Surgical Management of Tuberculosis-related Cerebral Disorders: A Retrospective Single-center Study.

BACKGROUND: Tuberculosis (TB) remains a significant global health concern, with extrapulmonary manifestations, including central nervous system involvement, posing substantial morbidity and mortality. While medical treatment with anti-TB drugs is the mainstay of therapy, certain TB-related cerebral complications, such as hydrocephalus, abscesses, and large symptomatic tuberculomas, may require surgical intervention. This study aimed to evaluate the outcomes of surgical management in patients with TB-related cerebral disorders. METHODS: A retrospective analysis was conducted on 24 patients who underwent surgical intervention for TB-related cerebral disorders, including tuberculomas, hydrocephalus, and abscesses, at a tertiary care center between 2005 and December 2020. Demographic data, clinical presentations, radiological findings, surgical techniques, and treatment outcomes were analyzed. RESULTS: The study cohort had a mean age of 35.8 ± 13.6 years, and the majority (62.5%) were male. Underlying immunodeficiency, primarily HIV infection, was present in 75% of the patients. The most common presenting symptoms were headache (83.3%), focal neurological deficits (75%), and altered mental status (54.2%). Radiological findings revealed 13 (54.2%) tuberculomas, 8 (33.3%) instances of hydrocephalus, and 3 (12.5%) abscesses. VP shunt inserted in 8 (33.3%) cases. Microscopic craniotomy performed in 7 (29.16%) cases. Aspiration through burr hole was done in 3 (12.5%) cases and stereotactic biopsy was performed in 6 (25%) cases. After 12 months of follow-up, favorable outcome achieved in 18 cases (75%) and the mortality occurred in 2 patients (8.3%). Surgical interventions included lesion resection (n = 10), stereotactic biopsy (n = 7), and ventriculoperitoneal (VP) shunt placement (n = 7). At 12-month follow-up, 18 (75%) patients had a favorable outcome, defined as clinical improvement or stabilization. Unfavorable outcomes were observed in 6 (25%) patients, including 2 deaths. CONCLUSION: Surgical management, in conjunction with appropriate anti-TB medical therapy, may be a valuable component of the comprehensive treatment approach for select patients with TB-related cerebral disorders. The favorable outcome rate observed in this study suggests that timely and tailored surgical intervention can contribute to improved patient outcomes. However, larger, prospective, multicenter studies are needed to further elucidate the role and long-term efficacy of surgical management in this patient population.

Development of innovative multi-epitope mRNA vaccine against central nervous system tuberculosis using in silico approaches.

Tuberculosis(TB) of the Central nervous system (CNS) is a rare and highly destructive disease. The emergence of drug resistance has increased treatment difficulty, leaving the Bacillus Calmette-Guérin (BCG) vaccine as the only licensed preventative immunization available. This study focused on identifying the epitopes of PknD (Rv0931c) and Rv0986 from Mycobacterium tuberculosis(Mtb) strain H37Rv using an in silico method. The goal was to develop a therapeutic mRNA vaccine for preventing CNS TB. The vaccine was designed to be non-allergenic, non-toxic, and highly antigenic. Codon optimization was performed to ensure effective translation in the human host. Additionally, the secondary and tertiary structures of the vaccine were predicted, and molecular docking with TLR-4 was carried out. A molecular dynamics simulation confirmed the stability of the complex. The results indicate that the vaccine structure shows effectiveness. Overall, the constructed vaccine exhibits ideal physicochemical properties, immune response, and stability, laying a theoretical foundation for future laboratory experiments.

Effective cerebral tuberculosis treatment via nose-to-brain transport of anti-TB drugs using mucoadhesive nano-aggregates.

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.

Clinical, Laboratory and Radiological Correlates of Xpert MTB/RIF Assay Study in Cerebrospinal Fluid in CNS Tuberculosis.

BACKGROUND: Cerebrospinal fluid (CSF) Xpert MTB/RIF assay is an initial test for the diagnosis of tuberculous meningitis (TBM). Nevertheless, it is not very clear which of the factors govern CSF-Gene Xpert/MTB positivity. OBJECTIVE: Hence, we aimed to assess the relationship, if any, between the clinical, laboratory and radiological parameters of the central nervous system (CNS) tuberculosis patients and the Gene Xpert study in CSF in such patients. METHODS AND MATERIAL: First, we studied 200 patients with CNS tuberculosis according to the case definition, and subsequently, we performed a Gene Xpert study on the CSF of these patients. Then, we correlated the clinical, radiological, and CSF criteria with the Gene Xpert positivity using the univariate binary logistic regression method via SPSS 20 (P-value <0.05). RESULTS: Seventy-five (37.5%) patients (57.3% females) of median 24 years of age, were CSF-Gene Xpert/MTB-positive and 125 (62.5%) patients were negative. The mean duration of illness (P = 0.017), weight loss or failure to thrive (P < 0.001), loss of consciousness or seizure (P = 0.001), signs of meningeal irritation (P = 0.027), stage III of TBM (P < 0.001), evidence of dissemination (P = 0.003), basal exudates (P = 0.004), hydrocephalus (P = 0.018), CSF lymphocytic predominance (P < 0.001), and reduced CSF glucose (P = 0.011) correlated significantly with positive the Gene Xpert/MTB results. Also, Gene Xpert had a sensitivity of 80% and a specificity of 74.84% against culture Xpert. CONCLUSIONS: Xpert MTB/RIF might be more useful in the later stages of the disease and those with more severe disease.

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.

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.

The etiological spectrum of miliary brain lesions: A systematic review of published cases and case series.

OBJECTIVE: This systematic review aimed to evaluate the published cases with miliary brain lesions and their etiological factors, clinical manifestations, diagnostic procedures, and outcomes. METHODS: A comprehensive search of PubMed, Scopus, Embase, and Google Scholar was conducted using the specified search strategy. Eligibility criteria included cases with miliary lesions in the brain confirmed through neuroimaging and various diagnostic procedures. The PRISMA guidelines were followed, and the PROSPERO registration number for the protocol is CRD42023445849. RESULTS: Data from 130 records provided details of 140 patients. Tuberculosis was the primary cause in 93 cases (66.4%), malignancies in 36 cases (25.7%), and other causes accounted for the remaining 11% cases. Tuberculosis patients averaged 35.7 years old, while those with malignancies averaged 55.44 years. Tuberculosis symptoms primarily included fever, headache, and altered sensorium, whereas malignant cases often exhibited progressive encephalopathy, headache, and specific neurological deficits. Distinctive indicators for CNS tuberculosis were choroidal tubercles and paradoxical reactions. Additionally, 63 tuberculosis patients showed miliary lung shadows and 49 had abnormal CSF findings. For the malignancy group, 13 exhibited miliary lung lesions, and 8 had CSF abnormalities. Regarding outcomes, a significant mortality disparity was observed, with 58.3% in the malignancy group, compared to 10.8% in the tuberculosis group and 27.3% in other cases. CONCLUSION: Miliary brain lesions are a crucial imaging abnormality that necessitates prompt work up. In an immunocompromised state, diagnostic possibilities of miliary brain lesions are more varied and often pose a bigger challenge.

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.

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.

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.