Ventilatory and Orthostatic Challenges Reveal Biomarkers for Neurocognition in Children and Young Adults With Congenital Central Hypoventilation Syndrome

Abstract

Background: Children and young adults with congenital central hypoventilation syndrome (CCHS) are at risk of cognitive deficits. They experience autonomic dysfunction and chemoreceptor insensitivity measured during ventilatory and orthostatic challenges, but relationships between these features are undefined.

Research question: Can a biomarker be identified from physiologic responses to ventilatory and orthostatic challenges that is related to neurocognitive outcomes in CCHS?

Study design and methods: This retrospective study included 25 children and young adults with CCHS tested over an inpatient stay. Relationships between physiologic measurements during hypercarbic and hypoxic ventilatory challenges, hypoxic ventilatory challenges, and orthostatic challenges and neurocognitive outcomes (by Wechsler intelligence indexes) were examined. Independent variable inclusion was determined by significant associations in Pearson's analyses. Multivariate linear regressions were used to assess relationships between measured physiologic responses to challenges and neurocognitive scores.

Results: Significant relationships were identified between areas of fluid intelligence and measures of oxygen saturation (SpO₂) and heart rate (HR) during challenges. Specifically, perceptual reasoning was related to HR (adjusted regression [β] coefficient, -0.68; 95% CI, 1.24 to -0.12; P = .02) during orthostasis. Working memory was related to change in HR (β, -1.33; 95% CI, -2.61 to -0.05; P = .042) during the hypoxic ventilatory challenge. Processing speed was related to HR (β, -1.19; 95% CI, -1.93 to -0.46; P = .003) during orthostasis, to baseline SpO₂ (hypercarbic and hypoxic β, 8.57 [95% CI, 1.63-15.51]; hypoxic β, 8.37 [95% CI, 3.65-13.11]; P = .002 for both) during the ventilatory challenges, and to intrachallenge SpO₂ (β, 5.89; 95% CI, 0.71-11.07; P = .028) during the hypoxic ventilatory challenge.

Interpretation: In children and young adults with CCHS, SpO₂ and HR-or change in HR-at rest and as a response to hypoxia and orthostasis are related to cognitive outcomes in domains of known risk, particularly fluid reasoning. These findings can guide additional research on the usefulness of these as biomarkers in understanding the impact of daily physical stressors on neurodevelopment in this high-risk group.

Keywords: ANSD; CCHS; autonomic nervous system dysfunction; cognitive outcomes; congenital central hypoventilation syndrome; head-up tilt; neurocognition; orthostatic challenges; ventilatory challenges.