Child with tuberculous meningitis and COVID-19 coinfection complicated by extensive cerebral sinus venous thrombosis

CITATION: Essajee Farida et al. 2020. Child with tuberculous meningitis and COVID-19 coinfection complicated by extensive cerebral sinus venous thrombosis. BMJ Case Reports, 2020:13, doi:10.1136/bcr-2020-238597.The original publication is available at: https://casereports.bmj.comWe herein report a case of a child with tuberculous meningitis and COVID-19 coinfection complicated by hydrocephalus, arterial ischaemic stroke and extensive cerebral sinus venous thrombosis. Both conditions induce a proinflammatory cytokine drive resulting, among others, in a prothrombotic state. The disruption of the coagulation system in this case was supported by elevated D-dimers, fibrinogen and ferritin levels, consistent with thrombotic complications reported in some adult patients infected with COVID-19. The child also exhibited prolonged viral shedding that suggests severe disease.Publisher's versio

The current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved]

CITATION: Seddon, J., et al. 2019. The current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved]. Wellcome Open Research, 4:167, doi:10.12688/wellcomeopenres.15535.1.The original publication is available at https://wellcomeopenresearch.orgTuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.https://wellcomeopenresearch.org/articles/4-167Publisher's versio

Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis [version 1; peer review: 2 approved]

CITATION: Davis, A. G., et al. 2019. Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis [version 1; peer review: 2 approved]. Wellcome Open Research, 4:178, doi:10.12688/wellcomeopenres.15516.1.The original publication is available at https://wellcomeopenresearch.orgENGLISH ABSTRACT: In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.https://wellcomeopenresearch.org/articles/4-178Publisher's versio

Trading Justice for Peace? Reframing reconciliation in TRC processes in South Africa, Canada and Nordic countries

Conflict in its various manifestations continues to be a defining feature in many places throughout the world. In an attempt to address such conflict, various forms of a Truth and Reconciliation Commission (TRC) have been introduced to facilitate the transition from social conflict to a new dispensation. The introduction and subsequent proceedings of TRCs in South Africa, Canada and Norway are widely regarded as good examples of this approach. Against this background, a number of researchers from VID Specialized University and the University of the Western Cape had an exploratory meeting in Oslo in 2018 where the possibility for a joint research project under the broad theme of ‘discourses on reconciliation’ was first discussed. This led to two further research symposia in Cape Town and Tromsø in 2019. With the inclusion of specialists working on the Canadian Truth and Reconciliation process, these meetings demonstrated common ground and a shared understanding of the issues at stake. Moreover, it pointed to the differences between the South African, Canadian and Norwegian Commissions. In comparing the South African, Canadian and Norwegian experiences, researchers identified that these countries were, in fact, at different stages of their respective truth and reconciliation processes. This has prompted scholars to revisit and problematise these processes in relation to ongoing societal challenges. In all cases, it is quite apparent that reconciliation between individuals and groups remains a significant challenge

Trading Justice for Peace? Reframing reconciliation in TRC processes in South Africa, Canada and Nordic countries

Conflict in its various manifestations continues to be a defining feature in many places throughout the world. In an attempt to address such conflict, various forms of a Truth and Reconciliation Commission (TRC) have been introduced to facilitate the transition from social conflict to a new dispensation. The introduction and subsequent proceedings of TRCs in South Africa, Canada and Norway are widely regarded as good examples of this approach. Against this background, a number of researchers from VID Specialized University and the University of the Western Cape had an exploratory meeting in Oslo in 2018 where the possibility for a joint research project under the broad theme of ‘discourses on reconciliation’ was first discussed. This led to two further research symposia in Cape Town and Tromsø in 2019. With the inclusion of specialists working on the Canadian Truth and Reconciliation process, these meetings demonstrated common ground and a shared understanding of the issues at stake. Moreover, it pointed to the differences between the South African, Canadian and Norwegian Commissions. In comparing the South African, Canadian and Norwegian experiences, researchers identified that these countries were, in fact, at different stages of their respective truth and reconciliation processes. This has prompted scholars to revisit and problematise these processes in relation to ongoing societal challenges. In all cases, it is quite apparent that reconciliation between individuals and groups remains a significant challenge

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of &lt;150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts &gt; 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.</ns4:p

Approach to headaches in children

CITATION: Solomons, R., Schoeman, J. & Van Toorn, R. 2011. Approach to headaches in children. Continuing Medical Education, 29(4):171-174.The original publication is available at http://www.cmej.org.zaHeadache is a common problem in childhood – up to 25% of schoolchildren suffer from chronic, recurrent headaches. Although primary headaches are far more common than those with a secondary cause, it is the latter that result in the most anxiety for families.1 A logical approach to investigating and managing headaches is needed.http://www.cmej.org.za/index.php/cmej/article/view/2162Publisher's versio

Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis

CITATION: Mason, S., Reinecke, C. J. & Solomons, R. 2017. Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis. Frontiers in Neuroscience, 11:534, doi:10.3389/fnins.2017.00534.The original publication is available at https://www.frontiersin.orgBackground: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.https://www.frontiersin.org/articles/10.3389/fnins.2017.00534/fullPublisher's versio

Tuberculous meningitis in infants and children : insights from nuclear magnetic resonance metabolomics

CITATION: Mason, S., et al. 2016. Tuberculous meningitis in infants and children : insights from nuclear magnetic resonance metabolomics. South African Journal of Science, 112((3/4), Art. #2015-0086, doi:10.17159/sajs.2016/20150086.The original publication is available at http://sajs.co.zaTuberculous meningitis (TBM) is a prevalent form of central nervous system tuberculosis (CNS-TB) and the most severe common form of bacterial meningitis in infants and children below the age of 13 years, especially in the Western Cape Province of South Africa. Research to identify markers for timely and accurate diagnosis and treatment outcomes remains high on the agenda for TBM, in respect of which the field of metabolomics is as yet largely unexploited. However, the national Department of Science and Technology (DST) recently established several biotechnology platforms at South African institutions, including one for metabolomics hosted at North-West University. We introduce this national platform for nuclear magnetic resonance (NMR) metabolomics by providing an overview of work on TBM. We focus on selected collaborative multidisciplinary approaches to this disease and conclude with the outcomes of an untargeted NMR metabolomics study of cerebrospinal fluid from TBM patients. This study enabled the formulation of a conceptual shuttle representing the unique metabolic plasticity of CNS metabolism towards the energy requirements for the microglia-driven neuroinflammatory responses, of which TBM is one example. From insights generated by this explorative NMR metabolomics investigation, we propose directions for future in-depth research strategies to address this devastating disease. In our view, the timely initiative of the DST, the operational expertise in metabolomics now available and the potential for involving national and international networks in this field of research offers remarkable opportunities for the future of metabolomics in South Africa and for an ever greater understanding of disease mechanisms.http://www.sajs.co.za/tuberculous-meningitis-infants-and-children-insights-nuclear-magnetic-resonance-metabolomics/shayne-mason-carolus-j-reinecke-regan-solomons-marceline-van-furthPublisher's versio