Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child.

BACKGROUND: Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens. CASE PRESENTATION: A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. Tracheal aspirate samples for mycobacterial DNA and culture from days 22 and 27 of illness were negative by PCR but grew Mycobacterium tuberculosis after 8 weeks, long after the child's passing. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread. CONCLUSION: The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

Multi-spectral Pattern of Clinical Presentation and the Resultant Outcome in Central Nervous System Tuberculosis: A Single Center Study on the Ubiquitous Pathogen.

Central nervous system (CNS) tuberculosis (TB) is a great medical masquerader having a multi-spectral pattern of clinical presentation, thereby complicating early diagnosis and appropriate management. This review article describes clinical presentation of CNS TB in a group of 47 patients, who were managed in the Nobel Medical College and Teaching Hospital in Biratnagar, Nepal during the last 2 years. We evaluated demographic profile, mode of management, and clinical outcome in these patients. The findings were that intracranial TB was present in 27 (57.5%) patients and the spinal involvement was in 20 (42.5%) patients. The most frequent presentation of the former was TB meningitis with hydrocephalus (55.5%) and that of the latter was Pott's spine with abscess in 50% of cases. TB meningitis with hydrocephalus was the commonest cause of mortality (83.3%) among the patients. CNS TB should be considered in the differential diagnosis in patients presenting with equivocal neurological signs and symptoms, especially in TB endemic regions. It seems prudent to commence early antitubercular therapy for safeguarding such patients from poor neurological outcome as well as mortality it harbingers.

Bacterial Genotyping of Central Nervous System Tuberculosis in South Africa: Heterogenic Mycobacterium tuberculosis Infection and Predominance of Lineage 4.

Tuberculous meningitis (TBM), the most severe extrapulmonary manifestation of tuberculosis, is caused by the pathogen Mycobacterium tuberculosis The M. tuberculosis complex includes seven lineages, all described to harbor a unique geographical dissemination pattern and clinical presentation. In this study, we set out to determine whether a certain M. tuberculosis lineage demonstrated tropism to cause TBM in patients from Cape Town, South Africa. DNA was extracted from formalin-fixed paraffin-embedded central nervous system (CNS) tissue from a unique neuropathological cohort of 83 TBM patients, collected between 1975 and 2012. M. tuberculosis lineages 1, 2, 3, and 4 were determined using an allele-specific PCR and Sanger sequencing. Of the 83 patient specimens tested, bacterial characterization could be performed on 46 specimens (55%). M. tuberculosis lineage 4 was present in 26 patient specimens (56%), and non-lineage 4 was identified in 10 cases (22%). Moreover, genomic heterogeneity was detected in the CNS specimens of 7 adults and 3 children. We could show that infection of the CNS is not restricted to a single M. tuberculosis lineage and that even young children with rapid progression of disease can harbor more than one M. tuberculosis lineage in the CNS.

Cerebral tuberculosis in a patient with systemic lupus erythematosus following cyclophosphamide treatment: a case report.

Central nervous system (CNS) tuberculosis (TB) is a rare but catastrophic event in patients with systemic lupus erythematosus (SLE). Here we report a case of cerebral TB in a patient with lupus myocarditis and nephritis, following cyclophosphamide immunosuppression. To our knowledge this is the first reported case of cerebral TB in SLE in a non-endemic country. A 31-year-old female with SLE and a history of regular travel to Kenya presented to our centre with clinical features of acute heart failure. She was diagnosed with severe lupus myocarditis, and a renal biopsy also confirmed lupus nephritis. Prior to admission, she had also had a cough, fever and weight loss and was under investigation for suspected TB infection. She was treated with ivabradine, beta-blockers and diuretics together with methylprednisolone and cyclophosphamide immunosuppression. Subsequent sputum cultures confirmed TB and she was commenced on triple therapy. Despite this, she developed confusion, dizziness, blurred vision and fluctuating consciousness. Magnetic resonance imaging (MRI) and lumbar puncture revealed CNS TB infection resulting in meningitis. This was later complicated by obstructive hydrocephalus due to TB abscesses. A ventriculoperitoneal (VP) shunt was inserted and TB medications were given intravenously (IV) with dexamethasone. Following a prolonged hospital admission, the patient eventually recovered and rituximab treatment was used to control her SLE. TB infection has been associated with SLE flares. It is likely in this case that TB exacerbated a lupus flare and subsequent immunosuppression resulted in mycobacterial dissemination to the CNS. Systemic and CNS features of TB and SLE are difficult to distinguish and their contemporaneous management represents a diagnostic and therapeutic challenge.

Evaluation of Xpert MTB/RIF for Detection of Mycobacterium tuberculosis in Cerebrospinal Fluid.

Studies investigating Xpert MTB/RIF diagnostic performance on cerebrospinal fluid (CSF) samples are lacking in resource-rich settings. Xpert MTB/RIF results for 740 CSF samples from 698 patients across England were retrospectively compared with the results of culture of the same and contemporary samples. The overall sensitivity was calculated at 55%.

Neurons are host cells for Mycobacterium tuberculosis.

Mycobacterium tuberculosis infection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions of M. tuberculosis with neurons in vitro and in vivo were investigated. The data obtained demonstrate that neurons can act as host cells for M. tuberculosis. M. tuberculosis bacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization of M. tuberculosis bacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalize M. tuberculosis. Internalized M. tuberculosis bacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h. M. tuberculosis bacillus infection of neurons was confirmed in vivo in the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells for M. tuberculosis within the central nervous system.

Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis.

BACKGROUND: Central nervous system disease is the most serious form of tuberculosis, and is associated with high mortality and severe neurological sequelae. Though recent clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with central nervous system disease, the microbial virulence factors required have not been described previously. RESULTS: We screened 398 unique M. tuberculosis mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found M. tuberculosis pknD (Rv0931c) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that pknD is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. M. tuberculosis pknD encodes a "eukaryotic-like" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the M. tuberculosis PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum. CONCLUSIONS: Our findings demonstrate a novel in vivo role for M. tuberculosis pknD and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children.

[Epidural abscess due to a Mycobacterium tuberculosis strain with primary resistance to isoniazid and ethambutol]. / Izoniazid ve Etambutole Primer Dirençli Mycobacterium tuberculosis'e Bagli Epidural Apse.

Tuberculosis is primarily characterized by pulmonary involvement, however, one third of the cases exhibit extrapulmonary tuberculosis. In this report, a case of epidural abscess due to Mycobacterium tuberculosis with primary resistance to isoniazid and ethambutol was presented. A 57-year-old male patient was admitted to emergency service with ten days history of weakness in legs, disability of walking and fever. Neurological examination revealed paraplegia of lower extremities, numbness distal to T2 disc level and hyperactivity of deep tendon reflexes indicating transverse myelitis. Laboratory findings were as follows; ESR: 74 mm/hour, CRP: 22 g/L, ALT: 42 IU/L, AST: 45 IU/L and white blood cell count 23.000/mm3 (45% polymorphonuclear leukocyte, 45% lymphocyte, 10% monocyte). Spinal magnetic resonance imaging showed a fusiform abscess localized at anterior epidural space and extending along levels of C5-6 and C6-7. The longitudinal dimension of the abscess was 3 cm. The lesion was hypointense on T1 and hyperintense on T2 weighted MRI images with prominent rim shaped contrast enhancement on contrast-enhanced T1-weighted images. At fourth day of hospitalization the patient underwent neurosurgical management. M.tuberculosis was isolated from the cultures of operation material by Mycobacteria Growth Incubator Tube system (MGIT, BBL; BD, USA) on the 12th day. The isolate was found susceptible to streptomycin and rifampisin, but resistant to isoniazid and ethambutol. The treatment was initiated with rifampicin 600 mg/day, pyrazinamid 2 g/day, ethambutol 1.5 g/day and levofloxacin 500 mg/day. At the end of second month levofloxacin 500 mg/day and rifampisin 600 mg/day combination was sustained and total treatment period was planned as nine months. As far as the national literature was considered, this was the first case of extrapulmonary tuberculosis with primary resistance to isoniazid and ethambutol.

Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways.

Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

The Use of Murine Infection Models to Investigate the Protective Role of TNF in Central Nervous System Tuberculosis.

Tuberculosis of the central nervous system (CNS-TB) is the most severe form of extra-pulmonary tuberculosis that is often associated with high mortality. Secretion of tumor necrosis factor (TNF) has important protective and immune modulatory functions for immune responses during CNS-TB. Therefore, by combining the approaches of aerosol and intracerebral infection in mice, this chapter describes the methods to investigate the contribution of TNF in protective immunity against CNS-TB infection.

Central nervous system tuberculomas in 23 patients.

Central nervous system tuberculomas are rare and severe complications of tuberculosis. We performed a retrospective study of the clinical, biological, radiological, pathological, and therapeutic features of 23 patients. Almost all patients were from countries with a high prevalence of tuberculosis (22/23). Their mean age was 37.3 y; 43.5% had laboratory-proven meningitis and 17.4% had biopsy-proven tuberculomas. For most of the patients, the duration of treatment lasted 13-18 months. The disease was controlled without relapse in 16 patients and 3 patients died. Diagnosis relies on magnetic resonance imaging and bacteriological specimens from all the involved sites. This study indicates that central nervous system tuberculomas occur in young patients from high risk countries. The anti-tuberculous drug regimen in this series was 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by at least 10 months of isoniazid and rifampin. Results did not contradict the use of a 12-month regimen as currently recommended.

Central nervous system tuberculosis: pathogenesis and clinical aspects.

Tuberculosis of the central nervous system (CNS) is a highly devastating form of tuberculosis, which, even in the setting of appropriate antitubercular therapy, leads to unacceptable levels of morbidity and mortality. Despite the development of promising molecular diagnostic techniques, diagnosis of CNS tuberculosis relies largely on microbiological methods that are insensitive, and as such, CNS tuberculosis remains a formidable diagnostic challenge. Insights into the basic neuropathogenesis of Mycobacterium tuberculosis and the development of an appropriate animal model are desperately needed. The optimal regimen and length of treatment are largely unknown, and with the rising incidence of multidrug-resistant strains of M. tuberculosis, the development of well-tolerated and effective antibiotics remains a continued need. While the most widely used vaccine in the world largely targets this manifestation of tuberculosis, the BCG vaccine has not fulfilled the promise of eliminating CNS tuberculosis. We put forth this review to highlight the current understanding of the neuropathogenesis of M. tuberculosis, to discuss certain epidemiological, clinical, diagnostic, and therapeutic aspects of CNS tuberculosis, and also to underscore the many unmet needs in this important field.

Mycobacterium tuberculosis and Pseudoramibacter alactolyticus coinfection in brain after dental extraction: A case report.

INTRODUCTION: More than 1200 different types of microbes were found in the human mouth, only some of these microorganisms were associated with intracranial bacterial infection. However, there are limited data available about the Pseudoramibacter alactolyticus (P alactolyticus) or Mycobacterium tuberculosis (MTB) intracranial infections oral origin. PATIENT CONCERNS: Here, we reported a rarely case with P alactolyticus and MTB coinfection in central nervous after dental extraction. The 44-year-old man presented with progressive headache over the last 2 weeks and a sustained fever >39°C, with a dental extraction performed 2 days before the onset of headache. DIAGNOSIS: P alactolyticus and MTB were confirmed by real-time polymerase chain reaction targeting the16S ribosomal RNA gene. The presence of MTB was also demonstrated by positive acid-fast staining of the purulent discharge. INTERVENTIONS: The patient was treated by metronidazole and anti-TB treatment OUTCOMES:: The patient fully recovered without sequela. CONCLUSION: In conclusion there should be awareness of the possibility of P alactolyticus or MTB intracranial infections following tooth extraction.

Diagnostic challenges of central nervous system tuberculosis.

Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis.

Challenges of diagnosis and management of tuberculosis and HIV coinfection in resource-limited settings: a case report from Lima, Peru.

We present a Peruvian human immunodeficiency virus (HIV)-positive patient receiving first-line therapy for tuberculosis who presents with neurological complications to highlight some of the major issues in the diagnosis and management of human immunodeficiency virus-related central nervous system complications in resource-poor settings. These include limited options for diagnosing extrapulmonary and drug-resistant tuberculosis; the importance of central nervous system . imaging; and the management conundrum when faced with a broad differential diagnosis. This patient was with drug-resistant tuberculosis of the brain, unmasked by immunologic recovery in the setting of recent initiation of antiretroviral treatment. We argue that aggressive and timely empiric multidrug-resistant tuberculosis treatment is important in cases where drug-resistant tuberculosis is suspected. Knowledge gaps include a limited understanding of immune reconstitution and the optimal timing of antiretroviral treatment in the setting of drug-resistant tuberculosis.

Human tuberculosis brain promotes neuronal apoptosis but not in astrocytes with high expression of vascular endothelial growth factor.

The present study aimed to investigate the involvement of the angiogenic marker vascular endothelia growth factor (VEGF) and apoptotic markers of Bcl-2 and Bax in the neurons and astrocytes in the brain infected by Mycobacterium tuberculosis. The immunohistochemistry staining was performed to analyze the expression of the VEGF, Bcl-2 and Bax in the astrocytes and neurons. The expression of VEGF was high in neurons and astrocytes in both the infected brain and control tissues with no difference of angiogenic activity (p = 0.40). Higher Bcl-2 expression was seen in astrocytes of infected brain tissues compared to the control tissues (p = 0.004) promoted a higher anti-apoptotic activity in astrocytes. The neurons expressed strong Bax expression in the infected brain tissues compared to the control tissues (p < 0.001), which indicated more apoptosis in neurons. Thus, neuronal death and survival of infected astrocytes together with high expression of VEGF might be associated with formation of brain tuberculosis. In conclusion, neurons could be more vulnerable than astrocytes in human tuberculosis brain with high expression of VEGF.