Browsing by Author "Figaji, Anthony"

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    Open Access
    An Examination of Lumbar and Ventricular Cerebrospinal Fluid Findings in Children with Tuberculous Meningitis and Hydrocephalus
    (2019) Mwenda, Lona Albertha; Figaji, Anthony; Rohlwink, Ursula; Diedericks, Ralph
    Background: Childhood tuberculous meningitis (TBM) has poor outcomes. These are often associated with delayed diagnosis because early diagnosis and treatment is challenging. Existing diagnostic criteria use CSF characteristics to suspect TBM. However, lumbar and ventricular CSF may differ. These differences have not been well characterised Sometimes only ventricular CSF is available and decisions about surgical treatment may be influenced by CSF characteristics. This study examined CSF parameters from lumbar and ventricular compartments in patients with TBM and hydrocephalus who required neurosurgical procedures, their CSF temporal profiles, differentials between compartments, and factors that may influence these results. Methodology: A descriptive cross-sectional study was conducted including data from two prospective TBM studies. Children treated for TBM and hydrocephalus at Red Cross War Memorial Children’s Hospital with lumbar and/ or ventricular samples were selected. Pooled lumbar verses ventricular samples and paired time-linked samples in individual patients were analysed. Differences in CSF cell counts and biochemistry parameters across compartments were analyzed using Wilcoxon signed rank test, and temporal profiles graphically presented. Associations between laboratory, clinical and radiological data were analyzed using Mann-Whitney’s U test. To test for associated factors, results of the nature of hydrocephalus (level of CSF obstruction) and spinal imaging were analyzed where available. Association between CSF parameters and morbidity was analyzed. Results: Eighty-one patients were studied, 29 had time-linked paired CSF. The mean patient age was 36 months (2- 156 months), 93% were HIV-uninfected, and the mortality rate was 13.6%. Seventy-two percent had communicating hydrocephalus, 16% non-communicating, and 12% uncertain (unable to demonstrate level of block). Medians of admission lumbar CSF showed low glucose (2.2 mmol/L), low chloride (112 mmol/L), raised protein (2g/L) and elevated white cell count (165 x 106 /L). Corresponding values for admission ventricular CSF were minimally affected glucose (3mmol/L), mildly low to normal chloride (114.5mmol/L), normal to mildly raised protein (0.5g/L) and less elevated white cell count (22 x 106 /L). In paired samples, all parameters were significantly different between lumbar and ventricular CSF. Ventricular CSF showed milder aberrations than lumbar CSF: lower protein and total white cell count, higher glucose and chloride. All paired samples showed higher lumbar CSF protein; lower lumbar CSF chloride in almost 80%; lower lumbar CSF glucose in 96%. Analysis of possible factors was limited by the small patient numbers who had full brain and spine imaging, and also paired CSF samples (n=17). However, maximum lumbar CSF protein was associated with severity of spinal disease on imaging. The lymphocyte ratio between lumbar and ventricular CSF was higher in patients with non-communicating and uncertain hydrocephalus. CSF parameters normalized slowly. White cell count and lymphocyte CSF differential were associated with favorable outcome in survivors. Conclusion: Lumbar CSF depicted a typical TBM pattern. Ventricular CSF differed: CSF parameters were less abnormal in both pooled analysis and across individual paired samples. Spinal disease severity and nature of hydrocephalus may affect this differential. The CSF compartment sampled is therefore clinically relevant when interpreting CSF characteristics for diagnostic and treatment decisions. Studies of TBM diagnosis, pathophysiology, biomarkers and drug concentrations should consider these differences.
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    Biomarkers of neurological tissue injury and inflammation in paediatric tuberculous meningitis
    (2014) Rohlwink, Ursula Karin; Figaji, Anthony
    [Background] Tuberculous meningitis (TBM) in children has high mortality and neurological morbidity rates. The assessment of disease severity and prognostication are difficult because several factors influence initial presentation, and advanced tools for these are lacking. Biomarkers of neurological injury could help to assess severity and to prognosticate, but have not been assessed in paediatric TBM. This study examined serum and cerebrospinal fluid (CSF) biomarkers of neurological injury in paediatric TBM in association with clinical and physiological data, radiology, inflammatory markers, and outcome. [ Methods ] Serum and CSF (ventricular and lumbar) samples were taken on admission and over 3 weeks in children with probable TBM and hydrocephalus. These were analysed with ELISA for neuromarkers S100B, neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP), and with Luminex multianalyte array assay for a panel of inflammatory markers. Results were compared with 2 controls groups. Computerized tomography was done on admission and magnetic resonance imaging (brain, spine and magnetic resonance angiography) at 3 weeks. Brain oxygenation was monitored invasively and non-invasively in selected patients. Clinical and neurodevelopmental outcomes were assessed at 6 months. Data were analysed with various statistical tools, including principal component analysis. [ Results ] Data were collected from 44 children. Of these, 16% died and 36% had disability (25% mildmoderate, 11% severe). S100B, NSE, GFAP and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Elevated neuromarkers were significantly associated with poor outcome and increased over time in patients who died, although combined inflammatory biomarkers decreased. Cerebral infarcts occurred in 66% of patients and were associated with neuromarker elevation. Novel findings on spinal MRI were the high frequency of asymptomatic disease. Cerebral vascular pathology was documented frequently on imaging but did not predict infarcts. Low brain oxygenation was common and in keeping with physiological events and outcome. [ Conclusion ] CSF neuro- and inflammatory markers are elevated in TBM. Neuromarkers were prognostic of clinical and radiological outcome and an increasing trend suggested ongoing injury. This does not appear to be related to ongoing inflammation as measured by cytokines but may reflect the ongoing secondary injury processes initiated by inflammation.
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    Cerebral autoregulation in children with traumatic brain injury: Comparing the autoregulatory index (ARI) to pressure reactivity index (PRx) and their associations with cerebral physiological parameters
    (2017) Patel, Maryam; Figaji, Anthony; Enslin, Johannes M N
    As an important hemodynamic mechanism, pressure autoregulation protects the brain against inappropriate fluctuations in cerebral blood flow subject to changing cerebral perfusion pressures. In acute neurological illnesses, including traumatic brain injury in children, impaired autoregulation is associated with a worse prognosis. It also has important clinical implications for managing blood pressure and intracranial pressure. Two common methods of measuring pressure autoregulation reported in the adult literature have been rarely reported in children. This pilot study aimed to examine the relationship between two autoregulatory indices, namely PRx (pressure reactivity index) and ARI (autoregulatory index) in children with severe TBI. The study also examined their relationship with the response of clinically relevant variables such as intracranial pressure (ICP), brain oxygenation (PbtO2) and local cerebral blood flow (loCBF) to dynamic testing. The study is a retrospective cohort study of prospectively collected data conducted at the Red Cross Children Hospital. We analyzed the results of 18 patients in 28 tests of autoregulation to determine the static state of autoregulation by calculating the autoregulatory index (ARI). These tests were done by controlled elevation of blood pressure to evaluate changes in transcranial Doppler-derived flow velocity of the middle cerebral artery. Concomitant recordings were made of ICP, PbtO2, and loCBF. Secondly, we also calculated the PRx as a moving correlation co-efficient between slow changes in blood pressure and ICP. Two time epochs of PRx were examined in relation to the static tests: 1 hour before and after the test, and 12 hours before and after the test. The results included 28 tests done for ARI and 27 calculations for PRx epochs; all tests had ICP and PbtO2 data and 23 had loCBF. PRx and ARI showed no significant relationship between them. However, there was a significant relationship between ARI and ΔICP (p=0.04), i.e. when autoregulation was weak the change in ICP with a change in blood pressure was greater; and between PRx and ΔPbtO2 (p=0.04). There was a trend in correlation analysis between loCBF and PRx but not in the linear mixed effects model In conclusion, the study showed no correlation between the two autoregulatory indices, PRx and ARI, probably because they assess different aspects of autoregulation. However, significant relationships exist between ARI and ΔICP as well as PRx and ΔPbtO2, which generate interesting hypotheses about autoregulation and have clinical implications. Both autoregulatory indices have benefits and limitations. Further studies on such relationships, taking into consideration a larger sample group, inclusion of unstable patients, and utilization of the same range in BP for calculating the indices, are recommended.
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    Development of an in vitro drug recovery model for paediatric tuberculous meningitis using microdialysis with in vivo application
    (2022) Lourens, Rentia; Figaji, Anthony
    Introduction: Tuberculous Meningitis (TBM) is the most devastating form of tuberculosis, leading to high rates of death and disability. Yet little has changed in drug regimens to treat TBM, in part due to the limitations of studying drugs at the site of the disease: the vast majority of studied samples are from spinal cerebrospinal fluid (CSF), most sampling is sporadic, and drug concentrations are usually reported as total (bound and unbound) concentrations. However, spinal CSF may not be the same as CSF derived directly from the brain (ventricular CSF), continuous or semi-continuous sampling would provide better pharmacokinetic data, and the unbound fraction of the drug would be more informative because it is the pharmacologically active component. Microdialysis (MD) is a method that is used in advanced clinical care to measure molecules in tissue, including the brain. It has some limitations, however, including the difficulty of calculating the relative recovery and potential anatomical compartmental effects in the brain. We aimed to adapt the method to address these limitations and for the first time produce high frequency data of unbound drugs in ventricular CSF using rifampicin in TBM as a model in vitro and in vivo. Aims: We aimed to establish a novel technique, using MD to continually measure Rifampicin in ventricular CSF of TBM patients. This involved 1) developing an appropriate system that could be used clinically, 2) determining the proportion of the drug that is recovered via the MD catheter (termed the recovery), 3) identifying parameters that affects the recovery, and 4) applying the model to the clinical setting. Methods: We developed a system with an embedded MD catheter to continuously drain artificial CSF with known concentration of Rifampicin and protein. The MD catheter had 20 kDa semipermeable membrane that allowed passage of only unbound drugs. To examine recovery, we compared rifampicin concentrations in hourly samples through the MD catheter (termed microdialysate) to total rifampicin in control CSF samples (obtained from the system before passage through the catheter). These were analysed using liquid chromatography – tandem mass spectrometry (LC-MS/MS). We considered several factors that may affect recovery in clinical practice, running several iterations that varied rifampicin concentration, protein concentration, MD perfusion pump rates, CSF draining rates, and system pressure (to mimic intracranial pressure). The method was then applied to paediatric TBM patients, where the MD catheter was placed in-line with an extra-ventricular drain (EVD) and the factors identified in vitro were stabilised. Rifampicin concentrations were measured in hourly microdialysate samples over 24 hours, and compared to control samples of ventricular CSF using LCMS/MS. Results: For the in vitro experiments, the effect of several variables on relative recovery were identified. Increased recovery was seen with a higher CSF draining rate and increased rifampicin concentration, while decreased recovery was seen with increased MD perfusion rate, increased protein concentration, and unexpectedly, increased pressure in the system (to mimic intracranial pressure). When translated to two patients with TBM we aimed to maintain intracranial pressure within a narrow range, and stable CSF drainage and MD pump rates. The in vivo unbound rifampicin concentrations from microdialysate were used to draw a 24-hour pharmacokinetic curve. The peak concentration (Cmax) in microdialysate was 221 ng/mL before enzyme induction (where drug administration had just started) and 100 ng/mL after enzyme induction (where the patient had been on Rifampicin for more than two weeks). The time of the peak (Tmax) in microdialysate was 11 hours after drug administration. The ratio of the unbound drug concentration to the total drug concentration of the control samples varied. Conclusion: This novel method is feasible to study unbound drug concentrations directly and continuously in the brain and provides high quality data for advanced neuropharmacokinetics. Factors in the clinical setting can be accounted for, and microdialysate results can be compared against sporadic control sampling. Clinical translation of this method was successful. These early data suggest very low concentrations of rifampicin in the brain with standard care. The results raise interesting hypotheses about the binding of Rifampicin to protein in the human brain. Our method can be applied to other drugs and data obtained from the method can inform dosing requirements and improve future drug development.
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    Evaluation of encapsulated liver cell spheroids in a fluidised-bed bioartificial liver for treatment of ischaemic acute liver failure in pigs in a translational setting
    (Public Library of Science, 2013) Selden, Clare; Spearman, Catherine Wendy; Kahn, Delawir; Miller, Malcolm; Figaji, Anthony; Erro, Eloy; Bundy, James; Massie, Isobel; Chalmers, Sherri-Ann; Arendse, Hiram
    Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4-6×10 10 cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale.
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    Exploring factors that influence academic and behavioural outcome and the specific role of premorbid functioning, in a sample of children with severe traumatic brain injury
    (2014) Dollman, Aimee; Schrieff-Elson, Leigh; Figaji, Anthony; Wolf, Pedro
    Children who have sustained severe traumatic brain injury (TBI) demonstrate a range of deficits in neurocognitive and behavioural domains (Anderson, Northam, Hendy, &Wrennall, 2001; Babikian & Asarnow, 2009; van’t Hooft, 2010). These impairments may have adverse effects on academic and behavioural outcomes and can therefore interfere with school re-entry, educational progress, and ultimately, quality of life of the injured child (Anderson & Yeates, 2010; Keenan & Bratton, 2006; Lallo & van As, 2004). Pre-injury characteristics may increase risk for, and play a role in, TBI outcome, however, many studies exclude children with known adverse premorbid functioning (Dennis et al., 2007; Farmer etal., 2002). There are also dearth of published studies incorporating a variety of factors affecting outcome (e.g., socio economic status (SES), age at injury, time since injury, premorbid functioning, family environment) as well as academic and/or behavioural outcome variables in the same study generally. The broad aim of the study was therefore to contribute to the existing pediatric TBI (pTBI) literature on outcomes and factors influencing outcomes. In this study, I focused on investigating both academic and behavioural outcomes in a group of South African children of school-going age who had sustained a severe TBI. This study includes two parts. For the first part of the study, the aim was to explore the relationship between commonly reported factors that influence outcome after TBI (premorbid functioning, age at injury, time since injury, family environment and SES), and academic and behavioural outcome. For the second part of the study, the aim was to investigate the specific role of premorbid functioning in academic and behavioural outcome. The sample included 27 children who had been admitted to Red Cross War Memorial Children’s Hospital (RXH) and received intracranial monitoring for closed severe TBI between 2006-2011, who were of school-going age at the time of the injury. In terms of part one of the study, the results show elevated problems with academic outcome, and behavioural and executive functioning in the sample. The results also show that in this sample, factors such as family environment and premorbid functioning are particularly important with regards outcome in the home environment; while factors such as age at injury, family environment and SES play more of a role within the classroom environment.
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    Hard hitting facts on childhood head trauma: an epidemiological analysis
    (2019) Ferreira, Yolandi; van As, Arjan B; Figaji, Anthony; Dix-Peek, Stewart
    Background: According to the World Health Organization (WHO), Traumatic Brain Injury (TBI) will become the third largest cause of global disease by the year 2020. Despite its astonishing numbers, TBI remains a silent or even forgotten epidemic with significant paucity in epidemiological data. TBI in developing countries represents a disproportionate burden of disease and data are lacking regarding the unique demographics in South Africa to design and implement focused prevention programmes. A valuable tool to assess the severity of TBI is the use of Computer tomography (CT). CT also is the main imaging modality to provide rapid identification and information for the management of children with TBI. CT scanning utilises ionising radiation and as an imaging modality poses risk to the patient. In order to guide decision protocol/algorithm, various Clinical Decision Rules (CDRs) have been established in High Income Countries. These protocols, including the need for CT scan might differ in a Medium/Low Income setting. Methodology: This is a prospective, single centre cohort study. Data were collected over an 18-month period (1 August 2015 - 31 January 2017). Children under the age of 13 years (n=3007) presenting to RCWCH after sustaining a head injury were included. Various epidemiological data were collected. A Road Safety Questionnaire was also used to evaluate safety knowledge of health care workers. Three different CDRs were compared to the standard of practice in RCWCH. A final analysis of demographics, mechanism of injury, radiology outcome, safety analysis and evaluation of a comparison of local protocol compared to the other CDRs was performed using descriptive statistics. Results: The mean age of paediatric patients presenting after a head injury was 4.6 years. There was a significant male predominance (66%) and almost two thirds of all children were of pre-school age. Falls (53%; n=1601) represented the most common mechanism of injury across all age groups, followed by road traffic related injuries (RTI) (29%; n=864), struck by or against an object (9%; n=279) and injuries as a result of interpersonal violence (8%; n=230). Within the subset of RTI (n=864) only 6 passengers were appropriately restrained, with 142 unrestrained and 56 passengers transported on the back of a goods vehicle. In the under 3-yearold age group, only 1 patient was appropriately transported in a car seat, with 51 unrestrained and 6 transported on the back of a goods vehicle. Pedestrian related injuries were by far the largest group of RTI (70%) with 50% of these under the age of 5 years. Intentional injuries inflicted by an adult were most common (34%) in the pre-verbal (under 2 years old) group. Interpersonal violence among minors (assault with a brick or stone) constituted 52% of intentional injuries. Eight firearm related injuries were recorded. Appliances and iron gates that were not correctly installed were additional causes of injury. CT scans were obtained according to the RCWCH protocol in 59% of cases and 34% showed an abnormal result. The sensitivity (98%) and specificity (93%) while using the standard of practice protocol was better than the 3 CDRs developed in High Income Countries. Analysing our Road Safety Questionnaire there appears great room for improvement regarding awareness of road safety guidelines and legislation. Conclusion: The performance of the current RCWCH CT scan protocol appears appropriate in our setting although there is some room for improvement using the strengths of the other CDRs. Valuable insight regarding the epidemiology of TBI in our setting has been highlighted. Of specific importance is the large proportion of very young children at risk of injury by all mechanisms of injury, particularly pedestrian-related injuries, unrestrained passengers and interpersonal violence among minors. Important gaps in knowledge about current recommendations for road safety were identified by the questionnaire. As long as these issues are not appropriately addressed through enhanced injury prevention programmes, children will continue to carry the heavy burden of TBI morbidity and mortality.
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    Impact of secondary insults on the outcome of paediatric traumatic brain injury : a retrospective cross sectional study at the Red Cross Children’s Hospital, Cape Town
    (2013) Mogere, Edwin; Figaji, Anthony
    Secondary insults in severe traumatic brain injury (TBI) may worsen outcome; however, these are poorly characterized in children. For example, despite the known association between intracranial pressure (ICP) and poor outcome, there are few large paediatric series on the subject, definitions vary, functional outcome is often not assessed, and the best measures to assess ICP for statistical analysis are unknown. We aimed to document the frequency of secondary insults, and the association of various ICP measures, with outcome in a large cohort of paediatric patients with severe TBI. A retrospective analysis of 5-year prospectively collected data was examined for the frequency of hypoxia, hypotension, raised ICP, and low cerebral perfusion pressure (CPP). ICP parameters included initial ICP, mean ICP in the first 24 hours, mean ICP overall, peak ICP, mean ICP over 20 mmHg, and episodes of ICP over 20 mmHg. Hypotension was defined by age †and height †adjusted mean arterial pressure ranges, and hypoxia was defined as arterial partial pressure of oxygen (PaO2) less than 8kPa or pulse oximetry less than 90%. We examined for univariate and multivariate associations with mortality and the Extended Paediatric Glasgow Outcome Score.
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    Investigating cerebrovascular pressure reactivity in a large cohort of children with severe traumatic brain injury
    (2021) Smith, Claudia Ann; Figaji, Anthony; Rohlwink, Ursula
    Introduction: Traumatic brain injury (TBI) contributes to worldwide death and disability more than any other traumatic event, but it is of particular concern in children in developing resource-scarce countries. Cerebral autoregulation (CA) is a homeostatic mechanism that aims to maintain constant cerebral blood flow within a range of systemic blood pressures, and the loss of this mechanism has been associated with mortality and worse outcomes in adult TBI. Paediatric studies of CA disturbance are few and consist of small cohorts. Given the differences between adult and paediatric TBI pathophysiology, CA needs examination in a larger cohort of paediatric TBI. This study aimed to describe the profile of PRx, a mathematical indicator of cerebrovascular pressure reactivity, in a large cohort of children with severe TBI. The specific aims were to 1) describe the characteristics of PRx; 2) examine associations between PRx, clinical and physiological variables, and 3) examine associations between PRx and mortality at 6 months, and PRx and dichotomized outcome (as well as survivors only) at ≥ 6 months post-injury. Methods: Patient demographics, clinical and monitoring data were recorded, and the temporal profile of median PRx was plotted by outcome groups. The associations between PRx, Glasgow Coma Score (GCS), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were examined with both summary measures and correlation analysis using high frequency data. Associations between PRx and mortality/outcome were examined with multiple regression analysis, and the prognostic ability of PRx, ICP and CPP was investigated with receiver operating curve analysis. Results: We examined 196 children with severe TBI. Mortality rate was 10.7%, and 70.4% of the cohort had unfavourable outcome. PRx was consistently higher in patients with poor outcome when examined by various summary statistics and over time. Hourly analysis showed that PRx had a moderate positive correlation with ICP (r = 0.35; p < 0.001) and a weak negative correlation with MAP (r = -0.10; p < 0.001) and CPP (r = -0.27; p < 0.001). PRx had a strong and independent association with mortality. Conclusion: This study calculated, described, and analysed PRx in the largest known cohort of children with severe TBI. PRx had a strong association with outcome (particularly mortality) that was independent of ICP, CPP and GCS. However, a combination of several PRx and ICP-related variables will likely be important for overall prognostication in paediatric severe TBI. Whether CA should be incorporated into clinical care, and if so, how, requires separate investigation.
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    Investigating history of concussion and data from head impact telemetry (xPatch) in relation to neuropsychological outcomes in a sample of adult rugby players in Cape Town
    (2016) Stephen, Dale C; Schrieff-Elson, Leigh; Thomas, Kevin; Figaji, Anthony
    While Rugby Union has worldwide popularity, with over 5 million registered and nonregistered players participating every year, the game lends itself to a high incidence of concussion among players. Rugby players, more so than that recorded for any other contact sport, including American Football, are also more frequently exposed to head collisions not resulting in concussion (i.e., subconcussive head injuries). Despite some evidence for a potential association between such injuries and acute neurological and neuropsychological difficulties, which may at times persist among some players, overt symptoms still guide the initial on-field response for further concussion management to be initiated. The aim of this study was threefold: 1) to investigate the relationship between rugby players' history of concussion and neuropsychological outcomes, 2) to explore the use of a head impact telemetry (HIT) device in describing high-impact head collisions (and potentially subconcussive injuries), and 3) to explore the relationship between that HIT data and neuropsychological outcomes. Study 1 investigated differences between non-contact sport participants (n = 23) and rugby players with (Rugby Concussed; n = 31), and without a history of concussion (Rugby Not Concussed; n = 26) in a baseline cognitive assessment. Results showed that at the beginning of the rugby season there were no differences in cognitive abilities at a group level; a more severe concussion history was largely not associated with a poorer performance on these cognitive outcomes. Study 2 was a pilot study utilising the xPatch to objectively capture a rugby player's exposure to head impacts in an amateur rugby team (UCT IRL team; n = 8). Although the majority of impacts captured were of a 'mild' severity, there were many acceleration forces, particularly rotational accelerations, recorded above an injury threshold potentially implicated with concussion. Following from this, Study 3 used a prospective and repeated-measures design with the same UCT IRL team, to evaluate a means for investigating a player's neuropsychological vulnerability to high-impact subconcussive head injuries. Using correlational analyses, the Reliable Change Index (RCI) and head collision data from Study 2, there was a lack of evidence to indicate that player's increased exposure to repeated high-impact head collisions results in a generally poorer neuropsychological performance. However, a number of test practice effects are noted. Combined, these findings suggest that (a) identifying possible enduring neuropsychological difficulties retrospectively is limited, and issues such as test-practice effects and test sensitivity should be considered in future, preferably prospective studies, (b) rugby players are vulnerable to sustaining multiple high-impact subconcussive head injuries and the data suggests utility in including HIT like the xPatch, and (c) that implementing a multi-faceted protocol for monitoring rugby players' that negates a reliance on concussion diagnosis is necessary to better understanding individual recovery trajectories.
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    Investigating the effects of acute intracranial pressure and brain oxygenation on neuropsychological outcomes 12 months after severe pediatric traumatic brain injury
    (2019) Dodge, Lydia; Schrieff, Leigh; Figaji, Anthony
    Traumatic brain injury (TBI) is one of the major causes of mortality and morbidity among children and adolescents all over the world and studies suggest a higher incidence of pediatric TBI (pTBI), as well as poorer post-TBI outcomes, in countries with extreme levels of socioeconomic inequality such as South Africa. pTBI leads to a multitude of long-term adverse outcomes in a wide range of domains and in general, a dose-response pattern is evident. Multiple acute and post-acute stage predictors of outcome have been investigated, however acute stage neurological and neurosurgical variables are relatively absent from this knowledge base. This study was conducted to better understand the heterogeneity in outcomes of pTBI: it aimed to investigate the nature and severity of neuropsychological deficits in pTBI patients one year after injury and to investigate the association between acute stage physiological changes in intracranial pressure (ICP) and brain tissue oxygenation (PbtO2) and neuropsychological outcomes one year after pTBI. Results of the study indicated that children who sustained TBI performed significantly poorer than healthy, matched controls on multiple cognitive, behavioural and quality of life domains, however, neither acute ICP nor PbtO2 reliably predicted within-TBI group performance. The results of the study emphasise the poor relationship of ICP and PbtO2, and the complexity of the relationship between acute physiological variables and outcomes after pTBI. Further studies of this kind should be done on large sample sizes and include multiple physiological variables.
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    Neuropsychological and Neuroimaging Outcomes Following Moderate to Severe Paediatric Traumatic Brain Injury in South Africa
    (2022) Mc Fie-Schwartz, Sarah; Schrieff, Leigh; Figaji, Anthony
    Paediatric traumatic brain injury (pTBI) is a leading cause of mortality and disability. South Africa is predicted to have a high pTBI rate and an adverse socioeconomic environment for recovery. Despite this, few studies have investigated the neuropsychological and/or neuroimaging outcomes of pTBI in South Africa. The study was designed as a capacity-building exercise to demonstrate the successful collection of data from different sites involved in a developing international collaboration. The aims were therefore to 1) provide a detailed description of the premorbid factors and neuropsychological and neuroimaging outcomes of a sample of South African children with moderate to severe pTBI, and 2) investigate the barriers to the successful implementation of neuropsychological and neuroimaging research in this population. Five patients with severe pTBI were enrolled during the 6-month recruitment window. These participants presented with 6-month post-TBI outcomes that ranged from mild neuropsychological deficits and no visible abnormalities on neuroimaging to severe neuropsychological deficits and evidence of multifocal pathology on imaging. There was a relatively high occurrence of adverse developmental, socioeconomic, and neuropsychological histories, which will need to be considered when selecting an appropriate control group or combining with other populations in a potential future multicentre study. Additional strategies will also be required to improve recruitment and increase the rate of successful imaging. Changes may need to be made to the neuropsychology assessment so as not to disadvantage this population, for example avoiding tests that are reliant on sequencing the alphabet. In conclusion, the study's findings will help to improve the likelihood of the much-needed large-scale research in this at-risk and understudied South African population.
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    Paediatric brain tumours: The University of Cape Town experience from 1996 - 2017
    (2019) Arnold-Day, Christel; Figaji, Anthony
    Brain tumours are the second most common malignancy in children(1) (2), and despite some advancements being made over the last 2 decades, patient outcomes in general remain poor when compared with other childhood cancers. Optimal treatment of children with brain tumours is challenging and expertise and resources are not widely available in South Africa. This is important because the outcomes of children with brain tumours depend critically on the expertise and resources of a multidisciplinary team tasked with their treatment. Despite the importance of paediatric brain tumours though, little is known about childhood brain tumours in South Africa as limited data have been published and there have been no funded studies to support research in this area. In addition, we know very little about the resources available across the country to treat these children. In international centres of excellence the best outcomes are achieved by combining good epidemiological data, strong multidisciplinary teams, centralization or regionalization of services, available resources, and a research foundation. To start, we need to know more about the patients presenting to us with brain tumours. PURPOSE The overall aim of this project was to collect epidemiological data for childhood brain tumours at a tertiary paediatric hospital in South Africa with a dedicated multidisciplinary team. METHODS Study design: A retrospective review of records of patients diagnosed with a primary brain tumour and who presented to Red Cross Children’s Hospital (RCCH) system from 1 January 1996 to 31 December 2017. 2 Patient selection & data collection: Patients were identified by combining databases and admission logs from paediatric neurosurgery, oncology, radiotherapy, histopathology and radiology. Data collected included: age at diagnosis, sex, province of referral, tumour site and diagnosis. RESULTS A total of 554 paediatric patients with primary brain tumours were identified over the study period. Tumours were more common among males (55.4%) and were located in the supratentorial compartment in 52%. The median age at diagnosis was 5.92 years. The commonest tumours were astrocytomas (n=114 patients; 20.3%), followed by medulloblastomas (incl. PNETs) (n=107 patients; 19.1%), and craniopharyngiomas (n=55; 9.8%). As expected, most patients referred and seen at RCCH/GSH were from the expected drainage area in the Western Cape (73%), but a significant number of referrals (27%) were from outside the province referrals, especially in the last 10 years. CONCLUSION Our findings were largely consistent with the published literature in terms of histological diagnosis, sex profile and age ranges for children diagnosed with brain tumours with some small differences possibly related to referral bias. More patients than expected were referred from outside of the province, which emphasizes the need for establishing an ongoing tumour database registry and co-ordinating patient care across institutions. A follow-up study to assess patient management and outcomes is of critical importance to assess resource availability and patient outcomes.
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    Paediatric traumatic Brain Injury: The relationship between Intracranial Pressure and Brain Oxygenation
    (2009) Rohlwink, Ursula Karin; Figaji, Anthony
    Introduction: Intracranial pressure (ICP) monitoring is a cornerstone of care for patients with severe traumatic brain injury (TBI). The primary goal of ICP treatment is to preserve brain oxygenation, and since brain oxygenation is usually not measured, the control of ICP is used as a surrogate marker. However studies indicating that cerebral hypoxia/ischemia may occur in the face of adequate ICP and cerebral perfusion pressure (CPP) suggest that the interaction between ICP and brain oxygenation is poorly understood and warrants further investigation. This is of particular importance in the context of children in whom the interpretation of relationships between intracranial factors is even more complex due to changing physiological norms with age. To date little scientific data exists in children and treatment threshold values are often extrapolated from adult guidelines. This study aims to better understand the relationship between ICP and brain oxygenation measured as brain tissue oxygen tension (PbtO2) in a large paediatric cohort suffering from severe TBI. Specifically analysis 1) investigated ICP and PbtO2 profiles over time following TBI, 2) examined the relationship between ICP and PbtO2 from time-linked paired observations, 3) explored various critical thresholds for ICP and PbtO2, and 4) interrogated digital data trends depicting the relationship between ICP and PbtO2. The level of agreement between hourly recorded and high frequency electronic data for ICP and PbtO2 was also evaluated. Method: Paired ICP and PbtO2 data from 75 children with severe TBI were tested with correlation and regression. Additional analyses controlled for mean arterial pressure (MAP), arterial partial pressure of oxygen (PaO2), CPP, arterial partial pressure of carbon dioxide (PaCO2) and haemoglobin (Hb) using multivariate logistic regression analysis and general estimating equations. Various thresholds for ICP were examined; these included age-related thresholds to account for the potential influence of age. Receiver-operating curves (ROCs) were used to graphically demonstrate the relationships between various thresholds of ICP and various definitions of low PbtO2. These were constructed for pooled and individual patient data. Interrogation of electronically recorded data allowed for case illustrations examining the relationship between ICP and PbtO2 at selected time points. Hourly and electronic data were compared using Bland and Altman plots and by contrasting the frequency of ICP and PbtO2 perturbations recorded with each system. 5 Result: Analyses using over 8300 hours of paired observations revealed a weak relationship between ICP and PbtO2, with an initially positive but weak slope (r = 0.05) that trended downwards only at higher values of ICP. Controlling for inter-individual differences, as well as MAP, CPP, PaO2, PaCO2 and Hb did not strengthen this association. This poor relationship was further reflected in the examination of threshold ICP values with ROCs, no singular critical ICP threshold for compromised brain oxygenation was discernible. Using age-based thresholds did not improve this relationship and individual patient ROCs demonstrated inter-individual heterogeneity in the relationship between ICP and PbtO2. However, it was clear that in individual patients ICP did exhibit a strong negative relationship with PbtO2 at particular time points, but various different relationships between the 2 variables were also demonstrated. A high level of agreement was found between hourly and electronic data. Conclusion: These results suggest that the relationship between ICP and PbtO2 is highly complex. Although the relationship in individual children at specific time points may be strong, pooled data for the entire cohort of patients, and even for individual patients, suggest only a weak relationship. This is likely because several other factors affect PbtO2 outside of ICP, and some factors affect both independently of each other. These results suggest that more study should be directed at optimising ICP thresholds for treatment in children. The use of complimentary monitoring modalities may assist in this task. Depending on the adequacy of measures of brain perfusion, metabolism or oxygenation, it is possible that targeting a range of ICP values in individual patients may be appropriate; however this would require detailed investigation.
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    Profiling medulloblastoma and juvenile pilocytic astrocytoma brain tumours in a South African paediatric cohort
    (2017) Nair, Omesan; Figaji, Anthony; Blackburn, Jonathan M
    Brain tumours in children are one of the most challenging diseases to treat, and so outcomes are variable and often lacking. There are currently no reliable data of presentation of disease, the spectrum of tumours treated, how these are treated, and what the outcomes are for children in South Africa, and certainly no molecular biology data. In this respect, this thesis investigated the two commonest types of childhood brain tumour, the highly malignant Medulloblastoma (MB) and the generally less aggressive Juvenile Pilocytic Astrocytoma (JPA) with relation to their molecular biology and their clinical correlates to begin to address this gap and build capacity for further molecular-based studies in an African context. The study design in this thesis takes a systematic approach and is structured into MB and JPA biochemical characterisation followed by 4 studies of their respective proteomic profiles. The study design involved creating appropriate patient cohorts and determining sample characteristics for interpretation of results. The statistical power achieved in this thesis showed a minimum of 2-fold difference for a power greater than 0.8 in each case. Proteomic clustering was used to validate or delineate any discrepancies in subtype assignments for MB. Molecular profiles together with proteomic data of MB and JPA cases in this thesis provide evidence for some novel molecular pathways, proteins and peptides associated with pathogenesis. This work therefore provides extensive data that is hypothesis generating for further studies that could build upon molecular understanding in a South African and larger African context.
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    Sequential improvement in paediatric medulloblastoma outcomes in a low-and-middle-income country setting over three decades
    (2021) Riedemann, Johann; Parkes, Jeannette; Davidson, Alan; Figaji, Anthony
    Background: Medulloblastoma (MB) is the commonest malignant brain tumour of childhood. Accurate clinical data for paediatric MB in the LMIC setting is lacking. Sequential improvements in outcome seen in high income countries are yet to be reflected in LMIC. Aim: Quantification of paediatric MB outcomes in the LMIC setting over three decades of advances in multidisciplinary intervention. Setting: Cape Town, South Africa Methods: This was a retrospective study of 136 children with MB diagnosed between 1985 and 2015. Modified Chang criteria were used for risk stratification. The primary study objective was overall survival (OS), quantified by analysis of epidemiological, clinical and pathological data. Results: OS improved significantly during the most recent decade (2005-2015) when compared with the preceding two decades (1985-1995 and 1995-2005). Despite reduced dose craniospinal irradiation for standard risk cases, OS was significantly greater than during the preceding two decades. High-risk disease was identified in 71.4% of cases and was associated with significantly inferior OS compared with standard risk cases. Improved OS was positively correlated with therapeutic era, 3-D conformal radiotherapy technique, older age at diagnosis, classic and desmoplastic histology, extent of resection and absence of leptomeningeal spread on imaging. Conclusion: Advances in multidisciplinary management of MB in our combined service are associated with improved survival. Access to improved imaging modalities, advances in surgical techniques, increased number of patients receiving risk-adapted combination chemo- and/or radiotherapy as well as craniospinal irradiation using a linear accelerator with 3D planning, are considered as contributing factors.
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    The Changing Face of Craniopharyngioma Treatment in Young Children and its Challenges at a Single Centre in a Developing World Context
    (2019) Mankahla, Ncedile; Figaji, Anthony
    Objective: To retrospectively review our institutional experience with the treatment of paediatric craniopharygiomas and assess the evolution in management and influence on patient outcomes. Patients and Methods: A retrospective review from January 1995 to December 2015 of children age <14 treated at a single institution. Data collected included admission clinical features, endocrine function, surgery performed, surgical outcome, intracystic therapy and radiotherapy. Long-term functional outcome was calculated considering hormonal dependence, level of independence and schooling. Results: There were 41 patients with a mean age of 84.2 months: 57% were female. Primary surgical resection was performed in 36 patients: 80.5% had subtotal resection, 11% had gross total resection and the rest had biopsy only. Of surgical approaches, 60,7% had pterional craniotomy and 39,2% supraorbital keyhole craniotomy. No surgical mortalities occurred but 2 patients had new post-operative neurological deficits. Stereotactic placement of intracystic catheters transitioned to endoscopic. Intracystic treatments transitioned from Yttrium (1) to Bleomycin (6) to Interferon Alpha (6). Radiotherapy was given in 30 patients, median dose 54Gy. Final Wen functional outcome was 21,8% Class I, 32% Class II and 46% Class III. There were no early deaths in the series but 5 patients died more than 6 years after diagnosis, mostly due to endocrine crises from poor chronic care. Conclusion: The findings reflect a multidisciplinary team approach consisting of maximal safe resection with radiotherapy, intracystic agents and endocrine support. For a cohort limited to young children, our results are similar in number and outcomes to other published series. Mortality remains low but lifelong dependence on endocrine replacement is a significant contributor to long-term morbidity and mortality. This has important implications for patients referred from large distances and where primary and secondary follow up care is poor.
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    The influence of fixation and cryopreservation of cerebrospinal fluid on antigen expression and cell percentages by flow cytometric analysis
    (2022) Singh, Gabriela; Rohlwink, Ursula; Figaji, Anthony
    Introduction: Infections of the central nervous system (CNS) remain a major burden of disease. Cerebrospinal fluid (CSF) is an essential sample for the investigation of CNS pathologies and flow cytometry enables detailed immunophenotyping of cells present in CSF.However, the pauci-cellular nature of CSF, and the rapid cell death following sampling, incumbers the use of flow cytometric analysis of these samples. Immediate processing and analysis of CSF for flow cytometry is not feasible in busy clinical environments where sample collection is unpredictable, and flow cytometers are not readily available. Therefore, developing a method to easily store CSF samples is highly desirable for clinically relevant research on CNS pathologies. Thus, the objective of this study was to examine 2 methods of long-term storage of CSF samples which ensured reliable measurement of cell percentages and relative proportion of cell subsets using flow cytometry. Aims: To examine percentages and relative proportion of subsets of selected peripheral leukocytes and brain derived cells in 1) cryopreserved CSF in comparison to freshly processed CSF, and 2) Transfix-treated CSF in comparison to freshly processed CSF. Method: CSF samples were prospectively collected and processed as follows 1) Freshwithin 24 hours (the current gold standard); 2) Cryopreserved- analysed after 1 month storage at..............Percentages of numerous white blood cell populations and brain-derived immune cells were analysed using flow cytometry and compared across these methods. The median fluorescent intensity of select markers was also compared across these methods. Results: The majority of cell percentages were not statistically significantly different between Fresh and Cryopreserved CSF, and cell proportions were comparable. Conversely, loss of marker expression of various lymphocyte sub-populations was observed in Transfixtreated CSF compared to Fresh, and certain cell populations could not be clearly distinguished in Transfix-treated CSF. Conclusion: Cryopreservation is a feasible option for long-term storage of CSF and allows quantification of cell percentages and immunophenotyping of peripheral and brain-derived cell populations by flow cytometry. This offers valuable opportunities for clinical research across a broad spectrum of CNS conditions (infectious and non-infectious). Further, this work highlights the potential to cryopreserve other surgical specimens for which the application of flow cytometry is currently limited by resource constraints and low cell counts.