Surgery for Central Nervous System Tuberculosis in Children.

Tuberculosis (TB) is the second most common cause of death due to a single infectious agent worldwide after COVID-19. Central nervous system tuberculosis is widely prevalent in the world, especially in the developing countries and continues to be a socioeconomic problem. It is highly devastating form of tuberculosis leading to unacceptable levels of morbidity and mortality despite appropriate antitubercular therapy. The clinical symptoms are varied and nonspecific. They can be easily overlooked. Tuberculous meningitis is the most common presentation and its sequelae viz. vasculitis, infarction and hydrocephalus can be devastating. The ensuing cognitive, intellectual, and endocrinological outcome can be a significant source of morbidity and mortality, especially in resource constrained countries. Early diagnosis and treatment of tuberculous meningitis and institution of treatment is helpful in limiting the course of disease process. The diagnosis of CNS tuberculosis remains a formidable diagnostic challenge. The microbiological methods alone cannot be relied upon. CSF diversion procedures need to be performed at the appropriate time in order to achieve good outcomes. Tuberculous pachymeningitis and arachnoiditis are morbid sequelae of tuberculous meningitis. Tuberculomas present as mass lesions in the craniospinal axis. Tuberculous abscess can mimic pyogenic abscess and requires high index of suspicion. Calvarial tuberculosis is seen in children and responds well to antituberculous chemotherapy. Tuberculosis of the spinal cord is seen similar to intracranial tuberculosis in pathogenesis but with its own unique clinical manifestations and management. Multidrug-resistant tuberculosis is a formidable problem, and alternate chemotherapy should be promptly instituted. The pathogenesis, clinical features, diagnosis, and management of central nervous system tuberculosis in children are summarized. Heightened clinical suspicion is paramount to ensure prompt investigation. Early diagnosis and treatment are essential to a gratifying outcome and prevent complications.

Neurotuberculosis: A mystery seeking it's answers in pulmonary tuberculosis.

Neurotuberculosis remains a mystery and presents a formidable challenge in diagnosis and management. While pulmonary tuberculosis has a well understood pathophysiology and well researched management strategies, CNS tuberculosis still has plenty of unanswered questions. The purpose of this review is to highlight the debatable issues in the current understanding of the clinical, diagnostic, and therapeutic aspects of Neurotuberculosis.

Pediatric and adult meningeal, parenchymal, and spinal tuberculosis: A neuroimaging review.

Neurotuberculosis is defined as a tuberculous infection of the meninges, brain parenchyma, vessels, cranial and spinal nerves, spinal cord, skull, and spine that can occur either in a localized or in a diffuse form. It is a heterogeneous disease characterized by many imaging appearances and it has been defined as "the great mimicker" due to similarities with many other conditions. The diagnosis of central nervous system (CNS) tuberculosis (TB) is based on clinical presentation, neuroimaging findings, laboratory and microbiological findings, and comprehensive evaluation of the response to anti-TB drug treatment. However, the absence of specific symptoms, the wide spectrum of neurological manifestations, the myriad of imaging findings, possible inconclusive laboratory results, and the paradoxical reaction to treatment make the diagnosis often challenging and difficult, potentially delaying adequate treatment with possible devastating short-term and long-term neurologic sequelae. Familiarity with the imaging characteristics helps in accurate diagnosis and may prevent or limit significantly morbidity and mortality. The goal of this review is to provide a comprehensive up-to-date overview of the conventional and advanced imaging features of CNS TB for radiologists, neuroradiologists, and pediatric radiologists. We discuss the most typical neurotuberculosis imaging findings and their differential diagnosis in children and adults with the goal to provide a global overview of this entity.

Diagnostic validity of MRI for central nervous system tuberculosis: protocol for a systematic review and meta-analysis.

INTRODUCTION: Central nervous system tuberculosis (CNSTB) is a severe condition, sometimes associated with a poor prognosis. Early diagnosis of CNSTB remains challenging, considering that conventional methods lack sensitivity or might lead to certain side effects. Herein, we presented a protocol for a systematic review and meta-analysis to assess the diagnostic efficacy of MRI for CNSTB. METHODS AND ANALYSIS: SinoMed, Wanfang database, China National Knowledge Infrastructure, Embase, the Cochrane Library and PubMed will be searched to identify studies reporting on the use of MRI in the diagnosis of CNSTB from database inception to December 2023. The following keywords will be applied: 'Intracranial tuberculosis', 'Cerebral tuberculosis', 'Central nervous system tuberculosis', 'Spinal tuberculous arachnoiditis' and 'Magnetic Resonance Imaging'. Studies that evaluate the diagnostic accuracy of MRI for the diagnosis of CNSTB and report clear reference criteria will be included. Studies from which full true positive, false positive, false negative and true negative values cannot be extracted, those published in languages other than English or Chinese, abstracts not reporting the full text, and case reports will be excluded. Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) will be used to evaluate the methodological quality of each included study. Stata V.15.0 and RevMan V.5.3 will be used to perform a meta-analysis and generate forest plots and summary receiver operating characteristic curves. In case of significant heterogeneity between studies, possible sources of heterogeneity will be explored through subgroup and meta-regression analyses. ETHICS AND DISSEMINATION: This research is based on public databases and does not require ethical approval. Results will be submitted for publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023415690.

Distinguishing clinical characteristics of central nervous system tuberculosis in immunodeficient and non-immunodeficient individuals: a 12-year retrospective study.

BACKGROUND: Central nervous system tuberculosis (CNS TB) is a severe Mycobacterium tuberculosis (MTB) infection. It is unclear whether a patient's immune status alters the clinical manifestations and treatment outcomes of CNS TB. METHODS: Between January 2007-December 2018, chart reviews of CNS TB, including tuberculous meningitis (TBM), tuberculoma/abscess, and TB myelitis, were made. Subjects were categorized as immunodeficient (ID) and non-immunodeficient (NID). RESULTS: Of 310 subjects, 160 (51.6%) were in the ID group-132 (42.6%) had HIV and 28 (9.0%) had another ID, and 150 (48.4%) were in the NID group. The mean age was 43.64 ± 16.76 years, and 188 (60.6%) were male. There were 285 (91.9%) TBM, 16 (5.2%) tuberculoma/abscess, and 9 (2.9%) myelitis cases. The TBM characteristics in the ID group were younger age (p = 0.003), deep subcortical location of tuberculoma (p = 0.030), lower hemoglobin level (p < 0.001), and lower peripheral white blood cell count (p < 0.001). Only HIV individuals with TBM had an infection by multidrug-resistant MTB (p = 0.013). TBM mortality was varied by immune status -HIV 22.8%, other ID 29.6%, and NID 14.8% (p < 0.001). Factors significantly associated with unfavorable outcomes in TBM also differed between the HIV and NID groups. CONCLUSIONS: TBM is the most significant proportion of CNS TB. Some of the clinical characteristics of TBM, such as age, radiographic findings, hematological derangement, and mortality, including factors associated with unfavorable outcomes, differed between ID and non-ID patients.

Time Elapsed from onset of symptoms to antituberculosis treatment in children with central nervous system tuberculosis in a tertiary hospital in South India: A mixed-methods pilot study.

A pilot study with a mixed-methods design was conducted to estimate the time for tuberculosis (TB) treatment initiation and associated factors among children with central nervous system-TB (CNS-TB). A total of 38 children were enrolled for the quantitative component, and 20 in-depth interviews were conducted. The median duration (interquartile range) from onset of symptoms to treatment initiation was 23 (11, 55) days. About 44% and 31% of the children presented with Stage II and Stage III of CNS-TB, respectively. The major reasons for delay were symptoms not taken seriously (50%) and too many referrals (21%). About 89% of the families went into catastrophic health expenditure due to the disease. The treatment delay may be due to both patient delay and health system delay. Tailoring approaches to target the pediatric population could further improve early detection and treatment initiation of CNS-TB.

Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.

BACKGROUND: Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. METHODS: We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. RESULTS: Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. CONCLUSIONS: Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.

Diagnostic Dilemma of Central Nervous System Tuberculosis with Neurocysticercosis and Neurosarcoidosis: A Case Report.

Multiple ring-enhancing lesions are commonly encountered abnormalities in neuroimaging. There are many differentials for such lesions as infections, neoplasms, vascular lesions, inflammatory and demyelinating conditions, and granulomatous diseases. In developing countries, tuberculoma and neurocysticercosis are the two important etiologies to be considered. This case report illustrates how multiple ring-enhancing lesions can lead to our management in one direction while the true diagnosis remains elusive. A 53-year-old male who presented with a headache was initially diagnosed and treated as neurocysticercosis, then neurosarcoidosis ultimately turned out to be a case of Central Nervous System Tuberculosis on further evaluation. Consideration of only clinical scenarios and neurological imaging can lead to diagnostic inaccuracy, mismanagement and poor outcome, therefore, other supporting lab investigations should be considered for making a correct diagnosis. Keywords: brain; case reports; neurocysticercosis; sarcoidosis; tuberculoma.

Tuberculosis revisted: classic imaging findings in childhood.

Tuberculosis (TB) remains one of the major public health threats worldwide, despite improved diagnostic and therapeutic methods. Tuberculosis is one of the main causes of infectious disease in the chest and is associated with substantial morbidity and mortality in paediatric populations, particularly in low- and middle-income countries. Due to the difficulty in obtaining microbiological confirmation of pulmonary TB in children, diagnosis often relies on a combination of clinical and radiological findings. The early diagnosis of central nervous system TB is challenging with presumptive diagnosis heavily reliant on imaging. Brain infection can present as a diffuse exudative basal leptomeningitis or as localised disease (tuberculoma, abscess, cerebritis). Spinal TB may present as radiculomyelitis, spinal tuberculoma or abscess or epidural phlegmon. Musculoskeletal manifestation accounts for 10% of extrapulmonary presentations but is easily overlooked with its insidious clinical course and non-specific imaging findings. Common musculoskeletal manifestations of TB include spondylitis, arthritis and osteomyelitis, while tenosynovitis and bursitis are less common. Abdominal TB presents with a triad of pain, fever and weight loss. Abdominal TB may occur in various forms, as tuberculous lymphadenopathy or peritoneal, gastrointestinal or visceral TB. Chest radiographs should be performed, as approximately 15% to 25% of children with abdominal TB have concomitant pulmonary infection. Urogenital TB is rare in children. This article will review the classic radiological findings in childhood TB in each of the major systems in order of clinical prevalence, namely chest, central nervous system, spine, musculoskeletal, abdomen and genitourinary system.

Neuroimaging of central nervous system tuberculosis.

A 20-month-old female, not immunized with Bacillus Calmette-Guérin (BCG) vaccine, was admitted due to a four-day history of fever and cough. In the past three months, she presented respiratory infections, weight loss and enlarged cervical lymph nodes. On day two of admission, she displayed drowsiness and positive Romberg's sign; cerebrospinal fluid (CSF) workout revealed 107/ul cells, low glucose and high protein levels. Ceftriaxone and acyclovir were initiated, and she was transferred to our tertiary hospital. Brain magnetic resonance imaging showed punctiform focal areas of restricted diffusion in left capsular lenticular region suggestive of vasculitis secondary to infection. Tuberculin skin test and interferon-gamma release assay were positive. She started tuberculostatic therapy, but two days later she presented tonic-clonic seizures and impaired consciousness. Cerebral computed tomography (CT) revealed tetrahydrocephalus (Figure 1), needing external ventricular derivation. She had a slow clinical improvement, requiring several neurosurgical interventions and developing a syndrome of inappropriate antidiuretic secretion alternating with cerebral salt wasting. Positive results for Mycobacterium tuberculosis were obtained by CSF culture and by polymerase chain reaction in CSF, bronchoalveolar lavage and gastric aspirate specimens. Repeated brain CT showed a large-vessel vasculitis with basal meningeal enhancement, typical of central nervous system (CNS) tuberculosis (Figure 2). She completed one month of corticosteroids and maintained antituberculosis treatment. At two years of age, she has spastic paraparesis and no language skills. Portugal had 1836 cases of tuberculosis (17.8 per 100000) in 2016 and was considered a low-incidence country; consequently, BCG vaccination is not universal (1). We present a severe case of CNS tuberculosis with intracranial hypertension, vasculitis and hyponatremia, associated with poorer outcomes (2). A high index of suspicion allowed prompt start of antituberculosis treatment. Diagnosis was corroborated by microbiological positivity and a typical triad in neuroimaging (hydrocephalus, vasculitis and basal meningeal enhancement) (3), which we wish to emphasize.

Seizures and epilepsy associated with central nervous system tuberculosis.

Central nervous system (CNS) tuberculosis is a life-threatening condition that usually presents with seizures, particularly in children and HIV-infected patients. Tuberculous meningitis (TBM) and tuberculomas are the two forms of CNS tuberculosis that can present with seizures. Seizures usually resolve after successful treatment of the underlying infection. However, the success of the treatment is usually based on an early diagnosis. Delay in the treatment of CNS tuberculosis increases the risk of its associated complications, such as stroke. This would lead to the development of epilepsy. Early seizures may be related to meningeal irritation and cerebral edema, whereas late seizures are often associated with structural brain lesions that generally require more advanced and prolonged treatment. Risk factors associated with the development of epilepsy include young age, refractory seizures, tuberculoma, cortical involvement, epileptiform discharges, and residual lesions. Treatment of CNS tuberculosis is based on early initiation of appropriate anti-tuberculous drugs, antiseizure medications, and correction of associated predisposing factors. Finally, further research into the mechanisms of seizures and the development of epilepsy in CNS tuberculosis could help improve management of these conditions.

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.

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.

Central Nervous System Mycobacterium Infection: Tuberculosis and Beyond.

Tuberculosis is a contagious infectious disease caused by Mycobacterium tuberculosis, and is the leading cause of death from a single infectious agent worldwide. Imaging plays an important role in the early diagnosis of central nervous system tuberculosis and may prevent unnecessary morbidity and mortality. This article presents an extensive review of pathogenesis, clinical symptoms, typical and atypical imaging appearances of intracranial and spinal tuberculosis, and advanced imaging of intracranial tuberculosis. Furthermore, we explore central nervous system infection of nontuberculous mycobacteria and leprosy and their imaging findings.

Absence of posterior pituitary bright spot in adults with CNS tuberculosis: A case-control study.

INTRODUCTION: Current diagnostic methods used in Central Nervous System Tuberculosis (CNS TB) are limited by the paucibacillary nature of this form of tuberculosis. Posterior pituitary bright spot (PPBS) refers to an area of T1 hyperintensity in the posterior pituitary in MR imaging of the brain. It is found in 80-90% of healthy children and adults. In children with CNS TB, nearly half have absence of PPBS. This finding has not been described in adults. Our study looked for absence of PPBS in MR imaging and its association with CNS tuberculosis. OBJECTIVE: To study prevalence of the absence of PPBS in patients with CNS tuberculosis when compared to a control group of normal patients. METHODS: This was a retrospective case-control study of 100 patients with CNS tuberculosis and 200 controls (matched in 1:2 ratio) of patients with normal MRI brain. The MRI images were presented to a blinded radiologist in a randomised sequence to report for absence of PPBS. The data was subsequently analysed to look for association of absence of PPBS with CNS tuberculosis. RESULTS: Absence of PPBS (cases (47%), controls (8.5%)) was significantly associated with CNS tuberculosis in (Odds ratio-7.90, 95%CI 4.04-15.44, P-value<0.0001). The specificity, sensitivity, positive predictive value and positive likelihood ratio are 91.5%, 47%, 73.4% and 5.53 respectively. Adding of absence of PPBS as an additional radiological feature in diagnosis of CNS TB increased the sensitivity from 77% to 84%. CONCLUSION: Absence of PPBS is significantly associated with CNS tuberculosis and could be a relatively simple diagnostic aid in the diagnosis of CNS tuberculosis.

Pelvic and central nervous system tuberculosis complicated by a paradoxical response manifesting as a spinal tuberculoma: a case report.

BACKGROUND: The post-partum period is a risk factor for tuberculosis (TB), possibly including the period after miscarriage as illustrated here. This case demonstrates how non-specific symptoms can hide widely disseminated TB. CASE PRESENTATION: A healthy 26-year-old female with a history of recent miscarriage presented to the emergency department with non-specific symptoms of headache, abdominal pain, and sub-acute fevers. She had immigrated to the United States from the Marshall Islands 9 years prior. Two months prior to presentation she had a miscarriage at 18 weeks of pregnancy. On admission, transvaginal ultrasound revealed retained products of conception and abdominal computed tomography revealed findings consistent with tubo-ovarian abscesses and peritonitis. The obstetrics and gynecology service performed dilation and curettage (D&C) to remove retained products of conception. Acid-fast bacilli cultures from cerebrospinal fluid as well as specimens from D&C and intra-abdominal abscesses subsequently all grew TB. She was diagnosed with TB meningitis, peritonitis, endometritis, and tubo-ovarian abscesses. Her treatment course was complicated by a paradoxical response resulting in a spinal tuberculoma causing lower extremity weakness. The tuberculoma was treated with surgical decompression as well as continuation of treatment with anti-tubercular chemotherapy and steroids. CONCLUSION: Disseminated and extrapulmonary TB can present with non-specific symptoms. Recognition of risk factors for TB is critical for prompt diagnostic evaluation and treatment of this deadly disease. A paradoxical reaction needs to be taken into consideration when any new neurological symptoms occur during TB treatment.

Disseminated tuberculosis associated with deficient interleukin-23/tyrosine kinase 2 signalling.

Tuberculosis (TB) remains a significant cause of morbidity and mortality globally. The disseminated form of the disease has a worse prognosis and is commonly associated with primary and acquired immunodeficiency states such as HIV/AIDS, post-organ transplant and malnutrition. However, disseminated TB in the context of isolated impaired cellular responses to interleukin (IL)-23 due to tyrosine kinase 2 (TYK2) deficiency has been rarely reported. We highlight the case of a young woman with pulmonary and central nervous system TB associated with previously undiagnosed IL-23/TYK2 signalling defects causing impaired response to IL-23. A significant clinical improvement was observed after introduction of adjunctive interferon-gamma therapy to her anti-tuberculous medications. This case emphasises the need to broadly evaluate for potential immune deficiencies in poorly responding patients with fully sensitive TB as well as the potential benefits of interferon-gamma therapy in patients with certain immune defects.