarding clinical management and the need for a deeper understanding of the risk factors contributing to these deaths. This study aimed to determine the predictors of mortality in patients with CNS-TB. Methods: We conducted a retrospective 1:2 propensity score-matched case-control study. Cases were TB patients diagnosed with TB of the meninges, brain, spinal cord, or peripheral nerves, as documented in the Florida Department of Health (FDOH) TB registry, between 2009 and 2021. Controls were TB patients without CNS-TB, also reported in the FDOH TB registry during the same timeframe. We employed conditional logistic regression models to investigate the factors contributing to mortality in cases compared with controls. Results: We analyzed data from 116 cases and 232 matched controls. Patients with CNS-TB had a 5.69-fold higher risk of death than those without CNS-TB (adjusted odds ratio [aOR], 5.69 [95% confidence interval {CI}, 2.91-11.6]). Increased risk of death was associated with human immunodeficiency virus (HIV) coinfection (aOR, 1.93 [95% CI, .82-4.37]) and diabetes (aOR, 3.13 [95% CI, 1.28-7.47]). Miliary TB and non-HIV immunosuppression were significantly associated with being a case, while cavitary TB was less likely to be associated with being a case. Conclusions: Clinical management should prioritize screening and close monitoring of patients with HIV coinfection and diabetes to improve patient outcomes.

Central nervous system tuberculosis in immunocompetent patients: Two case reports with literature review.

Central nervous system tuberculosis (CNS) is a rare but extremely dangerous condition that has been reported in 5%-10% of extrapulmonary tuberculosis cases and accounts for approximately 1% of all tuberculosis cases. We present 2 cases of isolated central system tuberculosis in immunocompetent patients: a 57-year-old female and a 22-year-old young man, both of whom had MRI findings consistent with meningitis and tuberculomas and were complicated by cerebral ischemic infarction in the second case. Despite delaying therapy, both patients who had positive TB tests (PCR and QuantiFERON-TB Gold) nevertheless demonstrated clinical improvement. Although central nervous system tuberculosis has a high mortality rate and a high level of neurological morbidity, diagnosing it remains difficult because clinical symptoms and radiological findings can mimic other conditions such as pyogenic abscess, toxoplasmosis, sarcoidosis, and malignancy.

Lessons learned from a fatal case of tuberculous meningitis with a rapid decline in an infant.

Tuberculous meningitis is a highly lethal, often underrecognized disease with characteristic clinical and imaging features which can be cured if the diagnosis and subsequent treatment are begun at early stages. Frequently, there is a delayed diagnosis of this condition due to unfamiliarity of clinicians in non-endemic areas about its presentation and diagnostic workup. This article presents a case of rapid decline and fatality due to tuberculous meningitis in an 11-month-old child from a non-TB-endemic area and describes the characteristic clinical presentation, imaging findings, and diagnostic pitfalls associated with this condition.

Cycloserine-Induced Insomnia and Psychosis in Multidrug-Resistant Pulmonary Tuberculosis - A Case Report.

Tuberculosis (TB) is a highly infectious disease due to Mycobacterium tuberculosis. The disease presents as drug-sensitive or drug-resistant TB (DR-TB). DR-TB could be of various types like isoniazid mono-resistant, multidrug-resistant tuberculosis (MDR-TB), MDR-rifampicin mono-resistant (MDR-RR), extensively drug-resistant TB (XDR-TB), or pre-extensively drug-resistant TB (pre-XDR-TB). Management of DR-TB is challenging mainly due to longer treatment duration, high pill burden, and adverse drug reactions (ADR) to the second-line anti-TB drugs. Some of these could be life-threatening and require immediate care. Herein, a case of ADR caused by cycloserine in a pulmonary MDR-TB case is presented. All the antitubercular drugs were put on hold, and the symptoms disappeared, only to reappear with the rechallenge of cycloserine. It is emphasized here that a high degree of suspicion with immediate management is imperative to avoid fatal outcomes.