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

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.

Keywords: Cerebral blood flow; Cerebral malaria; Paediatric; Transcranial Doppler Ultrasound.

Fig. 1

Flow diagram of patient screening and enrollment

Fig. 2

Frequency and time to normalization of each Transcranial Doppler Ultrasound phenotype. Only survivors are included in the time to normalization graph. TCD transcranial doppler ultrasound, MO microvascular obstruction, IPH isolated posterior circulation high flow

Fig. 3

Representative images of Transcranial Doppler Ultrasound phenotypes in children with cerebral malaria. A Normal middle cerebral artery (MCA) TCD flow velocities and waveform for a 3-year-old child. B TCD with increased systolic flow velocity, increased diastolic flow velocity, Lindegaard ratio (LR) < 3. These findings represent a child categorized as having hyperaemia. C TCD with decreased systolic flow velocity, decreased diastolic flow velocity, decreased mean flow velocity. These findings represent a child categorized as having low flow. D TCD with normal systolic flow velocity, reduced diastolic flow velocity, increased pulsatility index. These findings represent a child categorized as having microvascular obstruction. E TCD with increased systolic flow velocity, increased diastolic flow velocity, LR > 3. These findings represent a child categorized as having cerebral vasospasm. F TCD with increased systolic flow velocity, increased diastolic flow velocity, increased mean flow velocity in the basilar artery. At the same time, all measurements in the MCAs were normal. These findings represent a child categorized as having isolated posterior circulation high flow