Browsing by Author "Van Toorn, Ronald"

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    Approach to headaches in children
    (Health & Medical Publishing Group, 2011) Solomons, Regan; Schoeman, Johan; Van Toorn, Ronald
    Headache 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.
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    Child with tuberculous meningitis and COVID-19 coinfection complicated by extensive cerebral sinus venous thrombosis
    (BMJ Publishing Group, 2020) Essajee, Farida; Solomons, Regan; Goussard, Pierre; Van Toorn, Ronald
    We 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.
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    Childhood tuberculous meningitis : challenging current management strategies
    (Stellenbosch : Stellenbosch University, 2015-04) Van Toorn, Ronald; Schoeman, J. F.; Schaaf, Hendrik Simon; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
    ENGLISH ABSTRACT: Tuberculous meningitis (TBM) continues to be an important cause of mortality and neurological disability in resource-limited countries. Many questions remain about the best approaches to prevent, diagnose, and treat TBM, and there are still too fewanswers. The aim of this dissertation was to challenge current management strategies in childhood TBM. Accurate prediction of outcome in TBM is of critical importance when assessing the efficacy of different interventions. I conducted a retrospective cohort study of 554 children with TBM less than 13 years of age admitted to Tygerberg Children’s Hospital over a 20 year period (1985-2005) and reclassified all patients according to the criteria of all the currently available staging systems in childhood TBM (chapter 4). In this study, I found that the “Refined Medical Research Council (MRC) staging system after 1 week” had the highest predictive value of all TBM staging systems. It is created by subdivision of stage 2 (2a and 2b) of the existing MRC staging system. Additionally, I proposed and validated a simplified TBM staging system which is less dependent on clinical ability and neurological expertise than current staging systems. The simplified staging system was termed the “Tygerberg Children’s Hospital Scale” (TCH) and relies solely on the patient’s ability to visually fixate and follow and the motor response to pain on both sides. It demonstrated excellent predictive power of outcome after 1 week and did not differ significantly from the “Refined MRC staging system” in this regard. The optimal anti-TB drug regimen and duration of treatment for TBM is unknown. It has been suggested that intensive short-course (6 months) anti-TB therapy may be sufficient and safe. I conducted a prospective descriptive study of 184 consecutively treated children with TBM and found that short-course intensified anti-TB therapy aimed at treating TBM patients (anti-TBM therapy) is sufficient and safe in both HIV-uninfected and HIVinfected children with drug susceptible TBM (chapter 5). The overall study mortality of 3.8% at completion of treatment compares favourably with the median mortality rate of 33% (range 5-65%) reported in a recent review describing outcome in TBM treatmentstudies. TB-immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening complication in HIV-infected children with TB of the central nervous system. Little is known about the incidence, case fatality, underlying immunopathology and treatment approaches in HIV-infected children with neurological TB-IRIS. In a case series, I found that neurological TB-IRIS should be considered when new neurological signs develop after initiation of antiretroviral therapy (ART) in children with TBM (chapter 6.1). Manifestations of neurological TB-IRIS include headache, seizures, meningeal irritation, a decreased level of consciousness, ataxia and focal motor deficit. I also discussed the rational for using certain treatment modalities, includingthalidomide. Neurological tuberculous mass lesions (tuberculomas and pseudo-abscesses) may develop or enlarge in children on anti-TBM treatment. These lesions respond poorly to therapy, and may require surgical excision, but may be responsive to thalidomide, a potent inhibitor of tumour necrosis factor-alpha (TNF-alpha). The optimal dose and duration of thalidomide therapy and the correlation with magnetic resonance imaging (MRI) is yet to be explored. The primary objective of our next study was to investigate whether serial MRI is useful in evaluating treatment response and duration of thalidomide therapy (chapter 6.2). A secondary objective was to determine the value of thalidomide in the treatment of these lesions. In a prospective observational study over three years, serial MRI was performed in 16 consecutive children compromised by TB pseudo-abscesses who were treated with thalidomide. The rapid clinical response of most patients suggests that thalidomide provides substantial clinical benefit in this clinical context. I also identified a MRI marker of cure that is evolution of lesions from early stage “T2 bright” with edema to “T2 black.” This finding could be useful in the future management of these patients. Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with TBM, a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. Serial TCDI was performed on 20 TBM children with the aim of investigating cerebral haemodynamics and the relationship between pulsatility index (PI) and ICP (chapter 6.3). In this study, I found that TCDI-derived pulsatility index (PI) is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus which I attributed this to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. The study did confirm the efficacy of medical therapy in children with tuberculous communicating hydrocephalus. In all cases, the ICP normalized within 7 days after initiation of acetazolamide and furosemide. In the same cohort of children with TBM I also measured cerebral blood flow velocities (BFV) in the anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) on admission and after day 3 and 7. I found persistent high BFV in all the basal cerebral arteries suggesting stenosis due to vasculitis rather than functional vasospasm. Additionally, I found that complete MCA occlusion, subnormal mean MCA velocities (less than 40 cm/s) and a reduced PI (less than 0.4) correlated with radiological proven large cerebral infarcts. No side-to-side differences in MCA BFV or subnormal PI’s were detected in four TBM children with territory infarcts on admission. I attributed this to the occlusion of a limited number (one or two) of the 9 MCA perforators which has been shown not to affect the hemodynamics of the MCA. I concluded by highlighting the many questions that remain about the best approaches to prevent, diagnose, and treat TBM (chapter 2). In a second literature review, aimed at clinicians working in resource-limited countries, I describe novel approaches to the management of childhood TBM, including a treatment algorithm for tuberculous hydrocephalus, the role for short-course intensified anti-TBM treatment and home-based anti-TBM treatment (chapter 3). Even with the best diagnostic and treatment modalities, outcome in childhood TBM will remain poor if diagnosis is delayed. Our efforts should be on increased awareness and earlier diagnosis.
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    The conundrum of iron in multiple sclerosis – time for an individualised approach
    (Springer US, 2012-03) Janse Van Rensburg, Susan; Kotze, Maritha J.; Van Toorn, Ronald
    Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome - some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.
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    Host directed therapies for tuberculous meningitis
    (Wellcome Trust, 2020-07-01) Davis, Angharad G.; Donovan, Joseph; Bremer, Marise; Van Toorn, Ronald; Schoeman, Johan; Dadabhoy, Ariba; Lai, Rachel P. J.; Cresswell, Fiona V.; Boulware, David R.; Wilkinson, Robert J.; Thuong, Nguyen Thuy Thuong; Thwaites, Guy E.; Bahr, Nathan C.; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.
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    Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing
    (Elsevier, 2019-06) Van Rensburg, Susan J.; Peeters, Armand V.; Van Toorn, Ronald; Schoeman, Johan; Moremi, Kelebogile E.; Van Heerden, Carel J.; Kotze, Maritha J.
    Background: Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron. Methods: Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers. Results: WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients. Conclusion: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.
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    Management of intracranial tuberculous mass lesions : how long should we treat for? [version 3; peer review: 3 approved]
    (F1000Research, 2019) Marais, Suzaan; Van Toorn, Ronald; Chow, Felicia C.; Manesh, Abi; Siddiqi, Omar K.; Figaji, Anthony; Schoeman, Johan F.; Meintjes, Graeme; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis (M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.
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    Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity
    (Nature Research (part of Springer Nature), 2019) Rohlwink, Ursula K.; Figaji, Anthony; Wilkinson, Katalin A.; Horswell, Stuart; Sesay, Abdul K.; Deffur, Armin; Enslin, Nico; Solomons, Regan; Van Toorn, Ronald; Eley, Brian; Levin, Michael; Wilkinson, Robert J.; Lai, Rachel P. J.
    ENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. Here we conduct RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases are compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstrates a distinct immune response pattern in TBM, with significant increase in both canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicates that the ventricular profile represents brain injury whereas the lumbar profile represents protein translation and cytokine signaling. Together, transcriptomic analysis shows that disease processes differ between the periphery and the central nervous system, and within brain compartments.