Title

Admission Clinical and EEG Features Associated With Mortality and Long-term Neurologic and Cognitive Outcomes in Pediatric Cerebral Malaria

Authors

Daniel J. Clark, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi. daniel.clark@cchmc.org.
Caitlin Bond, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Alexander Andrews, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Daniel J. Muller, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Angela Sarkisian, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Robert O. Opoka, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Richard Idro, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Paul Bangirana, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Andy Witten, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Nicholas J. Sausen, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Gretchen L. Birbeck, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Chandy C. John, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.
Douglas G. Postels, From the Division of Neurology (D.J.C.), Nationwide Children's Hospital, Columbus, OH; Ryan White Center for Pediatric Infectious Diseases & Global Health (C.B., C.C.J.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (A.A.), MedStar Georgetown University Hospital; The George Washington University School of Medicine and Health Sciences (D.J.M., A.S., D.G.P.), Washington, DC; Department of Paediatrics and Child Health (R.O.O., R.I.), Makerere University College of Health Sciences; Department of Psychiatry (P.B.), Makerere University College of Health Sciences, Kampala, Uganda; Department of Neurosurgery (A.W.), Indiana University School of Medicine, Indianapolis; Department of Pediatrics (N.J.S.), Division of Emergency Medicine, University of Minnesota, Minneapolis; Department of Neurology (G.L.B.), University of Rochester, NY; University of Zambia (G.L.B.), School of Medicine, Lusaka; University Teaching Hospitals Children's Hospital (G.L.B.), Lusaka, Zambia; Children's National Medical Center (D.G.P.), Washington, DC; and Blantyre Malaria Project (D.G.P.), Kamuzu University of Health Sciences, Blantyre, Malawi.

Document Type

Journal Article

Publication Date

9-26-2023

Journal

Neurology

Volume

101

Issue

13

DOI

10.1212/WNL.0000000000207657

Abstract

BACKGROUND AND OBJECTIVES: For children with cerebral malaria, mortality is high, and in survivors, long-term neurologic and cognitive dysfunctions are common. While specific clinical factors are associated with death or long-term neurocognitive morbidity in cerebral malaria, the association of EEG features with these outcomes, particularly neurocognitive outcomes, is less well characterized. METHODS: In this prospective cohort study of 149 children age 6 months to 12 years who survived cerebral malaria in Kampala, Uganda, we evaluated whether depth of coma, number of clinical seizures, or EEG features during hospitalization were associated with mortality during hospitalization, short-term and long-term neurologic deficits, or long-term cognitive outcomes (overall cognition, attention, memory) over the 2-year follow-up. RESULTS: Higher Blantyre or Glasgow Coma Scores (BCS and GCS, respectively), higher background voltage, and presence of normal reactivity on EEG were each associated with lower mortality. Among clinical and EEG features, the presence of >4 seizures on admission had the best combination of negative and positive predictive values for neurologic deficits in follow-up. In multivariable modeling of cognitive outcomes, the number of seizures and specific EEG features showed independent association with better outcomes. In children younger than 5 years throughout the study, seizure number and presence of vertex sharp waves were independently associated with better posthospitalization cognitive performance, faster dominant frequency with better attention, and higher average background voltage and faster dominant background frequency with better associative memory. In children younger than 5 years at CM episode but 5 years or older at cognitive testing, seizure number, background dominant frequency, and the presence of vertex sharp waves were each associated with changes in cognition, seizure number and variability with attention, and seizure number with working memory. DISCUSSION: In children with cerebral malaria, seizure number is strongly associated with the risk of long-term neurologic deficits, while seizure number and specific EEG features (average background voltage, dominant rhythm frequency, presence of vertex sharp waves, presence of variability) are independently associated with cognitive outcomes. Future studies should evaluate the predictive value of these findings.

Department

Neurology

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