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Ray STJ, Fuller CE, Boubour A, Tshimangani T, Kafoteka E, Muiruri-Liomba A, Malenga A, Tebulo A, Pensulo P, Gushu MB, Nielsen M, Raees M, Stockdale E, Langton J, Birbeck GL, Waithira N, Bonnett LJ, Henrion MY, Fink EL, Postels DG, O'Brien N, Page AL, Baron E, Gordon SB, Molyneux E, Dondorp A, George EC, Maitland K, Michael BD, Solomon T, Chimalizeni Y, Lalloo DG, Moxon CA, Taylor T, Mallewa M, Idro R, Seydel K, Griffiths MJ. The aetiologies, mortality, and disability of non-traumatic coma in African children: a systematic review and meta-analysis. Lancet Glob Health 2025; 13:e1043-e1056. [PMID: 40280144 DOI: 10.1016/s2214-109x(25)00055-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 12/18/2024] [Accepted: 01/30/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Non-traumatic coma in African children is a common life-threatening presentation often leading to hospital attendance. We aimed to estimate the distribution of non-traumatic coma causes and outcomes, including disease-specific outcomes, for which evidence is scarce. METHODS We systematically reviewed MEDLINE, Embase, and Scopus databases from inception to Feb 6, 2024. We included studies recruiting children (aged 1 month to 16 years) with non-traumatic coma (Blantyre Coma Scale score ≤2, ie deep coma or comparable alternative) from any African country. Disease-specific studies were included if outcomes were reported. Primary data were requested where required. We used a DerSimonian-Laird random effects model to calculate pooled estimates for prevalence of causes, mortality, and morbidity (in-hospital and post-discharge), including analysis of mortality by temporality. This study was registered with PROSPERO (CRD4202014193). FINDINGS We screened 16 666 articles. 138 studies were eligible for analysis, reporting causes, outcome data, or both from 35 027 children with non-traumatic coma in 30 African countries. 114 (89%) of 128 studies were determined to be high quality. Among the causes, cerebral malaria had highest pooled prevalence at 58% (95% CI 48-69), encephalopathy of unknown cause was associated with 23% (9-36) of cases, and acute bacterial meningitis was the cause of 10% (8-12) of cases, with all other causes representing lower proportions of cases. Pooled overall case-fatality rates were 17% (16-19) for cerebral malaria, 37% (20-55) for unknown encephalopathy, and 45% (34-55) for acute bacterial meningitis. By meta-regression, there was no significant difference in cerebral malaria (p=0·98), acute bacterial meningitis (p=0·99), or all-cause coma (p=0·081) mortality by year of study. There was no substantial difference in deaths associated with cerebral malaria in-hospital compared with post-discharge (17% [16-19] vs (18% [16-20]). Mortality was higher post-discharge than in-hospital in most non-malarial comas, including acute bacterial meningitis (39% [26-52]) vs 53% [38-69]). Disability associated with cerebral malaria was 11% (9-12). Pooled disability outcomes associated with other non-malarial diseases were largely absent. INTERPRETATION The prevalence and outcomes of cerebral malaria and meningitis associated with non-traumatic coma were strikingly static across five decades. Enhanced molecular and radiological diagnostics, investment, policy making, community awareness, and health service provision are all required to facilitate earlier referral to specialist centres, to drive a step-change in diagnostic yield and treatment options to improve these outcomes. FUNDING Wellcome Trust. TRANSLATIONS For the Chichewa, French and Portuguese translations of the abstract see Supplementary Materials section.
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Affiliation(s)
- Stephen T J Ray
- Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Infectious Disease and Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Wilson Lab, Weil Institute for Neurosciences, University of San Francisco, San Francisco, CA, USA.
| | - Charlotte E Fuller
- The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; Department of Paediatric Immunology, Allergy and Infectious Diseases, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Alex Boubour
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Taty Tshimangani
- Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Edith Kafoteka
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Alice Muiruri-Liomba
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Albert Malenga
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Andrew Tebulo
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Paul Pensulo
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Monfort B Gushu
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Maryke Nielsen
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Madiha Raees
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Elisabeth Stockdale
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Josephine Langton
- Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Gretchen L Birbeck
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Neurology, University of Rochester, Rochester, NY, USA
| | - Naomi Waithira
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Nakhon Pathom, Thailand
| | - Laura J Bonnett
- Department of Health Data Science, University of Liverpool, Liverpool, UK
| | - Marc Yr Henrion
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK
| | - Ericka L Fink
- Division of Critical Care Medicine, Department of Anaesthesiology and Critical Care, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, PA, USA
| | - Douglas G Postels
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Division of Neurology, George Washington University and Children's National Health System, Washington, DC, USA
| | - Nicole O'Brien
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Hôpital Pédiatrique de Kalembe Lembe, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of the Congo; Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital and Ohio State University, Columbus, OH, USA
| | | | | | - Stephen B Gordon
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK
| | - Elizabeth Molyneux
- Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Arjen Dondorp
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Nakhon Pathom, Thailand
| | - Elizabeth C George
- Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK
| | - Kathryn Maitland
- Department of Infectious Disease and Institute of Global Health and Innovation, Faculty of Medicine, Imperial College, London, UK; Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
| | - Benedict D Michael
- The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Tom Solomon
- The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK; The Pandemic Institute, University of Liverpool, Liverpool, UK
| | - Yamikani Chimalizeni
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - David G Lalloo
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Liverpool School of Tropical Medicine, Liverpool, UK
| | - Christopher A Moxon
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; School of Infection and Immunity, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Terrie Taylor
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Macpherson Mallewa
- Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi
| | - Richard Idro
- Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Karl Seydel
- Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi; Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi; Department of Paediatrics and Child Health, Kamzu University of Health Sciences, Blantyre, Malawi; College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Michael J Griffiths
- The Brain Infection and Inflammation Group, University of Liverpool, Liverpool, UK; Centre for Child and Adolescent Health Research, Western Sydney (Baludarri) Precinct, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia
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de Lima RMS, Leão LKR, Martins LC, Passos ADCF, Batista EDJO, Herculano AM, Oliveira KRHM. Unveiling new perspectives about the onset of neurological and cognitive deficits in cerebral malaria: exploring cellular and neurochemical mechanisms. Front Cell Infect Microbiol 2025; 15:1506282. [PMID: 39981376 PMCID: PMC11839640 DOI: 10.3389/fcimb.2025.1506282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/02/2025] [Indexed: 02/22/2025] Open
Abstract
Cerebral malaria is the most severe and lethal complication caused by Plasmodium falciparum infection, leading to critical neurological impairments and long-term cognitive, behavioral, and neurological sequelae in survivors, particularly affecting children under the age of five. Various hypotheses have been proposed to explain the neurological syndrome associated to cerebral malaria condition, including vascular occlusion and sequestration, cytokine storm or inflammatory response, or a combination of these mechanisms and despite extensive research and a growing range of scientific information, the precise pathophysiological mechanism remains poorly understood. In this sense, this review aims to explore the neurological impairment in cerebral malaria and elucidate novel mechanisms to explain the severity of this disease. Recent evidence implicates glutamate and glutamatergic pathways in the onset of cerebral malaria, alongside the impairments in the metabolic activity of other molecules such as dopamine and kynurenic acid. These neurotransmitters pathways may play a crucial role in the pathogenesis of cerebral malaria, potentially interacting with other molecular players. By enhancing our understanding in the pathophysiology of cerebral malaria, this article seeks to explore new hypotheses regarding the involvement of neurotransmitters and their interactions with other molecular targets, thereby contributing to the overall pathology of cerebral malaria.
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Affiliation(s)
- Renato M. S. de Lima
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
| | - Luana K. R. Leão
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
| | - Luana C. Martins
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
| | - Adelaide da C. Fonseca Passos
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
| | | | - Anderson M. Herculano
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
| | - Karen R. H. M. Oliveira
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, Federal University of Pará, Belém, Brazil
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Opoka RO, Namazzi R, Datta D, Bangirana P, Conroy AL, Goings MJ, Mellencamp KA, John CC. Severe falciparum malaria in young children is associated with an increased risk of post-discharge hospitalization: a prospective cohort study. Malar J 2024; 23:367. [PMID: 39633351 PMCID: PMC11616343 DOI: 10.1186/s12936-024-05196-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Few studies have described post-discharge morbidity of children with specific manifestations of severe malaria (SM) beyond severe malarial anaemia or cerebral malaria. METHODS Children 6 months to 4 years of age admitted at Jinja and Mulago hospitals in Uganda, with one or more of the five most common forms of SM, cerebral malaria (n = 53), respiratory distress syndrome (n = 108), malaria with complicated seizures (n = 160), severe malarial anaemia (n = 155) or prostration (n = 75), were followed for 12 months after discharge, alongside asymptomatic community children (CC) (n = 120) of similar ages recruited from the households or neighbourhoods of the children with SM. Incidence and risk of hospitalizations, death or outpatient clinic visits were compared between children with SM and CC. RESULTS 312/551 (56.6%) of children with SM had one or more post-discharge hospitalization over 12 months, compared to 37/120 (30.8%) of CC. Frequency of hospitalization was similar across all forms of SM. Compared to CC, children with SM had a significantly higher risk of all-cause hospitalization (adjusted hazard ratio (aHR) 1.91, 95% confidence interval (CI) 1.39-2.63, p < 0.001) and hospitalization for severe malaria (aHR 1.94, CI 1.36-2.78, p < 0.001), but a similar risk of outpatient clinic visits for malaria (aHR 1.24, 95% CI 0.89-1.73, p = 0.20). 82% of hospitalizations in children with SM (575/700) and CC (50/61) were due to malaria. CONCLUSIONS In this malaria endemic region, children with the five most common forms of SM had higher rates of post-discharge hospitalization than asymptomatic community children, and > 80% of hospitalizations were due to severe malaria. Studies of post-discharge malaria chemoprevention are urgently needed for children with SM, to determine if this treatment can reduce post-discharge morbidity.
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Affiliation(s)
- Robert O Opoka
- Medical College East Africa, Aga Khan University, Nairobi, Kenya.
| | - Ruth Namazzi
- Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda
- Global Health Uganda (GHU) Research Collaboration, Kampala, Uganda
| | - Dibyadyuti Datta
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indiana, USA
| | - Paul Bangirana
- Global Health Uganda (GHU) Research Collaboration, Kampala, Uganda
- Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Andrea L Conroy
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indiana, USA
| | - Michael J Goings
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indiana, USA
| | - Kagan A Mellencamp
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indiana, USA
| | - Chandy C John
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indiana, USA
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Opoka RO, Namazzi R, Datta D, Bangirana P, Conroy AL, Goings MJ, Mellencamp KA, John CC. Severe falciparum malaria in young children is associated with an increased risk of post-discharge readmission or death: A prospective cohort study. RESEARCH SQUARE 2024:rs.3.rs-5104320. [PMID: 39606459 PMCID: PMC11601819 DOI: 10.21203/rs.3.rs-5104320/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Introduction Few studies have described post-discharge morbidity of children with specific manifestations of severe malaria (SM) beyond severe malarial anemia or cerebral malaria. Methods Children 6 months to 4 years of age admitted at Jinja and Mulago hospitals in Uganda, with one or more of the five most common manifestations of SM, cerebral malaria (n=53), respiratory distress syndrome (n=108), malaria with complicated seizures (n=160), severe malarial anemia (n=155) or prostration (n=75), were followed for 12 months after discharge, along with community children (CC) (n=120) recruited from the household or neighborhood of the children with SM. Incidence and risk of post-discharge readmission, death or outpatient clinic visits were compared between children with SM and CC. Results 312/551 (56.6%) of children with SM had one or more post-discharge readmission, compared to 37/120 (30.8%, p<0.001) of CC. Frequency of readmission was similar across all forms of SM. Compared to CC, children with SM had significantly higher risk of post-discharge readmission or death (adjusted hazard ratio (aHR) 2.06, 95% confidence interval (CI) 1.51-2.81, p<0.001), but a similar risk of outpatient malaria (aHR 1.30, 95% CI 0.97-1.74, p=0.08). 82% of readmissions in children with SM were due to malaria. Conclusions In this malaria endemic region, children with the most common forms of SM had higher rates of post-discharge readmission or death than CC, and >80% of readmissions were due to malaria. Studies of post-discharge malaria chemoprevention are urgently needed for children with SM, to determine if this treatment can reduce post-discharge morbidity and mortality.
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Mseza B, Kumbowi PK, Nduwimana M, Banga D, Busha ET, Egesa WI, Odong RJ, Ndeezi G. Prevalence and factors associated with cerebral malaria among children aged 6 to 59 months with severe malaria in Western Uganda: a hospital-based cross-sectional study. BMC Pediatr 2024; 24:704. [PMID: 39506687 PMCID: PMC11539429 DOI: 10.1186/s12887-024-05178-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/24/2024] [Indexed: 11/08/2024] Open
Abstract
INTRODUCTION Cerebral malaria, caused by Plasmodium falciparum, represents the most severe neurologic complication of malaria. Its association with high morbidity and mortality rates, especially among young children, underscores its clinical significance. In sub-Saharan Africa, including Uganda, cerebral malaria remains a major health challenge, contributing significantly to the high child mortality rate. Despite advances in malaria control, the burden of cerebral malaria among children under five is substantial, reflecting the need for targeted interventions and improved management strategies. This study aimed to determine the prevalence of cerebral malaria and identify associated factors among children admitted with severe malaria at a tertiary hospital in western Uganda. METHODS This was a cross-sectional, descriptive, and analytical study involving children aged 6 to 59 months admitted with severe malaria. The study was conducted from January to March 2023 at Fort Portal Regional Referral Hospital. Severe and cerebral malaria were defined as per the WHO criteria. Sociodemographic, clinical, and laboratory data were collected and analyzed using IBM SPSS version 27. Logistic regression analysis was used to evaluate the factors associated with cerebral malaria. A p-value < 0.05 indicated statistical significance. RESULTS A total of 250 children were recruited (mean age 33.1 ± 17.3 months). The prevalence of cerebral malaria was 12.8% (95% CI: 8.9-17.6). Cerebral malaria was independently associated with male sex (aOR: 3.05, 95% CI: 1.20-7.77, p = 0.02), abnormal bleeding (aOR: 13.22, 95% CI: 11.54-15.16, p = 0.001), history of convulsions (aOR 12.20, 95% CI: 10.7-21.69, p = 0.010), acute kidney injury (aOR: 4.50, 95% CI: 1.30-15.53, p = 0.02), and hyponatremia (aOR: 3.47, 95% CI: 1.34-8.96, p = 0.010). CONCLUSIONS AND RECOMMENDATIONS The prevalence of cerebral malaria was high among children with severe malaria. Factors associated with cerebral malaria included male gender, history of convulsions, abnormal bleeding, acute kidney injury, and hyponatremia. Targeted interventions and early management are essential to improve clinical outcomes.
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Affiliation(s)
- Banga Mseza
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda.
| | - Patrick Kumbakulu Kumbowi
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda
| | - Martin Nduwimana
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda
| | - Desire Banga
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda
| | - Emmanuel Tibasima Busha
- Department of Pediatrics and Child Health, Université Libre Des Pays Des Grands Lacs, Goma, Democratic Republic of Congo
| | - Walufu Ivan Egesa
- Department of Pediatrics, Nile International Hospital, Jinja, Uganda
| | - Richard Justin Odong
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda
| | - Grace Ndeezi
- Department of Pediatrics and Child Health, Faculty of Clinical Medicine and Dentistry, Kampala International University, Kampala, Uganda
- Department of Pediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
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Makasi CE, Ngowi B, Mahande MJ, Welte TM, Stelzle D, Guga G, Schmidt V, Rüther C, Lema Y, Fabien Prodjinotho U, Kilale A, Prazeres da Costa C, Mmbaga BT, Winkler AS. Neurocysticercosis and cognitive impairment among people with epilepsy in Taenia solium endemic regions of rural southern Tanzania: A hospital-based cross-sectional study in mental health clinics of selected sites in Tanzania. Epilepsy Behav 2024; 159:110010. [PMID: 39186856 DOI: 10.1016/j.yebeh.2024.110010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/20/2024] [Accepted: 08/20/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND Epilepsy poses a significant public health problem in many parts of the world. The majority of people with epilepsy (PWE) are from low-income and middle-income countries (LMICs). Taenia solium neurocysticercosis (NCC) is estimated to cause 30% of preventable epilepsy in PWE in areas of T. solium endemicity. This study was conducted to assess the prevalence of NCC in PWE, evaluate the presence of cognitive impairment in PWE and assess potentially contributing factors. METHODS PWE were recruited within a mental health clinic-based cross-sectional study in rural Southern Tanzania. PWE underwent a detailed neurological examination, including mental state, and a blood sample was collected for T. solium cysticercosis (CC) serology testing. Patients who were serologically positive for CC and those detected to have prominent neurological deficits apart from epilepsy were invited to receive a cerebral computed tomography (CT) examination. RESULTS Out of the 223 people with epilepsy (PWE) recruited, 221 underwent clinical examination. Among these, 26 (11.8 %) had cognitive impairment, and 2 had neurological signs or symptoms without cognitive impairment. Twenty-five of the 223 PWE (11.2 %) tested positive for CC, of which 4 had cognitive impairment. One hundred and ninety-eight (88.8 %) tested negative for CC, of which 22 had cognitive impairment. A total of 36 participants underwent CT scans, with 18 testing positive and 18 testing negative for CC. Of the 36 who had CT scans, 8 (22.2 %) were diagnosed with NCC; 7 were CC positive, and 1 was CC negative; only the latter had cognitive impairment. Multivariate logistic regression confirmed that cognitive impairment in PWE was 8.62 times higher for Kongwa participants than Chunya, with a statistically significant association (95 % CI: 1.75, 156; p = 0.037). Additionally, having and education was associated with a 91 % reduction in the odds of cognitive impairment (OR = 0.09) compared to no education, which was also statistically significant (95 % CI: 0.01, 0.33; p = 0.002). There was no association between cognitive impairment and NCC. CONCLUSION Our study found a 22.2 % prevalence of NCC among PWE. Cognitive impairment was present in 11.8 % of PWE but was not significantly associated with NCC. Socioeconomic and educational factors may play a larger role in cognitive impairment among PWE.
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Affiliation(s)
- Charles E Makasi
- National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania; Kilimanjaro Christian Medical University College, Moshi, Tanzania.
| | - Bernard Ngowi
- Mbeya College of Health and Allied Sciences, University of Dar es Salaam, Mbeya, Tanzania.
| | - Michael J Mahande
- Department of Epidemiology & Biostatistics, Institute of Public Health, Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Tamara M Welte
- Department of Neurology, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany.
| | - Dominik Stelzle
- Department of Neurology, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany.
| | - Godfrey Guga
- Haydom Global Health Research Centre, Haydom Lutheran Hospital, Mbulu, Tanzania
| | - Veronika Schmidt
- Department of Neurology, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany.
| | - Charlotte Rüther
- Department of Neuroradiology, Faculty of Medicine, Technical University of Munich, Munich, Germany.
| | - Yakobo Lema
- National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania
| | - Ulrich Fabien Prodjinotho
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany.
| | - Andrew Kilale
- National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania
| | - Clarissa Prazeres da Costa
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany; German Center for Infection and Research (DZIF), Munich, Germany.
| | - Blandina T Mmbaga
- Kilimanjaro Christian Medical University College, Moshi, Tanzania; Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre, Moshi, Tanzania
| | - Andrea S Winkler
- Department of Neurology, Technical University of Munich, Munich, Germany; Center for Global Health, Technical University of Munich, Munich, Germany; Department of Community Medicine and Global Health, Institute of Health and Society, University of Oslo, Oslo, Norway; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
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Chilombe MB, Seydel KB, Hammond CA, Mwanza S, Patel AA, Lungu F, wa Somwe S, Kampondeni S, Potchen MJ, McDermott MP, Birbeck GL. Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria? PLoS One 2024; 19:e0294823. [PMID: 38640099 PMCID: PMC11029645 DOI: 10.1371/journal.pone.0294823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/20/2024] [Indexed: 04/21/2024] Open
Abstract
BACKGROUND Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. METHODS This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. DISCUSSION Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.
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Affiliation(s)
- Moses B. Chilombe
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
| | - Karl B. Seydel
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
- Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, United States of America
| | - Colleen A. Hammond
- Department of Radiology, Michigan State University, East Lansing, Michigan, United States of America
| | - Suzanna Mwanza
- Department of Pediatrics and Child Health, Chipata Central Hospital, Chipata, Zambia
| | - Archana A. Patel
- Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Frank Lungu
- Neurology Research Office, University Teaching Hospitals Children’s Hospital, Lusaka, Zambia
| | - Somwe wa Somwe
- Neurology Research Office, University Teaching Hospitals Children’s Hospital, Lusaka, Zambia
| | - Sam Kampondeni
- Mpingwe Clinic, Limbe, Malawi
- Department of Imaging Sciences, University of Rochester, Rochester, New York, United States of America
| | - Michael J. Potchen
- Department of Imaging Sciences, University of Rochester, Rochester, New York, United States of America
- Zambia College of Medicine and Surgery, Lusaka, Zambia
| | - Michael P. McDermott
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, United States of America
- Department of Neurology, University of Rochester, Rochester, New York, United States of America
| | - Gretchen L. Birbeck
- Neurology Research Office, University Teaching Hospitals Children’s Hospital, Lusaka, Zambia
- Department of Neurology, University of Rochester, Rochester, New York, United States of America
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Zoumenou R, Bodeau-Livinec F, Chausseboeuf L, Boivin MJ, Wendland J. Is Neurodevelopmental Assessment in Early Childhood Predictive of Performance Assessed Later in Childhood and Adolescence in Sub-Saharan Africa? A Systematic Review of the Literature. Arch Clin Neuropsychol 2024; 39:98-116. [PMID: 37470401 PMCID: PMC10802230 DOI: 10.1093/arclin/acad051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Most neurodevelopmental tests used to assess child development in sub-Saharan Africa were developed in western or high-income countries, raising the question of their usefulness with African children. OBJECTIVE This systematic review identified and synthesized key findings from studies measuring development in children in Sub-Saharan Africa in early childhood and again at school age, to assess neurocognitive associations longitudinally from infancy through middle childhood. METHODS The study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, selecting articles referenced in the PubMed, PsycInfo, and Embase databases using the following inclusion criteria: published between 2000 and 2022, written in French or English, and presenting results dealing with the objective assessment of child's neurodevelopment. All articles were registered in the Zotero reference manager and analyzed by title, abstract, and full text. RESULTS Several of the seven selected studies confirmed that attention and working memory in infancy can predict children's neurocognitive performance, including mathematical ability, at school age. In two of the studies, children with poor mental development at 1 year of age are more likely to present with poorer behavioral development at school age, including learning difficulties in school and risk for grade repetition. CONCLUSION Cognitive ability assessed in early childhood is strongly associated with performance at school age in cohorts of African children followed longitudinally. Even with assessments adapted cross-culturally, infants and preschoolers at risk for poor developmental outcomes can be identified to better receive strategic early interventions to enhance their development.
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Affiliation(s)
- Roméo Zoumenou
- Institut de Recherche pour le Developpement, Mère et enfant face aux infections tropicales, 75006 Paris, France
- Laboratoire psychopathologie et processus en santé, Institute de psychologie, 92774 Boulogne, France
| | - Florence Bodeau-Livinec
- Institut de recherche en santé, environnement et travail (IRSET), Ecole des hautes etudes en santé (EHESP), 93210 Saint-Denis, France
| | - Léa Chausseboeuf
- Laboratoire psychopathologie et processus en santé, Institute de psychologie, 92774 Boulogne, France
| | - Michael J Boivin
- Department of Psychiatry and Department of Neurology & Ophthalmology, Michigan State University, East Lansing, MI 48824 USA
- Department of Psychiatry, University of Michigan, Ann Arbor, MI 48104, USA
| | - Jaqueline Wendland
- Laboratoire psychopathologie et processus en santé, Institute de psychologie, 92774 Boulogne, France
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9
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Engeda EH, Aldersey HM, Davison CM, Gelaye KA, Abebe AB, Chala MB, Fayed N. Severe malaria-related disability in African children: a scoping review. Disabil Rehabil 2024; 46:31-39. [PMID: 36533299 DOI: 10.1080/09638288.2022.2157053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE Disability is a consequence of severe malaria for a significant proportion of African children. This scoping review aims to describe the impact of severe malaria on African children according to current literature using an international biopsychical classification and framework of disability and functioning. MATERIALS AND METHODS MEDLINE, EMBASE, Global Health, and CINHAL databases were searched for original research conducted on African children aged 0-18 using terms related to severe malaria and components of disability. Independent and dependent variables were extracted and classified using the World Health Organization's International Classification of Functioning, Disability, and Health-Children and Youth version (ICF-CY) using standardized coding methods. RESULTS Seventy-two percent of the measured variables in the 34 included studies were coded as "body functions," (i.e., impairments), such as mental, neuromusculoskeletal, movement, and sensory functions, and 23.3% of variables were coded as "activities and participation" (i.e., activity limitations/participation restrictions), such as difficulties with general tasks and demands, communication, mobility, interpersonal interactions, and relationships. "Environment" variables such as family support, health access, education, or societal attitudes were not found in the included studies. CONCLUSIONS Existing peer-reviewed quantitative research of severe malaria-related disability is focused on neurological sequelae, with less research about activity limitations and participation restrictions.
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Affiliation(s)
- Eshetu Haileselassie Engeda
- Department of Pediatrics and Child Health Nursing, School of Nursing, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada
| | - Heather M Aldersey
- School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada
| | - Colleen M Davison
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Kassahun Alemu Gelaye
- Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abey Bekele Abebe
- School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada
- Department of Physiotherapy, School of Medicine, Gondar University Specialized Comprehensive Hospital, University of Gondar, Gondar, Ethiopia
| | - Mulugeta Bayisa Chala
- School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada
- Department of Physiotherapy, School of Medicine, Gondar University Specialized Comprehensive Hospital, University of Gondar, Gondar, Ethiopia
| | - Nora Fayed
- School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada
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10
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Chilombe MB, Seydel KB, Hammond C, Mwanza S, Patel AA, Lungu F, Somwe SW, Kampondeni S, Potchen MJ, McDermott MP, Birbeck GL. Protocol for a Magnetic Resonance Imaging (MRI) Study of Participants in the Fever Randomized Controlled Trial: Does fever control prevent brain injury in malaria? MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.10.23298374. [PMID: 37986869 PMCID: PMC10659499 DOI: 10.1101/2023.11.10.23298374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Background Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. Methods This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. Discussion Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.
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Affiliation(s)
- Moses B. Chilombe
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
| | - Karl B. Seydel
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi
- Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, Michigan, USA
| | - Colleen Hammond
- Department of Radiology, Michigan State University, East Lansing, Michigan, USA
| | - Suzanna Mwanza
- Department of Pediatrics and Child Health, Chipata Central Hospital, Chipata, Zambia
| | - Archana A. Patel
- Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Frank Lungu
- University Teaching Hospitals Children’s Hospital, Neurology Research Office, Lusaka, Zambia
| | - Somwe wa Somwe
- University Teaching Hospitals Children’s Hospital, Neurology Research Office, Lusaka, Zambia
| | - Sam Kampondeni
- Mpingwe Clinic, Limbe, Malawi
- Department of Imaging Sciences, University of Rochester, Rochester, New York, USA
| | - Michael J. Potchen
- Department of Imaging Sciences, University of Rochester, Rochester, New York, USA
- Zambia College of Medicine and Surgery, Lusaka, Zambia
| | - Michael P. McDermott
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA
- Department of Neurology, University of Rochester, Rochester, New York, USA
| | - Gretchen L. Birbeck
- University Teaching Hospitals Children’s Hospital, Neurology Research Office, Lusaka, Zambia
- Department of Neurology, University of Rochester, Rochester, New York, USA
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11
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Ssemata AS, Nakitende AJ, Kizito S, Thomas MR, Islam S, Bangirana P, Nakasujja N, Yang Z, Yu Y, Tran TM, John CC, McHenry MS. Association of severe malaria with cognitive and behavioural outcomes in low- and middle-income countries: a meta-analysis and systematic review. Malar J 2023; 22:227. [PMID: 37537555 PMCID: PMC10401769 DOI: 10.1186/s12936-023-04653-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 07/22/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Malaria affects 24 million children globally, resulting in nearly 500,000 child deaths annually in low- and middle-income countries (LMICs). Recent studies have provided evidence that severe malaria infection results in sustained impairment in cognition and behaviour among young children; however, a formal meta-analysis has not been published. The objective was to assess the association between severe malaria infection with cognitive and behavioural outcomes among children living in LMICs. METHODS Six online bibliographic databases were searched and reviewed in November 2022. Studies included involved children < 18 years of age living in LMICs with active or past severe malaria infection and measured cognitive and/or behaviour outcomes. The quality of studies was assessed. Definitions of severe malaria included cerebral malaria, severe malarial anaemia, and author-defined severe malaria. Results from all studies were qualitatively summarized. For studies with relevant data on attention, learning, memory, language, internalizing behaviour and externalizing behaviour, results were pooled and a meta-analysis was performed. A random-effects model was used across included cohorts, yielding a standardized mean difference between the severe malaria group and control group. RESULTS Out of 3,803 initial records meeting the search criteria, 24 studies were included in the review, with data from 14 studies eligible for meta-analysis inclusion. Studies across sub-Saharan Africa assessed 11 cohorts of children from pre-school to school age. Of all the studies, composite measures of cognition were the most affected areas of development. Overall, attention, memory, and behavioural problems were domains most commonly found to have lower scores in children with severe malaria. Meta-analysis revealed that children with severe malaria had worse scores compared to children without malaria in attention (standardized mean difference (SMD) -0.68, 95% CI -1.26 to -0.10), memory (SMD -0.52, 95% CI -0.99 to -0.06), and externalizing behavioural problems (SMD 0.45, 95% CI 0.13-0.78). CONCLUSION Severe malaria is associated with worse neuropsychological outcomes for children living in LMICs, specifically in attention, memory, and externalizing behaviours. More research is needed to identify the long-term implications of these findings. Further interventions are needed to prevent cognitive and behavioural problems after severe malaria infection. TRIAL REGISTRATION This systematic review was registered under PROSPERO: CRD42020154777.
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Affiliation(s)
- Andrew Sentoogo Ssemata
- Department of Psychiatry, School of Medicine, Makerere University, P. O. Box 7072, Kampala, Uganda.
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK.
| | | | - Simon Kizito
- Department of Mental Health and Community Psychology, School of Psychology, Makerere University, Kampala, Uganda
| | - Melissa R Thomas
- Richard M. Fairbanks School of Public Health, Indiana University-Purdue University, Indianapolis, USA
| | - Sumaiya Islam
- School of Medicine, City University of New York (CUNY), New York City, USA
- Mailman School of Public Health, Columbia University, New York City, USA
| | - Paul Bangirana
- Department of Psychiatry, School of Medicine, Makerere University, P. O. Box 7072, Kampala, Uganda
- Global Health Uganda, Kampala, Uganda
| | - Noeline Nakasujja
- Department of Psychiatry, School of Medicine, Makerere University, P. O. Box 7072, Kampala, Uganda
| | - Ziyi Yang
- Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, USA
| | - Yunpeng Yu
- Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, USA
| | - Tuan M Tran
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chandy C John
- Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Megan S McHenry
- Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
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12
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Namazzi R, Opoka R, Datta D, Bangirana P, Batte A, Berrens Z, Goings MJ, Schwaderer AL, Conroy AL, John CC. Acute Kidney Injury Interacts With Coma, Acidosis, and Impaired Perfusion to Significantly Increase Risk of Death in Children With Severe Malaria. Clin Infect Dis 2022; 75:1511-1519. [PMID: 35349633 PMCID: PMC9617576 DOI: 10.1093/cid/ciac229] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Mortality in severe malaria remains high in children treated with intravenous artesunate. Acute kidney injury (AKI) is a common complication of severe malaria, but the interactions between AKI and other complications on the risk of mortality in severe malaria are not well characterized. METHODS Between 2014 and 2017, 600 children aged 6-48 months to 4 years hospitalized with severe malaria were enrolled in a prospective clinical cohort study evaluating clinical predictors of mortality in children with severe malaria. RESULTS The mean age of children in this cohort was 2.1 years (standard deviation, 0.9 years) and 338 children (56.3%) were male. Mortality was 7.3%, and 52.3% of deaths occurred within 12 hours of admission. Coma, acidosis, impaired perfusion, AKI, elevated blood urea nitrogen (BUN), and hyperkalemia were associated with increased mortality (all P < .001). AKI interacted with each risk factor to increase mortality (P < .001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared with those with no indications for dialysis (odds ratio, 6.56; 95% confidence interval, 3.41-12.59). CONCLUSIONS AKI interacts with coma, acidosis, or impaired perfusion to significantly increase the risk of death in severe malaria. Among children with AKI, those who have hyperkalemia or elevated BUN have a higher risk of death. A better understanding of the causes of these complications of severe malaria, and development and implementation of measures to prevent and treat them, such as dialysis, are needed to reduce mortality in severe malaria.
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Affiliation(s)
- Ruth Namazzi
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
- Global Health Uganda, Kampala, Uganda
| | - Robert Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
- Global Health Uganda, Kampala, Uganda
| | - Dibyadyuti Datta
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Paul Bangirana
- Global Health Uganda, Kampala, Uganda
- Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Anthony Batte
- Child Development Centre, Makerere University, Kampala, Uganda
| | - Zachary Berrens
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Michael J Goings
- Indiana University Center for Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Andrew L Schwaderer
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Andrea L Conroy
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Indiana University Center for Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Chandy C John
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Indiana University Center for Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA
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13
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Chilombe MB, McDermott MP, Seydel KB, Mathews M, Mwenechanya M, Birbeck GL. Aggressive antipyretics in central nervous system malaria: Study protocol of a randomized-controlled trial assessing antipyretic efficacy and parasite clearance effects (Malaria FEVER study). PLoS One 2022; 17:e0268414. [PMID: 36206262 PMCID: PMC9543763 DOI: 10.1371/journal.pone.0268414] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/15/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. METHODS In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment. DISCUSSION This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.
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Affiliation(s)
- Moses B. Chilombe
- Blantyre Malaria Project, Queen Elizabeth Central Hospital, Blantyre, Malawi
| | - Michael P. McDermott
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, United States of America
| | - Karl B. Seydel
- Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Manoj Mathews
- University Teaching Hospitals Children’s Hospital, Lusaka, Zambia
| | | | - Gretchen L. Birbeck
- University Teaching Hospitals Children’s Hospital, Lusaka, Zambia
- University of Zambia School of Medicine, Lusaka, Zambia
- Department of Neurology, University of Rochester, Rochester, New York, United States of America
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14
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Lengeler C, Burri C, Awor P, Athieno P, Kimera J, Tumukunde G, Angiro I, Tshefu A, Okitawutshu J, Kalenga JC, Omoluabi E, Akano B, Ayodeji K, Okon C, Yusuf O, Brunner NC, Delvento G, Lee T, Lambiris M, Visser T, Napier HG, Cohen JM, Buj V, Signorell A, Hetzel MW, The CARAMAL Consortium. Community access to rectal artesunate for malaria (CARAMAL): A large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda. PLOS GLOBAL PUBLIC HEALTH 2022; 2:e0000464. [PMID: 36962706 PMCID: PMC10022208 DOI: 10.1371/journal.pgph.0000464] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022]
Abstract
The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention.
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Affiliation(s)
- Christian Lengeler
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Christian Burri
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Phyllis Awor
- School of Public Health, Makerere University, Kampala, Uganda
| | | | - Joseph Kimera
- School of Public Health, Makerere University, Kampala, Uganda
| | | | - Irene Angiro
- School of Public Health, Makerere University, Kampala, Uganda
| | - Antoinette Tshefu
- Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo
| | - Jean Okitawutshu
- Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo
| | - Jean-Claude Kalenga
- Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo
| | | | | | | | | | | | - Nina C. Brunner
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Giulia Delvento
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Tristan Lee
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Mark Lambiris
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Theodoor Visser
- Clinton Health Access Initiative, Boston, Massachusetts, United States of America
| | - Harriet G. Napier
- Clinton Health Access Initiative, Boston, Massachusetts, United States of America
| | - Justin M. Cohen
- Clinton Health Access Initiative, Boston, Massachusetts, United States of America
| | - Valentina Buj
- UNICEF, New York, New York, United States of America
| | - Aita Signorell
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Manuel W. Hetzel
- Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
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15
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Abstract
PURPOSE OF REVIEW To discuss the neurological complications and pathophysiology of organ damage following malaria infection. RECENT FINDINGS The principal advancement made in malaria research has been a better understanding of the pathogenesis of cerebral malaria (CM), the most dreaded neurological complication generally caused by Plasmodium falciparum infection. However, no definitive treatment has yet been evolved other than the use of antimalarial drugs and supportive care. The development of severe cerebral edema in CM results from two distinct pathophysiologic mechanisms. First, the development of "sticky" red blood cells (RBCs) leads to cytoadherence, where red blood cells (RBCs) get stuck to the endothelial walls and between themselves, resulting in clogging of the brain microvasculature with resultant hypoxemia and cerebral edema. In addition, the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) molecules protrude from the raised knob structures on the RBCs walls and are in themselves made of a combination of human and parasite proteins in a tight complex. Antibodies to surfins, rifins, and stevors from the parasite are also located in the RBC membrane. On the human microvascular side, a range of molecules involved in host-parasite interactions, including CD36 and intracellular adhesion molecule 1, is activated during interaction with other molecules such as endothelial protein C receptor and thrombospondin. As a result, an inflammatory response occurs with the dysregulated release of cytokines (TNF, interleukins 1 and 10) which damage the blood-brain barrier (BBB), causing plasma leakage and brain edema. This second mechanism of CNS injury often involves multiple organs in adult patients in endemic areas but remains localized only to the central nervous system (CNS) among African children. Neurological sequelae may follow both P. falciparum and P. vivax infections. The major brain pathology of CM is brain edema with diffuse brain swelling resulting from the combined effects of reduced perfusion and hypoxemia of cerebral neurons due to blockage of the microvasculature by parasitized RBCs as well as the neurotoxic effect of released cytokines from a hyper-acute immune host reaction. A plethora of additional neurological manifestations have been associated with malaria, including posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), malarial retinopathy, post-malarial neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), and cerebellar ataxia. Lastly, the impact of the COVID-19 pandemic on worldwide malaria control programs and the possible threat from co-infections is briefly discussed.
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Affiliation(s)
- Sweety Trivedi
- Department of Neurology, Sanjay Gandhi Post-graduate Institute of Medical Science, Lucknow, India
| | - Ambar Chakravarty
- Department of Neurology, Vivekananda Institute of Medical Science, Kolkata, India.
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16
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Borgstein A, Zhang B, Lam C, Gushu MB, Liomba AW, Malenga A, Pensulo P, Tebulo A, Small DS, Taylor T, Seydel K. Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi. Malar J 2022; 21:60. [PMID: 35193585 PMCID: PMC8864854 DOI: 10.1186/s12936-022-04080-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 02/06/2022] [Indexed: 11/10/2022] Open
Abstract
Background Cerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi. Methods This retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome. Results A total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007–1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986–1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983–0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993–1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090–1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973–1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome. Conclusions In Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s12936-022-04080-2.
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Affiliation(s)
- Arabella Borgstein
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi.,St. George's University of London/University of Nicosia Medical School, Nicosia, Cyprus
| | - Bo Zhang
- Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, USA
| | - Colin Lam
- Bronx High School of Science, Bronx, NY, USA
| | - Montfort Bernard Gushu
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi
| | - Alice Wangui Liomba
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi
| | - Albert Malenga
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi
| | - Paul Pensulo
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi
| | - Andrew Tebulo
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi
| | - Dylan S Small
- Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, USA
| | - Terrie Taylor
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi.,Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Karl Seydel
- Blantyre Malaria Project, Kamuzu University of Health Sciences, Private Bag 360, Blantyre, Malawi. .,Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA. .,Malawi-Liverpool-Wellcome Trust Research Programme, Kamuzu University of Health Sciences, Blantyre, Malawi.
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17
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Rosa-Gonçalves P, Ribeiro-Gomes FL, Daniel-Ribeiro CT. Malaria Related Neurocognitive Deficits and Behavioral Alterations. Front Cell Infect Microbiol 2022; 12:829413. [PMID: 35281436 PMCID: PMC8904205 DOI: 10.3389/fcimb.2022.829413] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 01/31/2022] [Indexed: 01/29/2023] Open
Abstract
Typical of tropical and subtropical regions, malaria is caused by protozoa of the genus Plasmodium and is, still today, despite all efforts and advances in controlling the disease, a major issue of public health. Its clinical course can present either as the classic episodes of fever, sweating, chills and headache or as nonspecific symptoms of acute febrile syndromes and may evolve to severe forms. Survivors of cerebral malaria, the most severe and lethal complication of the disease, might develop neurological, cognitive and behavioral sequelae. This overview discusses the neurocognitive deficits and behavioral alterations resulting from human naturally acquired infections and murine experimental models of malaria. We highlighted recent reports of cognitive and behavioral sequelae of non-severe malaria, the most prevalent clinical form of the disease worldwide. These sequelae have gained more attention in recent years and therapies for them are required and demand advances in the understanding of neuropathogenesis. Recent studies using experimental murine models point to immunomodulation as a potential approach to prevent or revert neurocognitive sequelae of malaria.
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Affiliation(s)
- Pamela Rosa-Gonçalves
- Laboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Centro de Pesquisa, Diagnóstico e Treinamento em Malária, Fiocruz and Secretaria de Vigilância em Saúde, Ministério da Saúde, Rio de Janeiro, Brazil
- Laboratório de Biologia, campus Duque de Caxias, Colégio Pedro II, Duque de Caxias, Brazil
- *Correspondence: Pamela Rosa-Gonçalves,
| | - Flávia Lima Ribeiro-Gomes
- Laboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Centro de Pesquisa, Diagnóstico e Treinamento em Malária, Fiocruz and Secretaria de Vigilância em Saúde, Ministério da Saúde, Rio de Janeiro, Brazil
| | - Cláudio Tadeu Daniel-Ribeiro
- Laboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
- Centro de Pesquisa, Diagnóstico e Treinamento em Malária, Fiocruz and Secretaria de Vigilância em Saúde, Ministério da Saúde, Rio de Janeiro, Brazil
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18
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Conroy AL, Opoka RO, Bangirana P, Namazzi R, Okullo AE, Georgieff MK, Cusick S, Idro R, Ssenkusu JM, John CC. Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria. BMC Med 2021; 19:168. [PMID: 34315456 PMCID: PMC8317420 DOI: 10.1186/s12916-021-02033-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/11/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM. METHODS From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up. RESULTS 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07-0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine. CONCLUSIONS Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.
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Affiliation(s)
- Andrea L Conroy
- Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, R4 402C 1044 West Walnut St, Indianapolis, IN, 46202, USA.
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Paul Bangirana
- Department of Psychiatry, Makerere University College of Health Sciences, Kampala, Uganda
| | - Ruth Namazzi
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Allen E Okullo
- Clinical Epidemiology Unit, Makerere University College of Health Sciences, Kampala, Uganda
| | | | - Sarah Cusick
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Richard Idro
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - John M Ssenkusu
- Department of Epidemiology and Biostatistics, Makerere University School of Public Health, Kampala, Uganda
| | - Chandy C John
- Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, R4 402C 1044 West Walnut St, Indianapolis, IN, 46202, USA.,Division of Global Pediatrics, University of Minnesota Medical School, Minneapolis, USA
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19
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Thierry A, Falilatou A, Covalic B, Elodie D, Mendinatou A, Didier A, Alphonse N, Joseph A. Epilepsy and Malaria in Children Aged 1 to 15 Years in Parakou in 2018: Case-Control Study. Child Neurol Open 2020; 7:2329048X20954111. [PMID: 33117857 PMCID: PMC7573707 DOI: 10.1177/2329048x20954111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 07/13/2020] [Accepted: 08/06/2020] [Indexed: 11/25/2022] Open
Abstract
Objective: To study the link between malaria and epilepsy in children in Parakou district. Methods: This case-control study included children 1-15 years of age with epilepsy. Each case of epilepsy was matched to 2 controls for age, sex and neighborhood of residence. The exposure variables were a history of malaria (number and type), family history of epilepsy and other past medical history. The odds ratios (OR) and their confidence interval were used to estimate association. Results: A total of 123 children including 41 children with epilepsy and 82 controls were included. The overall average number of malaria episodes per year in both groups combined was 1.8 ± 0.9 episodes. In the multivariate analysis, cerebral malaria (OR: 50.35 [5.28-480.30]), family history of epilepsy (OR: 12.17 [2.15-69.01]) and number of malaria episodes (OR: 13.27 [4.53-98.48]) were associated. Conclusion: This study supports the association between cerebral malaria and the onset of epilepsy.
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Affiliation(s)
- Adoukonou Thierry
- Teaching and Research Unit of Neurology, University of Parakou, Parakou, Benin.,Cinic of Neurology, University Teaching Hospital of Parakou, Parakou, Benin
| | - Agbeille Falilatou
- Pediatry Teaching and Research Unit, University of Parakou, Parakou, Benin
| | - Bokossa Covalic
- Cinic of Neurology, University Teaching Hospital of Parakou, Parakou, Benin
| | - Dovoedo Elodie
- Cinic of Neurology, University Teaching Hospital of Parakou, Parakou, Benin
| | - Agbétou Mendinatou
- Teaching and Research Unit of Neurology, University of Parakou, Parakou, Benin.,Cinic of Neurology, University Teaching Hospital of Parakou, Parakou, Benin
| | - Adedemy Didier
- Pediatry Teaching and Research Unit, University of Parakou, Parakou, Benin
| | | | - Agossou Joseph
- Pediatry Teaching and Research Unit, University of Parakou, Parakou, Benin
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20
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Ataide BJDA, Kauffmann N, Mendes NDSF, Torres MLM, Dos Anjos LM, Passos ADCF, de Moraes SAS, Batista EDJO, Herculano AM, Oliveira KRHM. Melatonin Prevents Brain Damage and Neurocognitive Impairment Induced by Plasmodium Berghei ANKA Infection in Murine Model of Cerebral Malaria. Front Cell Infect Microbiol 2020; 10:541624. [PMID: 33102250 PMCID: PMC7554304 DOI: 10.3389/fcimb.2020.541624] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 08/18/2020] [Indexed: 12/27/2022] Open
Abstract
Cerebral malaria is characterized by permanent cognitive impairments in Plasmodium-infected children. Antimalarial therapies show little effectiveness to avoid neurological deficits and brain tissue alterations elicited by severe malaria. Melatonin is a well-recognized endogenous hormone involved in the control of brain functions and maintenance of blood–brain barrier integrity. The current study has evaluated the effect of melatonin on the histological alterations, blood–brain barrier leakage, and neurocognitive impairments in mice developing cerebral malaria. Swiss mice infected with Plasmodium berghei ANKA strain was used as cerebral malaria model. Melatonin treatment (5 and 10 mg/kg) was performed for four consecutive days after the infection, and data have shown an increased survival rate in infected mice treated with melatonin. It was also observed that melatonin treatment blocked brain edema and prevented the breakdown of blood–brain barrier induced by the Plasmodium infection. Furthermore, hematoxylin and eosin staining revealed that melatonin mitigates the histological alterations in Plasmodium-infected animals. Melatonin was also able to prevent motor and cognitive impairments in infected mice. Taken together, these results show for the first time that melatonin treatment prevents histological brain damages and neurocognitive alterations induced by cerebral malaria.
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Affiliation(s)
| | - Nayara Kauffmann
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, UFPa, Belém, Brazil
| | | | - Marjorie Lujan Marques Torres
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, UFPa, Belém, Brazil.,Laboratory of Protozoology, Topical Medicine Nucleus, UFPa, Belém, Brazil
| | - Larissa Medeiros Dos Anjos
- Laboratory of Experimental Neuropharmacology, Biological Science Institute, UFPa, Belém, Brazil.,Laboratory of Protozoology, Topical Medicine Nucleus, UFPa, Belém, Brazil
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21
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Schiess N, Villabona-Rueda A, Cottier KE, Huether K, Chipeta J, Stins MF. Pathophysiology and neurologic sequelae of cerebral malaria. Malar J 2020; 19:266. [PMID: 32703204 PMCID: PMC7376930 DOI: 10.1186/s12936-020-03336-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 07/13/2020] [Indexed: 12/14/2022] Open
Abstract
Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and under-investigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite- and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.
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Affiliation(s)
- Nicoline Schiess
- Department of Neurology, Johns Hopkins School of Medicine, 600 N. Wolfe St., Meyer 6-113, Baltimore, MD, 21287, USA
| | - Andres Villabona-Rueda
- Malaria Research Institute, Dept Molecular Microbiology Immunology, Johns Hopkins School of Public Health, 615 N Wolfe Street, Baltimore, MD, 21205, USA
| | - Karissa E Cottier
- Malaria Research Institute, Dept Molecular Microbiology Immunology, Johns Hopkins School of Public Health, 615 N Wolfe Street, Baltimore, MD, 21205, USA.,BioIVT, 1450 South Rolling Road, Baltimore, MD, USA
| | | | - James Chipeta
- Department of Paediatrics, University Teaching Hospital, Nationalist Road, Lusaka, Zambia
| | - Monique F Stins
- Malaria Research Institute, Dept Molecular Microbiology Immunology, Johns Hopkins School of Public Health, 615 N Wolfe Street, Baltimore, MD, 21205, USA.
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Siddiqui AJ, Adnan M, Jahan S, Redman W, Saeed M, Patel M. Neurological disorder and psychosocial aspects of cerebral malaria: what is new on its pathogenesis and complications? A minireview. Folia Parasitol (Praha) 2020; 67. [PMID: 32636351 DOI: 10.14411/fp.2020.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/06/2020] [Indexed: 01/21/2023]
Abstract
Recently, malaria is remain considered as the most prevalent infectious disease, affecting the human health globally. High morbidity and mortality worldwide is often allied with cerebral malaria (CM) based disorders of the central nervous system, especially across many tropical and sub-tropical regions. These disorders are characterised by the infection of Plasmodium species, which leads to acute or chronic neurological disorders, even after having active/effective antimalarial drugs. Furthermore, even during the treatment, individual remain sensitive for neurological impairments in the form of decrease blood flow and vascular obstruction in brain including many more other changes. This review briefly explains and update on the epidemiology, burden of disease, pathogenesis and role of CM in neurological disorders with behaviour and function in mouse and human models. Moreover, the social stigma, which plays an important role in neurological disorders and a factor for assessing CM, is also discussed in this review.
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Affiliation(s)
| | | | - Sadaf Jahan
- Department of Medical Laboratory, College of Applied Medical Sciences, Majmaah University, Majmaah city, Saudi Arabia
| | - Whitni Redman
- Surgery Department, Division of Biomedical Research, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Mοhd Saeed
- Department of Biology, College of Science, University of Hail, Hail, PO Box 2440, Saudi Arabia
| | - Mitesh Patel
- Bapalal Vaidya Botanical Research Centre, Department of Biosciences, Veer Narmad South Gujarat University, Surat, Gujarat, India
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23
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Zoonotic and vector-borne parasites and epilepsy in low-income and middle-income countries. Nat Rev Neurol 2020; 16:333-345. [PMID: 32427939 DOI: 10.1038/s41582-020-0361-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2020] [Indexed: 12/22/2022]
Abstract
Zoonotic and vector-borne parasites are important preventable risk factors for epilepsy. Three parasitic infections - cerebral malaria, Taenia solium cysticercosis and onchocerciasis - have an established association with epilepsy. Parasitoses are widely prevalent in low-income and middle-income countries, which are home to 80% of the people with epilepsy in the world. Once a parasitic infection has taken hold in the brain, therapeutic measures do not seem to influence the development of epilepsy in the long term. Consequently, strategies to control, eliminate and eradicate parasites represent the most feasible way to reduce the epilepsy burden at present. The elucidation of immune mechanisms underpinning the parasitic infections, some of which are parasite-specific, opens up new therapeutic possibilities. In this Review, we explore the pathophysiological basis of the link between parasitic infections and epilepsy, and we consider preventive and therapeutic approaches to reduce the burden of epilepsy attributable to parasitic disorders. We conclude that a concerted approach involving medical, veterinary, parasitological and ecological experts, backed by robust political support and sustainable funding, is the key to reducing this burden.
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Association between Malaria Infection and Early Childhood Development Mediated by Anemia in Rural Kenya. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17030902. [PMID: 32024214 PMCID: PMC7037381 DOI: 10.3390/ijerph17030902] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 02/08/2023]
Abstract
Malaria is a leading cause of morbidity and mortality among children under five years of age, with most cases occurring in Sub-Saharan Africa. Children in this age group in Africa are at greatest risk worldwide for developmental deficits. There are research gaps in quantifying the risks of mild malaria cases, understanding the pathways linking malaria infection and poor child development, and evaluating the impact of malaria on the development of children under five years. We analyzed the association between malaria infection and gross motor, communication, and personal social development in 592 children age 24 months in rural, western Kenya as part of the WASH Benefits environmental enteric dysfunction sub-study. Eighteen percent of children had malaria, 20% were at risk for gross motor delay, 21% were at risk for communication delay, and 23% were at risk for personal social delay. Having a positive malaria test was associated with increased risk for gross motor, communication, and personal social delay while adjusting for child characteristics, household demographics, study cluster, and intervention treatment arm. Mediation analyses suggested that anemia was a significant mediator in the pathway between malaria infection and risk for gross motor, communication, and personal social development delays. The proportion of the total effect of malaria on the risk of developmental delay that is mediated by anemia across the subscales was small (ranging from 9% of the effect on gross motor development to 16% of the effect on communication development mediated by anemia). Overall, malaria may be associated with short-term developmental delays during a vulnerable period of early life. Therefore, preventative malaria measures and immediate treatment are imperative for children’s optimal development, particularly in light of projections of continued high malaria transmission in Kenya and Africa.
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25
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Reiterer E, Reider S, Lackner P, Fischer N, Dejaco D, Riechelmann H, Zorowka P, Kremsner PG, Adegnika AA, Schmutzhard E, Schmutzhard J. A long-term follow-up study on otoacoustic emissions testing in paediatric patients with severe malaria in Gabon. Malar J 2019; 18:212. [PMID: 31234890 PMCID: PMC6591898 DOI: 10.1186/s12936-019-2840-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 06/17/2019] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND In a previous study, severe and cerebral malaria have been connected with acute cochlear malfunction in children, demonstrated by a decrease of transitory evoked otoacoustic emissions (TEOAEs) reproducibility. This study aims to determine whether cochlear malfunction persists for 4 years after recovery from severe malaria in a subset of the previous study's collective. Follow-up TEOAEs were performed on site (CERMEL, Hôpital Albert Schweitzer, Lambaréné, Gabon) or at the participants' homes; 33 out of 90 participants included in the initial investigation by Schmutzhard et al. could be retrieved and were re-examined, 31/33 could be included. Of the 57 missing participants, 51 could not be contacted, 1 had moved away, 4 refused to cooperate, and 1 had died. METHODS As in the initial investigation, participants of this prospective follow-up study were subjected to TEOAE examination on both ears separately. A wave correlation rate of > 60% on both ears was considered a "pass"; if one ear failed to pass, the examination was considered a "fail". The results were compared to the primary control group. Additionally, a questionnaire has been applied focusing on subsequent malaria infections between the primary inclusion and follow-up and subjective impairment of hearing and/or understanding. RESULTS The cohort's mean age was 9 years, 14 children were female, 18 male. 31 had been originally admitted with severe, one with cerebral malaria. 83.8% of participants (n = 26) presented with a TEOAE correlation rate of > 60% on both ears (the cut-off for good cochlear function); in the control group, 92.2% (n = 83) had passed TEOAE examination on both ears. Recurrent severe malaria was associated with a worse TEOAE correlation rate. Age at infection and gender had no influence on the outcome. CONCLUSIONS Cochlear malfunction seems to be persistent after 4 years in more than 16% of children hospitalized for malaria. In a healthy control group, this proportion was 7.8%. Yet, the severity of the initial TEOAE-decrease did not predict a worse outcome.
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Affiliation(s)
- Elisa Reiterer
- Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Simon Reider
- Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria
| | - Peter Lackner
- Department of Neurology, NICU, Medical University Innsbruck, Innsbruck, Austria
| | - Natalie Fischer
- Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Daniel Dejaco
- Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Patrick Zorowka
- Department of Hearing, Speech and Voice Disorders, Medical University, Innsbruck, Austria
| | - Peter G Kremsner
- Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital (MRUG), Lambaréné, Gabon.,Institut für Tropenmedizin, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Ayola Akim Adegnika
- Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital (MRUG), Lambaréné, Gabon
| | - Erich Schmutzhard
- Department of Neurology, NICU, Medical University Innsbruck, Innsbruck, Austria
| | - Joachim Schmutzhard
- Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
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Mwangala PN, Kariuki SM, Nyongesa MK, Mwangi P, Chongwo E, Newton CR, Abubakar A. Cognition, mood and quality-of-life outcomes among low literacy adults living with epilepsy in rural Kenya: A preliminary study. Epilepsy Behav 2018; 85:45-51. [PMID: 29908383 PMCID: PMC6086937 DOI: 10.1016/j.yebeh.2018.05.032] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/18/2018] [Accepted: 05/19/2018] [Indexed: 12/25/2022]
Abstract
Epilepsy is frequently associated with neurocognitive impairments, mental health, and psychosocial problems but these are rarely documented in low- and middle-income countries. The aim of this study was to examine the neurocognitive outcomes, depressive symptoms, and psychosocial adjustments of people with epilepsy (PWE) in Kilifi, Kenya. We evaluated the impact of these outcomes on health-related quality of life. Self-report, interviewer-administered measures of depression (Major Depression Inventory) and quality of life (RAND SF-36) were administered to 63 PWE and 83 community controls. Neurocognitive functioning was assessed using Raven's Standard Progressive Matrices, Digit Span, and Contingency Naming Test. The results show that PWE have poorer scores for executive function, working memory, intelligence quotient (IQ), depression, and quality of life than controls. Twenty-seven (27%) of PWE had depressive symptoms, which was significantly greater than in controls (6%); P < 0.001. Quality-of-life scores were significantly lower in PWE with depressive symptoms than in those without depressive symptoms (Mean QoL scores (standard deviation (SD)): 46.43 (13.27) versus 64.18 (17.69); P = 0.01. On adjusted linear regression models, depression affected total quality-of-life scores (P = 0.07) as well as individual health indicator domains touching on pain (P = 0.04), lethargy/fatigue (P = 0.01), and emotional well-being (P = 0.02). Our results show that epilepsy is associated with a significant burden of mental health and neurocognitive impairments in the community; however, community-based studies are needed to provide precise estimates of these disorders.
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Affiliation(s)
- Patrick N. Mwangala
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya,Corresponding author at: Center for Geographic Medicine Research (Coast), Kenya Medical Research Institute, PO Box 230, 80108 Kilifi, Kenya.
| | - Symon M. Kariuki
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Moses K. Nyongesa
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Paul Mwangi
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Esther Chongwo
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya,Department of Public Health, Pwani University, Kilifi, Kenya
| | - Charles R. Newton
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya,Department of Public Health, Pwani University, Kilifi, Kenya,Department of Psychiatry, University of Oxford, Oxford, UK
| | - Amina Abubakar
- Neuroassessment Group, KEMRI-Wellcome Trust Research Programme, Center for Geographic Medicine Research (Coast), Kilifi, Kenya,Department of Public Health, Pwani University, Kilifi, Kenya,Department of Psychiatry, University of Oxford, Oxford, UK
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Traumatic Brain Injury and Infectious Encephalopathy in Children From Four Resource-Limited Settings in Africa. Pediatr Crit Care Med 2018; 19:649-657. [PMID: 29664874 DOI: 10.1097/pcc.0000000000001554] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To assess the frequency, interventions, and outcomes of children presenting with traumatic brain injury or infectious encephalopathy in low-resource settings. DESIGN Prospective study. SETTING Four hospitals in Sub-Saharan Africa. PATIENTS Children age 1 day to 17 years old evaluated at the hospital with traumatic brain injury or infectious encephalopathy. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We evaluated the frequency and outcomes of children presenting consecutively over 4 weeks to any hospital department with traumatic brain injury or infectious encephalopathy. Pediatric Cerebral Performance Category score was assessed pre morbidity and at hospital discharge. Overall, 130 children were studied (58 [45%] had traumatic brain injury) from hospitals in Ethiopia (n = 51), Kenya (n = 50), Rwanda (n = 20), and Ghana (n = 7). Forty-six percent had no prehospital care, and 64% required interhospital transport over 18 km (1-521 km). On comparing traumatic brain injury with infectious encephalopathy, there was no difference in presentation with altered mental state (80% vs 82%), but a greater proportion of traumatic brain injury cases had loss of consciousness (80% vs 53%; p = 0.004). Traumatic brain injury patients were older (median [range], 120 mo [6-204 mo] vs 13 mo [0.3-204 mo]), p value of less than 0.001, and more likely male (73% vs 51%), p value of less than 0.01. In 78% of infectious encephalopathy cases, cause was unknown. More infectious encephalopathy cases had a seizure (69% vs 12%; p < 0.001). In regard to outcome, infectious encephalopathy versus traumatic brain injury: hospital lengths of stay were longer for infectious encephalopathy (8 d [2-30 d] vs 4 d [1-36 d]; p = 0.003), discharge rate to home, or for inpatient rehabilitation, or death differed between infectious encephalopathy (85%, 1%, and 13%) and traumatic brain injury (79%, 12%, and 1%), respectively, p value equals to 0.044. There was no difference in the proportion of children surviving with normal or mild disability (73% traumatic brain injury vs 79% infectious encephalopathy; p = 0.526). CONCLUSIONS The epidemiology and outcomes of pediatric traumatic brain injury and infectious encephalopathy varied by center and disease. To improve outcomes of these conditions in low-resource setting, focus should be on neurocritical care protocols for pre-hospital, hospital, and rehabilitative care.
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Klejnstrup NR, Buhl-Wiggers J, Jones S, Rand J. Early life malaria exposure and academic performance. PLoS One 2018; 13:e0199542. [PMID: 29933388 PMCID: PMC6014671 DOI: 10.1371/journal.pone.0199542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 06/08/2018] [Indexed: 11/19/2022] Open
Abstract
Malaria is a major cause of morbidity and mortality in sub-Saharan Africa. It is also a dynamic contributor to poverty through its effects on children's cognitive development. This paper examines the degree to which malaria in early childhood impacts on educational achievement in later childhood. The substantial decline in malaria in the region over recent years allows an assessment of its impact to be made. Focusing on Tanzania, we combine data from the Malaria Atlas Project and the 2010-2014 Uwezo household surveys (N = 246,325). We relate the district-level risk of malaria in a child's year of birth to his/her performance in tests of acquired cognitive skills (literacy and numeracy). For causal identification, we rely on differences across districts in the pace of decline in malaria prevalence occurring over the last 15 years. We control for time-invariant district level, age, birth cohort and survey year effects, as well as district-level trends and individual and household-specific factors. In addition, we use sibling variation in birth-year exposure to malaria to strengthen our identification. A ten percentage-point decrease in malaria prevalence in birth year is associated with a 0.06 standard deviation (p = 0.000) increase in English literacy achievement. This estimate is comparable in magnitude to education intervention programs with very large effects. Our results are robust to a large number of sensitivity analyses. We find no statistically significant effects of birth-year malaria exposure on attainments in numeracy and Kiswahili, and we argue that this is probably attributable to strong ceiling effects in these test scores. We conclude that in Tanzania malaria is an important factor in geographical variation in English literacy. This indicates that malaria is a significant public health challenge to educational achievement in this country, and probably in other regions with malaria.
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Affiliation(s)
- Ninja Ritter Klejnstrup
- Department of Food and Resource Economics, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
| | | | - Sam Jones
- Department of Economics, University of Copenhagen, Copenhagen, Denmark
| | - John Rand
- Department of Economics, University of Copenhagen, Copenhagen, Denmark
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29
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Bangirana P, Conroy AL, Opoka RO, Hawkes MT, Hermann L, Miller C, Namasopo S, Liles WC, John CC, Kain KC. Inhaled nitric oxide and cognition in pediatric severe malaria: A randomized double-blind placebo controlled trial. PLoS One 2018; 13:e0191550. [PMID: 29370261 PMCID: PMC5784958 DOI: 10.1371/journal.pone.0191550] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 01/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Severe malaria is a leading cause of acquired neurodisability in Africa and is associated with reduced nitric oxide (NO) bioavailability. A neuroprotective role for inhaled NO has been reported in animal studies, and administration of inhaled NO in preterm neonates with respiratory distress syndrome is associated with a 47% reduced risk of cognitive impairment at two years of age. METHODS A randomized double-blind placebo-controlled trial of inhaled NO versus placebo as an adjunctive therapy for severe malaria was conducted in Uganda between 2011 and 2013. Children received study gas for a maximum 72 hours (inhaled NO, 80 parts per million; room air placebo). Neurocognitive testing was performed on children<5 years at 6 month follow-up. The neurocognitive outcomes assessed were overall cognition (a composite of fine motor, visual reception, receptive language, and expressive language), attention, associative memory, and the global executive composite. Main outcomes were attention, associative memory, and overall cognitive ability. RESULTS Sixty-one children receiving iNO and 59 children receiving placebo were evaluated. Forty-two children (35.0%) were impaired in at least one neurocognitive domain. By intention-to-treat analysis, there were no differences in unadjusted or unadjusted age-adjusted z-scores for overall cognition (β (95% CI): 0.26 (-0.19, 0.72), p = 0.260), attention (0.18 (-0.14, 0.51), p = 0.267), or memory (0.14 (-0.02, 0.30), p = 0.094) between groups by linear regression. Children receiving inhaled NO had a 64% reduced relative risk of fine motor impairment than children receiving placebo (relative risk, 95% CI: 0.36, 0.14-0.96) by log binomial regression following adjustment for anticonvulsant use. CONCLUSIONS Severe malaria is associated with high rates of neurocognitive impairment. Treatment with inhaled NO was associated with reduced risk of fine motor impairment. These results need to be prospectively validated in a larger study powered to assess cognitive outcomes in order to evaluate whether strategies to increase bioavailable NO are neuroprotective in children with severe malaria. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01255215.
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Affiliation(s)
- Paul Bangirana
- Department of Psychiatry, Makerere University College of Health Sciences, Kampala, Uganda
| | - Andrea L Conroy
- Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Michael T Hawkes
- Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.,Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada
| | - Laura Hermann
- Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Christopher Miller
- Department of Respiratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Sophie Namasopo
- Department of Paediatrics, Jinja Regional Referral Hospital, Jinja, Uganda
| | - W Conrad Liles
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Chandy C John
- Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Kevin C Kain
- Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.,Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada
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30
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Kitsao-Wekulo P, Holding PA, Kvalsvig JD, Alcock KJ, Taylor HG. Measurement of expressive vocabulary in school-age children: Development and application of the Kilifi Naming Test (KNT). APPLIED NEUROPSYCHOLOGY-CHILD 2017; 8:24-39. [PMID: 29023138 DOI: 10.1080/21622965.2017.1378579] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The dearth of locally developed measures of language makes it difficult to detect language and communication problems among school-age children in sub-Saharan African settings. We sought to describe variability in vocabulary acquisition as an important element of global cognitive functioning. Our primary aims were to establish the psychometric properties of an expressive vocabulary measure, examine sources of variability, and investigate the measure's associations with non-verbal reasoning and educational achievement. The study included 308 boys and girls living in a predominantly rural district in Kenya. The developed measure, the Kilifi Naming Test (KNT), had excellent reliability and acceptable convergent validity. However, concurrent validity was not adequately demonstrated. In the final regression model, significant effects of schooling and area of residence were recorded. Contextual factors should be taken into account in the interpretation of test scores. There is need for future studies to explore the concurrent validity of the KNT further.
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Affiliation(s)
- Patricia Kitsao-Wekulo
- a African Population and Health Research Center , Nairobi , Kenya.,b School of Applied Human Sciences, University of KwaZulu-Natal , Durban , South Africa.,c KEMRI-Wellcome Trust Research Programme , Kilifi , Kenya
| | | | - Jane D Kvalsvig
- f School of Public Health Medicine , University of KwaZulu-Natal , Durban , South Africa
| | - Katherine J Alcock
- d Department of Psychology , Lancaster University , Lancaster , United Kingdom
| | - H Gerry Taylor
- e Department of Pediatrics, School of Medicine , Case Western Reserve University , Cleveland , OH , USA
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31
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Opoka RO, Hamre KES, Brand N, Bangirana P, Idro R, John CC. High Postdischarge Morbidity in Ugandan Children With Severe Malarial Anemia or Cerebral Malaria. J Pediatric Infect Dis Soc 2017; 6:e41-e48. [PMID: 28339598 PMCID: PMC5907851 DOI: 10.1093/jpids/piw060] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 09/12/2016] [Indexed: 11/14/2022]
Abstract
BACKGROUND Cerebral malaria (CM) and severe malarial anemia (SMA) account for a substantial proportion of malaria-related deaths in sub-Saharan Africa. However, postdischarge morbidity in children with CM or SMA has not been well established. METHODS Children 18 months to 12 years of age, enrolled on admission to Mulago National Referral Hospital in Kampala, Uganda (CM, n = 162; SMA, n = 138), and healthy children recruited from the community (CC) (n = 133) were followed up for 6 months. The incidences of hospitalizations and outpatient clinic visits for illness during the follow-up period were compared between children with CM or SMA and the CC. RESULTS After adjustment for age, sex, and nutritional status, children with SMA had a higher incidence rate ratio (IRR) than CC for hospitalization (95% confidence interval [CI], 20.81 [2.48-174.68]), hospitalization with malaria (17.29 [95% CI, 2.02-148.35]), and clinic visits for any illness (95% CI, 2.35 [1.22-4.51]). Adjusted IRRs for children with CM were also increased for all measures compared with those for CC, but they achieved statistical significance only for clinic visits for any illness (2.24 [95% CI, 1.20-4.15]). In both groups, the primary reason for the clinic visits and hospitalizations was malaria. CONCLUSIONS In the 6 months after initial hospitalization, children with SMA have an increased risk of repeated hospitalization, and children with CM or SMA have an increased risk of outpatient illness. Malaria is the main cause of inpatient and outpatient morbidity. Malaria prophylaxis has the potential to decrease postdischarge morbidity rates in children with SMA or CM.
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Affiliation(s)
| | - Karen E S Hamre
- Division of Global Pediatrics, University of Minnesota, Minneapolis
| | - Nathan Brand
- Columbia College of Physicians and Surgeons, New York; and
| | | | | | - Chandy C John
- Division of Global Pediatrics, University of Minnesota, Minneapolis;,Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University, Indianapolis,Corresponding Author: C. C. John, MD, MS, Ryan White Center for Pediatric Infectious Disease and Global Health, 1044 W. Walnut St, R4 402D, Indianapolis, IN 44202. E-mail:
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32
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Bitta MA, Kariuki SM, Mwita C, Gwer S, Mwai L, Newton CRJC. Antimalarial drugs and the prevalence of mental and neurological manifestations: A systematic review and meta-analysis. Wellcome Open Res 2017. [PMID: 28630942 PMCID: PMC5473418 DOI: 10.12688/wellcomeopenres.10658.2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans. Methods: We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques. Results: Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug. Conclusions: Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs.
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Affiliation(s)
- Mary A Bitta
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Symon M Kariuki
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Clifford Mwita
- Department of Surgery, Thika Level 5 Hospital, Thika, Kenya.,Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya
| | - Samson Gwer
- Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya.,Department of Medical Physiology, School of Medicine, Kenyatta University, Nairobi, Kenya
| | - Leah Mwai
- Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya
| | - Charles R J C Newton
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya.,Department of Psychiatry, University of Oxford, Oxford, UK
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33
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Bitta MA, Kariuki SM, Mwita C, Gwer S, Mwai L, Newton CRJC. Antimalarial drugs and the prevalence of mental and neurological manifestations: A systematic review and meta-analysis. Wellcome Open Res 2017. [PMID: 28630942 DOI: 10.12688/wellcomeopenres.10658.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans. Methods: We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques. Results: Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug. Conclusions: Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs.
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Affiliation(s)
- Mary A Bitta
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Symon M Kariuki
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya
| | - Clifford Mwita
- Department of Surgery, Thika Level 5 Hospital, Thika, Kenya.,Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya
| | - Samson Gwer
- Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya.,Department of Medical Physiology, School of Medicine, Kenyatta University, Nairobi, Kenya
| | - Leah Mwai
- Joanna Briggs Institute (JBI) Affiliate Centre for Evidence-Based Healthcare in Kenya, Clinical Research Evidence Synthesis and Translation Unit, Afya Research Africa, Nairobi, Kenya
| | - Charles R J C Newton
- KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), Kilifi, Kenya.,Department of Psychiatry, University of Oxford, Oxford, UK
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34
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Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Bila R, Mucavele H, Mayor A, Bassat Q, Kain KC. Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria. Malar J 2017; 16:215. [PMID: 28535809 PMCID: PMC5442675 DOI: 10.1186/s12936-017-1858-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 05/12/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention. METHODS In this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem®) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations. RESULTS Thirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters. CONCLUSIONS Adjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria. The trial is registered with Clinicaltrials.gov, NCT02694874.
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Affiliation(s)
- Rosauro Varo
- ISGlobal, Barcelona Institute for Global Health, Hospital Clínic, Universitat de Barcelona, Rosselló 132, 5th Floor, 08036, Barcelona, Spain.,Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Valerie M Crowley
- S. A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
| | - Antonio Sitoe
- Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Lola Madrid
- ISGlobal, Barcelona Institute for Global Health, Hospital Clínic, Universitat de Barcelona, Rosselló 132, 5th Floor, 08036, Barcelona, Spain.,Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Lena Serghides
- Toronto General Research Institute (TGRI), University Health Network, Toronto, Canada.,Women's College Research Institute, Women's College Hospital, Toronto, Canada.,Department of Immunology and Institute of Medical Sciences University of Toronto, Toronto, Canada
| | - Rubao Bila
- Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Helio Mucavele
- Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Alfredo Mayor
- ISGlobal, Barcelona Institute for Global Health, Hospital Clínic, Universitat de Barcelona, Rosselló 132, 5th Floor, 08036, Barcelona, Spain.,Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique
| | - Quique Bassat
- ISGlobal, Barcelona Institute for Global Health, Hospital Clínic, Universitat de Barcelona, Rosselló 132, 5th Floor, 08036, Barcelona, Spain. .,Centro de Investigação em Saúde de Manhiça, Rua 12, Vila da Manhiça, 1929, Maputo, Mozambique. .,ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain.
| | - Kevin C Kain
- S. A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,Tropical Diseases Unit, Division of Infectious Diseases, Department of Medicine, UHN-Toronto General Hospital, Toronto, ON, Canada
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John CC, Black MM, Nelson CA. Neurodevelopment: The Impact of Nutrition and Inflammation During Early to Middle Childhood in Low-Resource Settings. Pediatrics 2017; 139:S59-S71. [PMID: 28562249 PMCID: PMC5694688 DOI: 10.1542/peds.2016-2828h] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2016] [Indexed: 01/21/2023] Open
Abstract
The early to middle childhood years are a critical period for child neurodevelopment. Nutritional deficiencies, infection, and inflammation are major contributors to impaired child neurodevelopment in these years, particularly in low-resource settings. This review identifies global research priorities relating to nutrition, infection, and inflammation in early to middle childhood neurodevelopment. The research priority areas identified include: (1) assessment of how nutrition, infection, or inflammation in the preconception, prenatal, and infancy periods (or interventions in these periods) affect function in early to middle childhood; (2) assessment of whether effects of nutritional interventions vary by poverty or inflammation; (3) determination of the feasibility of preschool- and school-based integrated nutritional interventions; (4) improved assessment of the epidemiology of infection- and inflammation-related neurodevelopmental impairment (NDI); (5) identification of mechanisms through which infection causes NDI; (6) identification of noninfectious causes of inflammation-related NDI and interventions for causes already identified (eg, environmental factors); and (7) studies on the effects of interactions between nutritional, infectious, and inflammatory factors on neurodevelopment in early to middle childhood. Areas of emerging importance that require additional study include the effects of maternal Zika virus infection, childhood environmental enteropathy, and alterations in the child's microbiome on neurodevelopment in early to middle childhood. Research in these key areas will be critical to the development of interventions to optimize the neurodevelopmental potential of children worldwide in the early to middle childhood years.
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Affiliation(s)
- Chandy C. John
- Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, Indiana;,Address correspondence to Chandy C. John, MD, MS, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, 1044 W. Walnut St, R4 402D, Indianapolis, IN 46202. E-mail:
| | - Maureen M. Black
- Departments of Pediatrics and,Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland;,RTI International, Research Triangle Park, North Carolina
| | - Charles A. Nelson
- Laboratories of Cognitive Neuroscience, Boston Children's Hospital, Boston, Massachusetts;,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and,Department of Human Development, Harvard Graduate School of Education, Cambridge, Massachusetts
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Mubaraki MA, Hafiz TA, Al-Quraishy S, Dkhil MA. Oxidative stress and genes regulation of cerebral malaria upon Zizyphus spina-christi treatment in a murine model. Microb Pathog 2017; 107:69-74. [PMID: 28336326 DOI: 10.1016/j.micpath.2017.03.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/07/2017] [Accepted: 03/16/2017] [Indexed: 10/19/2022]
Abstract
The development and spread of multidrug-resistant strains of malarial parasites have led to an overwhelming increase in the resistance to current antimalarial drugs. The urgent need for alternative antimalarial drugs has directed some of the current studies toward folkloric medicine approaches. Interestingly, the Zizyphus spina Cristi leaf extract (ZLE) has been found to exhibit antiplasmodial activity. This study evaluated the protective effect of ZLE against Plasmodium berghei-induced cerebral tissue injuries in mice. Male C57Bl/6 mice received an injection of P. berghei-infected red blood cells. Mice were divided into three groups (control, infected, and ZLE-treated), and were subjected to histological, biochemical, and molecular analyses. Murine malaria infections induced significant weight loss; however, upon ZLE treatment, the weight of mice was markedly restored. Additionally, infected mice showed brain histopathological changes and induction of oxidative damage. Significantly, ZLE treatment restored the levels of oxidative markers and antioxidant enzyme to the normal ranges. The mRNA expression of several genes in the brain of mice including Cacnb4, Adam23, Glrb, Vdac3, and Cabp1 was significantly upregulated during P. berghei infection. In contrast, ZLE markedly reduced the mRNA expression of these genes. To conclude, the results indicate that ZLE could play an important role in reducing the destructive effect of P. berghei-induced cerebral malaria owing to its antiplasmodial and antioxidant activities.
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Affiliation(s)
- Murad A Mubaraki
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Saudi Arabia.
| | - Taghreed A Hafiz
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Saudi Arabia
| | - Saleh Al-Quraishy
- Department of Zoology, College of Science, King Saud University, Saudi Arabia
| | - Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud University, Saudi Arabia; Department of Zoology and Entomology, Faculty of Science, Helwan University, Egypt
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Kariuki SM, Abubakar A, Stein A, Marsh K, Newton CRJC. Prevalence, causes, and behavioral and emotional comorbidities of acute symptomatic seizures in Africa: A critical review. Epilepsia Open 2017; 2:8-19. [PMID: 29750209 PMCID: PMC5939456 DOI: 10.1002/epi4.12035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2016] [Indexed: 12/19/2022] Open
Abstract
Seizures with fever includes both febrile seizures (due to nonneurological febrile infections) and acute symptomatic seizures (due to neurological febrile infections). The cumulative incidence (lifetime prevalence) of febrile seizures in children aged ≤6 years is 2-5% in American and European studies, but there are no community-based data on acute symptomatic seizures in Africa. The incidence of acute symptomatic seizures in sub-Saharan Africa is more than twice that in high-income countries. However, most studies of acute symptomatic seizures from Africa are based on hospital samples or do not conduct surveys in demographic surveillance systems, which underestimates the burden. It is difficult to differentiate between febrile seizures and acute symptomatic seizures in Africa, especially in malaria-endemic areas where malaria parasites can sequester in the brain microvasculature; but this challenge can be addressed by robust identification of underlying causes. The proportion of complex acute symptomatic seizures (i.e., seizures that are focal, repetitive, or prolonged) in Africa are twice that reported in other parts of the world (>60% vs. ∼30%), which is often attributed to falciparum malaria. These complex phenotypes of acute symptomatic seizures can be associated with behavioral and emotional problems in high-income countries, and outcomes may be even worse in Africa. One Kenyan study reported behavioral and emotional problems in approximately 10% of children admitted with acute symptomatic seizures, but it is not clear whether the behavioral and emotional problems were due to the seizures, shared genetic susceptibility, etiology, or underlying neurological damage. The underlying neurological damage in acute symptomatic seizures can lead not only to behavioral and emotional problems but also to neurocognitive impairment and epilepsy. Electroencephalography may have a prognostic role in African children with acute symptomatic seizures. There are significant knowledge gaps regarding acute symptomatic seizures in Africa, which results in lack of reliable estimates for planning interventions. Future epidemiological studies of acute symptomatic seizures should be set up in Africa.
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Affiliation(s)
| | - Amina Abubakar
- KEMRI‐Wellcome Trust Research ProgrammeKilifiKenya
- Department of Public HealthPwani UniversityKilifiKenya
- Department of PsychiatryUniversity of OxfordOxfordUnited Kingdom
| | - Alan Stein
- Department of PsychiatryUniversity of OxfordOxfordUnited Kingdom
| | - Kevin Marsh
- KEMRI‐Wellcome Trust Research ProgrammeKilifiKenya
- Nuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
- Alliance for Accelerating Excellence in Science in AfricaAfrican Academy of SciencesNairobiKenya
| | - Charles R. J. C. Newton
- KEMRI‐Wellcome Trust Research ProgrammeKilifiKenya
- Department of PsychiatryUniversity of OxfordOxfordUnited Kingdom
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Ssenkusu JM, Hodges JS, Opoka RO, Idro R, Shapiro E, John CC, Bangirana P. Long-term Behavioral Problems in Children With Severe Malaria. Pediatrics 2016; 138:peds.2016-1965. [PMID: 27940786 PMCID: PMC5079082 DOI: 10.1542/peds.2016-1965] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/05/2016] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Severe malaria in children is associated with long-term neurocognitive impairment, but it is unclear whether it is associated with long-term behavioral problems. METHODS Children <5 years old with cerebral malaria (CM) or severe malarial anemia (SMA) treated at Mulago Hospital, Kampala, Uganda were assessed for behavioral outcomes at 0, 6, 12, and 24 months using the Child Behavior Checklist. Sample sizes at 0, 12, and 24 months were 122, 100, and 80 in the CM group, 130, 98, and 81 in the SMA group, and 149, 123, and 90 in healthy community control (CC) children, respectively. Age adjusted z-scores for behavioral outcomes were computed using scores for the CC group. Study groups were compared using regression models adjusted for age, nutritional status, preschool education, and socioeconomic status. RESULTS At 12 months, children with SMA had higher z-scores than CC children for internalizing (mean difference, 0.49; SE, 0.14; P = .001), externalizing (mean difference, 0.49; SE, 0.15; P = .001), and total problems (mean difference, 0.51; SE, 0.15; P < .001). Children with CM had higher adjusted z-scores than CC children for externalizing problems (mean difference, 0.39; SE, 0.15; P = .009) but not internalizing or total problems. At 24 months, children with CM or SMA both had increased internalizing and externalizing behavioral problems compared with CC children (P ≤ .05 for all). CONCLUSIONS CM and SMA are associated with long-term internalizing and externalizing behavioral problems in children. They may contribute substantially to mental health morbidity in children <5 years old in malaria endemic areas.
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Affiliation(s)
| | | | | | | | - Elsa Shapiro
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | | | - Paul Bangirana
- Psychiatry, Makerere University College of Health Sciences, Kampala, Uganda; and
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Knox PC, MacCormick IJC, Mbale E, Malewa M, Czanner G, Harding SP. Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond. PLoS One 2016; 11:e0164885. [PMID: 27764173 PMCID: PMC5072745 DOI: 10.1371/journal.pone.0164885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 10/03/2016] [Indexed: 01/17/2023] Open
Abstract
Paediatric cerebral malaria is the most serious complication of Plasmodium falciparum infection. While the majority recover, long-term cognitive impairment has been highlighted as a significant and neglected problem. Persistent or serious deficits in processes such as attention or behavioural inhibition should be manifest in changes to performance on oculomotor tasks. Therefore we investigated the impact of cerebral malaria on the development of reflexive pro-saccades and antisaccades. In a longitudinal study, 47 children previously admitted with retinopathy-confirmed cerebral malaria (mean age at admission 54 months), were compared with 37 local healthy controls (mean ages at first study visit 117 and 110 months respectively). In each of three or four test sessions, over a period of up to 32 months, participants completed 100 prosaccade tasks and 100 antisaccade tasks. Eye movements were recorded using infrared reflectance oculography; prosaccade, correct antisaccade and error prosaccade latency, and antisaccade directional error rate were calculated. Hierarchical linear modelling was used to investigate the effect of age and the influence of cerebral malaria on these parameters. Data were also collected from an independent, older group (mean age 183 months) of 37 local healthy participants in a separate cross-sectional study. Longitudinal data exhibited the expected decrease in latency with age for all saccade types, and a decrease in the antisaccade directional error rate. Hierarchical linear modelling confirmed that age had a statistically significant effect on all parameters (p< = 0.001). However, there were no statistically significant differences between the cerebral malaria and control groups. Combining groups, comparison with the literature demonstrated that antisaccade directional error rate for the Malawi sample was significantly higher than expected, while latencies for all saccade types were indistinguishable from published. The high directional error rate was also confirmed in the older, healthy Malawian participants from the cross sectional study. Our observation of similar oculomotor performance in cerebral malaria and control groups at long follow-up periods suggests that cerebral malaria survivors are not at a generally increased risk of persistent cognitive deficits. Our data raise questions about the prevailing hypothesis that cerebral malaria has gross impacts on the development of processes such as attention and behavioural inhibition. More importantly, our novel finding of a clear difference in antisaccade performance between all of the Malawi participants and published data suggests that the Malawian paediatric population as a whole faces serious challenges to cognitive development beyond cerebral malaria.
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Affiliation(s)
- Paul C. Knox
- Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, William Duncan Building, Liverpool, L7 ATX, United Kingdom
- * E-mail:
| | - Ian J. C. MacCormick
- Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, William Duncan Building, Liverpool, L7 ATX, United Kingdom
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre, Malawi
| | - Emme Mbale
- University of Malawi College of Medicine, College of Medicine, P/Bag 360 Chichiri, Blantyre, Malawi
| | - Macpherson Malewa
- University of Malawi College of Medicine, College of Medicine, P/Bag 360 Chichiri, Blantyre, Malawi
| | - Gabriela Czanner
- Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, William Duncan Building, Liverpool, L7 ATX, United Kingdom
- Department of Biostatistics, University of Liverpool, Waterhouse Building, Liverpool, L69 3GL, United Kingdom
| | - Simon P. Harding
- Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, William Duncan Building, Liverpool, L7 ATX, United Kingdom
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Singh VB, Kumar H, Meena BL, Chandra S, Agrawal J, Kanogiya N. Neuropsychiatric Profile in Malaria: An Overview. J Clin Diagn Res 2016; 10:OC24-8. [PMID: 27630883 PMCID: PMC5020222 DOI: 10.7860/jcdr/2016/19035.8169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/21/2016] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Malaria is the most important parasitic disease of humans causes clinical illness over 300-500 million people globally and over one million death every year globally. The involvement of the nervous system in malaria is studied in this paper, to help formulate a strategy for better malaria management. AIM To study the Neuropsychiatric manifestation in malaria. MATERIALS AND METHODS This was a prospective observational study in 170 patients with a clinical diagnosis of malaria admitted in various medical wards of medicine department of PBM Hospital, Bikaner during epidemic of malaria. It included both sexes of all age groups except the paediatric range. The diagnosis of malaria was confirmed by examination of thick and thin smear/optimal test/strip test. Only those cases that had asexual form of parasite of malaria in the blood by smear examination or optimal test were included in the study. RESULTS Out of total 170 patients 104 (62%) reported Plasmodium falciparum (PF), Plasmodium vivax (PV) were 57 (33.5%) followed by mixed (PF+PV) 9 (5.3%) cases. The total PBF-MP test positivity was 84.5%. Maximum patients were belonging to the age range of 21-40 year with male predominance. Neuropsychiatric manifestation seen in falciparum malaria (n=111) as follow: altered consciousness 20 (18.01%), headache 17 (15.32%), neck rigidity 5 (4.5%), convulsion 5 (4.55%), extra pyramidal rigidity 2 (1.8%), decorticate rigidity 1 (0.90%), decerebrate rigidity 1 (0.90%), cerebellar ataxia 3 (2.7%), subarachnoid haemorrhage 1 (0.90%), aphasia 2 (1.8%), subconjunctival haemorrhage 1 (0.90%), conjugate deviation of eye 1 (0.90%) and psychosis 6 (5.40%). Twenty one patients presented with cerebral malaria out of 111 patients. Most patients of cerebral malaria presented with altered level of consciousness followed by headache and psychosis. Acute confusional state with clouding of consciousness was the most common presentation of psychosis (50%). CONCLUSION Neuropsychiatric manifestations are not an uncommon presentation of malaria. Most commonly caused by PF malaria. Malaria should be thought as a differential diagnosis in pyrexia with neuropsychiatric manifestation. Observation obtained in the study will be highly useful for the diagnosis and management of patients suffering from malaria.
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Affiliation(s)
- Veer Bahadur Singh
- Senior Professor, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
| | - Harish Kumar
- Senior Resident, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
| | - Babu Lal Meena
- Assistant Professor, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
| | - Subhash Chandra
- Assistant Professor, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
| | - Jatin Agrawal
- Registrar, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
| | - Naresh Kanogiya
- Student, Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
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Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J 2016; 15:332. [PMID: 27335053 PMCID: PMC4918116 DOI: 10.1186/s12936-016-1391-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 06/15/2016] [Indexed: 11/10/2022] Open
Abstract
The modern medical literature implicates malaria, and particularly the potentially fatal form of cerebral malaria, with a risk of neurocognitive impairment. Yet historically, even milder forms of malaria were associated in the literature with a broad range of psychiatric effects, including disorders of personality, mood, memory, attention, thought, and behaviour. In this article, the history of psychiatric effects attributed to malaria and post-malaria syndromes is reviewed, and insights from the historical practice of malariotherapy in contributing to understanding of these effects are considered. This review concludes with a discussion of the potentially confounding role of the adverse effects of anti-malarial drugs, particularly of the quinoline class, in the unique attribution of certain psychiatric effects to malaria, and of the need for a critical reevaluation of the literature in light of emerging evidence of the chronic nature of these adverse drug effects.
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Affiliation(s)
- Remington L. Nevin
- />Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 N. Broadway, Room 782, Baltimore, MD 21205 USA
| | - Ashley M. Croft
- />School of Pharmacy and Biomedical Science, University of Portsmouth, James Watson Building (West), Portsmouth, Hants PO1 2FR UK
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A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. Blood 2015; 127:1192-201. [PMID: 26511133 DOI: 10.1182/blood-2015-07-654921] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/19/2015] [Indexed: 01/28/2023] Open
Abstract
Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF(-/-) C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF(-/-) mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF(-/-) and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood-brain barrier permeability was significantly attenuated in VWF(-/-) mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.
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Christensen SS, Eslick GD. Cerebral malaria as a risk factor for the development of epilepsy and other long-term neurological conditions: a meta-analysis. Trans R Soc Trop Med Hyg 2015; 109:233-238. [PMID: 25631856 DOI: 10.1093/trstmh/trv005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cerebral malaria (CM) is the most common and severe acute neurological manifestation of Plasmodium falciparum malaria. Children living in malaria-endemic areas of sub-Saharan Africa are at the highest risk of developing CM, and the long-term effect of CM on neurological function is uncertain. We conducted a meta-analysis to quantitatively assess the association between CM and development of long-term neurological impairment. We performed a systematic search through PubMed (including MEDLINE; 1946 to December 2014) and EMBASE (1974 to January 2015) to identify relevant articles. Eligible studies assessed the association between CM and neurological sequelae and were included if they met the criteria allowing a complete extraction of data. Eight studies were included in the final analysis, and in total, 2005 individuals were analysed (cases: n=842, controls: n=1163), most of whom were children. CM was associated with an increased risk of epilepsy (OR 4.68, 95% CI: 2.52-8.70), an increased risk of intelligence quotient (IQ) impairment (OR 4.72, 95% CI: 0.78-28.49), an increased risk of neurodisabilities (OR 16.16, 95% CI: 1.34-195.45), and an increased risk of behavioural disorder (OR 8.47, 95% CI: 2.75-26.04). Our findings suggest that children who survive CM are at increased risk of long-term neurological adverse outcome, including epilepsy. This may present a major public health problem in terms of education and development in malaria-endemic areas. Measures to avoid neurological morbidity are warranted.
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Affiliation(s)
- Stephanie S Christensen
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School Nepean, Penrith, NSW, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School Nepean, Penrith, NSW, Australia.
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Bangirana P, Opoka RO, Boivin MJ, Idro R, Hodges JS, John CC. Neurocognitive domains affected by cerebral malaria and severe malarial anemia in children. LEARNING AND INDIVIDUAL DIFFERENCES 2015; 46:38-44. [PMID: 27212870 DOI: 10.1016/j.lindif.2015.01.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
This study assessed the effects of cerebral malaria (CM) and severe malarial anemia (SMA) on individual neurocognitive domains. Eighty children with CM, 86 with SMA, and 61 community children (CC) were assessed for gross motor skills, fine motor skills, visual reception, receptive language, and expressive language a week after discharge (CM or SMA) or at enrolment (CC), and 6 and 12 months later. At 12-months follow-up, children with CM had significantly lower scores than CC for all outcomes. Children with SMA had significantly lower scores than CC for visual reception, receptive language, and expressive language, and scores that were lower but did not reach significance for gross and fine motor skills. Children with CM had significantly lower scores than children with SMA for fine motor skills. Children with SMA and CM have long-term impairment in multiple neurocognitive domains. Fine motor skills may be affected more profoundly in CM than SMA.
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Affiliation(s)
- Paul Bangirana
- Department of Psychiatry, Makerere University College of Health Sciences, Kampala, Uganda
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Michael J Boivin
- Department of Psychiatry, Michigan State University, East Lansing, Michigan
| | - Richard Idro
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - James S Hodges
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota
| | - Chandy C John
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
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46
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Guha SK, Tillu R, Sood A, Patgaonkar M, Nanavaty IN, Sengupta A, Sharma S, Vaidya VA, Pathak S. Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior. Brain Behav Immun 2014; 42:123-37. [PMID: 24953429 DOI: 10.1016/j.bbi.2014.06.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 06/09/2014] [Accepted: 06/13/2014] [Indexed: 12/26/2022] Open
Abstract
Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post-parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial activation and redistribution, and a definitive, but transient, suppression of adult hippocampal neurogenesis.
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Affiliation(s)
- Suman K Guha
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Rucha Tillu
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Ankit Sood
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Mandar Patgaonkar
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Ishira N Nanavaty
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Arjun Sengupta
- Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Shobhona Sharma
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Vidita A Vaidya
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
| | - Sulabha Pathak
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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Nankabirwa J, Brooker SJ, Clarke SE, Fernando D, Gitonga CW, Schellenberg D, Greenwood B. Malaria in school-age children in Africa: an increasingly important challenge. Trop Med Int Health 2014; 19:1294-309. [PMID: 25145389 PMCID: PMC4285305 DOI: 10.1111/tmi.12374] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
School-age children have attracted relatively little attention as a group in need of special measures to protect them against malaria. However, increasing success in lowering the level of malaria transmission in many previously highly endemic areas will result in children acquiring immunity to malaria later in life than has been the case in the past. Thus, it can be anticipated that in the coming years there will be an increase in the incidence of both uncomplicated and severe malaria in school-age children in many previously highly endemic areas. In this review, which focuses primarily on Africa, recent data on the prevalence of malaria parasitaemia and on the incidence of clinical malaria in African school-age children are presented and evidence that malaria adversely effects school performance is reviewed. Long-lasting insecticide treated bednets (LLIN) are an effective method of malaria control but several studies have shown that school-age children use LLINs less frequently than other population groups. Antimalarial drugs are being used in different ways to control malaria in school-age children including screening and treatment and intermittent preventive treatment. Some studies of chemoprevention in school-age children have shown reductions in anaemia and improved school performance but this has not been the case in all trials and more research is needed to identify the situations in which chemoprevention is likely to be most effective and, in these situations, which type of intervention should be used. In the longer term, malaria vaccines may have an important role in protecting this important section of the community from malaria. Regardless of the control approach selected, it is important this is incorporated into the overall programme of measures being undertaken to enhance the health of African school-age children.
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Carter JA, Murira G, Gona J, Tumaini J, Lees J, Neville BG, Newton CR. Speech and Language Disorders in Kenyan Children: Adapting Tools for Regions with Few Assessment Resources. JOURNAL OF PSYCHOLOGY IN AFRICA 2014. [DOI: 10.1080/14330237.2012.10820514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Julie Anne Carter
- The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute Centre for International Health and Development, Institute of Child Health
| | - Grace Murira
- The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute
| | - Joseph Gona
- The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute
| | - Judy Tumaini
- The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute
| | - Janet Lees
- Neurosciences Unit, Institute of Child Health
| | | | - Charles Richard Newton
- The Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute Neurosciences Unit, Institute of Child Health, University of Oxford
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Bangirana P, Opoka RO, Boivin MJ, Idro R, Hodges JS, Romero RA, Shapiro E, John CC. Severe malarial anemia is associated with long-term neurocognitive impairment. Clin Infect Dis 2014; 59:336-44. [PMID: 24771329 DOI: 10.1093/cid/ciu293] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Cerebral malaria (CM) is associated with long-term neurocognitive impairment in children ≥5 years of age. No prospective studies to date have assessed neurocognitive impairment in children with CM <5 years of age, or in children with severe malarial anemia (SMA), a form of severe malaria estimated to affect as many as 5 million children annually. METHODS Children <5 years of age presenting to Mulago Hospital, Kampala, Uganda, with CM (n = 80) or SMA (n = 86) were assessed for overall cognitive ability, attention, and associative memory 1 week after discharge and 6 and 12 months later. The z scores for each domain were computed based on scores of 61 healthy community children (CC), who were also tested at enrollment and 6 and 12 months later. Groups were compared using mixed linear models, adjusted for age, weight for age, and child's education. RESULTS At 12 months, children with CM had lower adjusted scores than CC in cognitive ability (P < .001), attention (P = .02), and associative memory, (P = .002). Children with SMA had lower scores than CC in cognitive ability (P = .01) but not attention or associative memory. Cognitive ability scores in children with CM and SMA did not differ significantly. CONCLUSIONS In children <5 years of age, SMA is associated with long-term impairment in cognitive ability, whereas CM is associated with additional impairment in the areas of attention and associative memory. SMA may be a major contributor to long-term neurocognitive impairment in children in sub-Saharan Africa.
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Affiliation(s)
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Michael J Boivin
- Department of Psychiatry, Michigan State University School of Human Medicine, East Lansing
| | - Richard Idro
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | | | - Regilda A Romero
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis
| | - Elsa Shapiro
- Department of Epidemiology, University of Minnesota School of Public Health, and
| | - Chandy C John
- Department of Biostatistics, and Department of Epidemiology, University of Minnesota School of Public Health, and
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Monteiro MC, Oliveira FR, Oliveira GB, Romao PRT, Maia CSF. Neurological and behavioral manifestations of cerebral malaria: An update. World J Transl Med 2014; 3:9-16. [DOI: 10.5528/wjtm.v3.i1.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 02/28/2014] [Accepted: 03/14/2014] [Indexed: 02/05/2023] Open
Abstract
Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the physiological changes they induce in their hosts. Malaria is a disease caused by Plasmodium sp. that in its cerebral form may lead to acute or long-term neurological deficits, even with effective antimalarial therapy, causing vascular obstruction, reduced cerebral blood flow and many other changes. However, Plasmodium falciparum infection can also develop into a cerebral malaria (CM) disease that can produce neurological damage. This review will discuss the mechanisms involved in the neuropathology caused by CM, focusing on alterations in cognitive, behavior and neurological functions in human and experimental models.
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