Kirsten A. Donald

Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review

Objective This paper reviews the magnetic resonance imaging (MRI) literature on the effects of prenatal alcohol exposure on the developing human brain. Method A literature search was conducted through the following databases: PubMed, PsycINFO and Google Scholar. Combinations of the following search terms and keywords were used to identify relevant studies: ‘alcohol’, ‘fetal alcohol spectrum disorders’, ‘fetal alcohol syndrome’, ‘FAS’, ‘FASD’, ‘MRI’, ‘DTI’, ‘MRS’, ‘neuroimaging’, ‘children’ and ‘infants’. Results A total of 64 relevant articles were identified across all modalities. Overall, studies reported smaller total brain volume as well as smaller volume of both the white and grey matter in specific cortical regions. The most consistently reported structural MRI findings were alterations in the shape and volume of the corpus callosum, as well as smaller volume in the basal ganglia and hippocampi. The most consistent finding from diffusion tensor imaging studies was lower fractional anisotropy in the corpus callosum. Proton magnetic resonance spectroscopy studies are few to date, but showed altered neurometabolic profiles in the frontal and parietal cortex, thalamus and dentate nuclei. Resting-state functional MRI studies reported reduced functional connectivity between cortical and deep grey matter structures. Discussion There is a critical gap in the literature of MRI studies in alcohol-exposed children under 5 years of age across all MRI modalities. The dynamic nature of brain maturation and appreciation of the effects of alcohol exposure on the developing trajectory of the structural and functional network argue for the prioritisation of studies that include a longitudinal approach to understanding this spectrum of effects and potential therapeutic time points.

Pediatric Cerebral Palsy in Africa: A Systematic Review

Cerebral palsy is a common neurologic problem in children and is reported as occurring in approximately 2-2.5 of 1000 live births globally. As is the case with many pediatric neurologic conditions, very little has been reported on this condition in the African context. Resource-limited settings such as those found across the continent are likely to result in a different spectrum of etiologies, prevalence, severity as well as management approaches. This review aims to establish what has been reported on this condition from the African continent so as to better define key clinical and research questions.

Risk Factors for Antenatal Depression and Associations with Infant Birth Outcomes: Results From a South African Birth Cohort Study

BACKGROUND Maternal antenatal depression may be particularly prevalent in low- and middle-income countries, but there is a paucity of data on its effect on birth outcomes in such settings. We investigated risk factors for antenatal depression and the associations between depression and infant birth outcomes in the Drakenstein Child Health Study (DCHS), a birth cohort study in the Western Cape, South Africa. METHODS The prevalence of depression in pregnant women enrolled in the DCHS from primary care antenatal clinics was measured using the Beck Depression Inventory (BDI-II). Predictors of antenatal depression were investigated using logistic regression, and the associations between depression and infant birth outcomes were examined in linear regression models. RESULTS Among 726 pregnant women (median age: 26 years), 156 (21%) had BDI-II scores suggesting depression. Independent predictors of depression included single marital status, low socioeconomic status (SES), recent stressful life events, unplanned pregnancy, childhood trauma, and past-year intimate partner violence. No association was observed between antenatal depression and preterm birth. Strong associations were observed between antenatal depression and decreased infant weight-for-age (WAZ) and head circumference-for-age (HCAZ) z-scores at birth. In multivariable analysis, the association between depression and decreased HCAZ remained significant, when adjusted for clinic, SES, and recent stressful life events. CONCLUSIONS Antenatal depression and associated risk factors are highly prevalent in this setting and are associated with adverse fetal growth. Maternal mental health may be an important predictor of infant growth in utero.

Pediatric Cerebral Palsy in Africa: Where Are We?

Cerebral palsy is the most common cause of physical disability in children worldwide. However, little is reported on this condition in the African context. Doctors from 22 countries in Africa, and representatives from a further 5 countries outside Africa, met to discuss the challenges in the evaluation and management of children with cerebral palsy in Africa and to propose service needs and further research. Basic care is limited by the poor availability of diagnostic facilities or medical personnel with experience and expertise in managing cerebral palsy, exacerbated by lack of available interventions such as medications, surgical procedures, or even regular therapy input. Relevant guidelines are lacking. In order to guide services for children with existing disabilities, to effectively target the main etiologies and to develop preventive strategies for the continent, research priorities must include multicenter collaborative studies looking at the prevalence, risk factors, and treatment of cerebral palsy.

Systematic review of neuroimaging studies in vertically transmitted HIV positive children and adolescents

One of the most serious consequences of vertical HIV-infection is its impact on the central nervous system (CNS). Although much work has been done to elucidate the complex mechanism of HIV associated neurotoxicity, several questions remain unanswered. The purpose of this review is to summarise what is already known in the field of neuroimaging in vertically acquired HIV, addressing three aims and to highlight possible future directions in using neuroimaging and neurocognitive testing to understand the spectrum of neurocognitive disorders in HIV positve children. Here we aim to address several clinically relevant questions in pediatric neuroHIV, using the current evidence base by conducting a systematic review. We aim to investigate what is known about the relationship between cognitive impairment and central nervous system damage in HIV as seen in neuroimaging studies, and to search for any evidence in the current literature which suggests a spectrum of neuocognitive disorders in vertically infected HIV. Secondly, we aim to enquire whether children with a clinical diagnosis of encephalopathy are clearly distinguishable from HIV positive children without encephalopathy on neuroimaging and neurocognitive testing. Finally aim to investigate what is known about the effect on the CNS of antiretroviral therapy in paediatric HIV. Three separate databases were searched and two investigators systematically evaluated the titles, abstracts, and keywords associated with each individual article to determine those that may have met the inclusion and exclusion criteria. Following this process 11 studies were included in the review. Thus there was limited available data to address the 3 questions posed.

White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa.

Objective:To describe the effect of HIV on white matter integrity and neurocognitive function in children vertically infected with HIV, compared to a HIV-negative healthy control group. Design:Cross-sectional. Methods:We compared 75 HIV-infected children aged 6–16 years, including children on antiretroviral therapy (ART) and those who were ART-naive, with 30 controls on diffusion tensor imaging and a neuropsychological battery sensitive to fronto-striatal pathology. In a secondary analysis, we compared ‘slow progressor’ ART-naive children, children on ART without a diagnosis of encephalopathy and children on ART with HIV encephalopathy. Results:Compared to controls (n = 30), HIV-infected children (n = 75) displayed decreased fractional anisotropy and axial diffusion, and increased mean diffusivity and radial diffusion, indicating damaged neuronal microstructure. HIV-infected children performed poorly on the neuropsychological battery (P = <0.001). Within the HIV-infected group, children with HIV encephalopathy (n = 14) had poor white matter integrity when compared to ART-treated children without encephalopathy (n = 41), and there was significant myelin loss in ART-naive children (n = 20), compared with ART-treated children. ART-treated children had significant axonal damage in the corpus callosum (P = 0.009). Conclusion:Children infected with HIV, irrespective of treatment status, displayed significantly poorer white matter integrity and impaired cognition compared to HIV-negative controls. Our findings suggest that despite immune recovery in children on ART, they remain at risk for developing central nervous system disease, and that initiation of ART as early as possible may reduce the risk of developing white matter damage in ART-naive slow progressors.

HIV Encephalopathy: pediatric case series description and insights from the clinic coalface

BackgroundThe Human Immune Deficiency Virus (HIV) can manifest neurologically in both adults and children. Early invasion of the central nervous system by the virus, affecting the developing brain, is believed to result in the most common primary HIV-related neurological complication, HIV Encephalopathy (HIVE). In countries such as South Africa where many children have not been initiated on antiretroviral treatment early, HIVE remains a significant clinical problem.MethodsChildren were selected from a clinic for children with neurologic complications of HIV, located at the Red Cross War Memorial Children’s Hospital, South Africa 2008–2012. Eligible subjects fulfilled the following inclusion criteria: aged 6 months-13 years; positive diagnosis of HIV infection, vertically infected and HIVE as defined by CDC criteria. Each participant was prospectively assessed by a Pediatric Neurologist using a standardized proforma which collated relevant details of background, clinical and immunological status.Results The median age of the 87 children was 64 months (interquartile range 27–95 months). All except one child were on antiretroviral treatment, 45% had commenced treatment <12 months of age. Delayed early motor milestones were reported in 80% and delayed early speech in 75% of children in whom we had the information. Twenty percent had a history of one or more seizures and 41% had a history of behavior problems. Forty-eight percent had microcephaly and 63% a spastic diplegia. CD4 percentages followed a normal distribution with mean of 30.3% (SD 8.69). Viral loads were undetectable (<log 1.6) in 70% of the children. Brain imaging was performed on 56% with 71% of those imaged demonstrating at least one abnormality, most commonly white matter volume loss or signal abnormality. ConclusionsAmongst the cohort of children referred to this clinic, the diagnosis of HIVE was unrecognized in the general medical services, even in its most severe form. Developmental delay and school failure were major presenting problems. Co-morbidities are a frequent finding and should be sought actively in order to optimize management and promote best possible outcomes for this vulnerable group of children.

Update on the key developments of the neurologic complications in children infected with HIV.

Purpose of reviewTo discuss recent research findings of neurologic complications in HIV-infected children, specifically addressing neuroinfections, cerebrovascular disease, epilepsy and neurocognitive complications. The range of neurologic childhood onset complications is diverse and often overlaps diseases previously considered only to manifest in adults. In the pediatric population, these complications frequently have their own unique disease identity, which may be related to maturational patterns evident in the developing brain. Recent findingsDevelopments regarding the pathogenesis of neuroAIDS, treatment of tuberculous meningitis and prevention of bacterial meningitis are described. With the advent of neuroimaging, there is greater insight into silent cerebrovascular events and the progression of vasculopathy in HIV-infected children. The role of surgical intervention for affected cases is a novel area that could alter the otherwise poor prognosis. Epilepsy, although common as a burden of disease, carries its own additional complications with regard to cross reactivity with various antiretroviral therapies. Increased risk of low bone mineral density supports a role for supplementation with vitamin D in people receiving antiretroviral therapy and antiepileptic drugs. Recognition of the early neurobiological, as well as spectrum of neurocognitive effects of the HIV on the developing brain, is evolving, as greater numbers of children are treated early. Developments in these critical areas are described. SummaryRecent research reflects the need for improved strategies to prevent neuroinfections, more effective screening and interventions for vasculopathy and better antiepileptic drugs for HIV-infected children. Furthermore, our understanding of the timing and spectrum of neurocognitive complications is evolving.

Neurologic Complications of Pediatric Human Immunodeficiency Virus: Implications for Clinical Practice and Management Challenges in the African Setting

Approximately 3.4 million children worldwide are affected with human immunodeficiency virus (HIV)/AIDS with more than 90% of them residing in sub-Saharan Africa, according to the World Health Organization. A significant proportion of the children eligible for treatment with antiretroviral therapy are not currently receiving it. Neurologic manifestations of HIV are common in both adults and children. There is a large spectrum of neurologic conditions that may be caused by the virus; however, early invasion of the central nervous system by the virus, affecting the developing fetal and infant brain, is believed to result in the most common primary HIV-related central nervous system complication, HIV encephalopathy. This article summarizes the spectrum of neuro-HIV in children, focuses on the neurocognitive and behavioral sequelae, reviews the effects of treatment on the primary neurologic effects of the disease, and discusses the specific challenges of identifying and managing these problems in resource-limited contexts, such as those found on the African continent.

Structural brain changes in prenatal methamphetamine-exposed children.

The global use of methamphetamine (MA) has increased substantially in recent years, but the effect of MA on brain structure in prenatally exposed children is understudied. Here we aimed to investigate potential changes in brain volumes and cortical thickness of children with prenatal MA-exposure compared to unexposed controls. Eighteen 6-year old children with MA-exposure during pregnancy and 18 healthy controls matched for age, gender and socio-economic background underwent structural imaging. Brain volumes and cortical thickness were assessed using Freesurfer and compared using ANOVA. Left putamen volume was significantly increased, and reduced cortical thickness was observed in the left hemisphere of the inferior parietal, parsopercularis and precuneus areas of MA-exposed children compared to controls. Compared to control males, prenatal MA-exposed males had greater volumes in striatal and associated areas, whereas MA-exposed females predominantly had greater cortical thickness compared to control females. In utero exposure to MA results in changes in the striatum of the developing child. In addition, changes within the striatal, frontal, and parietal areas are in part gender dependent.