Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive

Nicole F. O'Brien, Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43502, USA. Nicole.obrien@nationwidechildrens.org.
Yudy Fonseca, Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43502, USA.
Hunter C. Johnson, Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43502, USA.
Douglas Postels, Department of Neurology, George Washington University/Children's National Medical Center, Washington, DC, USA.
Gretchen L. Birbeck, Department of Neurology, University of Rochester, Rochester, NY, USA.
Yamikani Chimalizeni, Department of Pediatrics and Child Health, Kamuzu University of Health Sciences, Chichiri, Blantyre 3, Malawi.
Karl B. Seydel, Dept of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, 48824, USA.
Montfort Bernard Gushu, Queen Elizabeth Central Hospital, The Blantyre Malaria Project, Private Bag 360, Chichiri, Blantyre 3, Malawi.
Tusekile Phiri, Queen Elizabeth Central Hospital, The Blantyre Malaria Project, Private Bag 360, Chichiri, Blantyre 3, Malawi.
Sylvester June, Queen Elizabeth Central Hospital, The Blantyre Malaria Project, Private Bag 360, Chichiri, Blantyre 3, Malawi.
Karen Chetcuti, Department of Pediatrics and Child Health, Kamuzu University of Health Sciences, Chichiri, Blantyre 3, Malawi.
Lorenna Vidal, Department of Radiology, Division of Neuroradiology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Manu S. Goyal, Washington University School of Medicine, St. Louis, MO, USA.
Terrie E. Taylor, Dept of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, 48824, USA.

Document Type

Journal Article

Publication Date

6-21-2022

Journal

Malaria journal

Volume

21

Issue

1

DOI

10.1186/s12936-022-04163-0

Keywords

Cerebral blood flow; Cerebral malaria; Paediatric; Transcranial Doppler Ultrasound

Abstract

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p < 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p < 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored.

Department

Neurology

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