Neurocognitive Outcome as a Metric for Evaluating Therapeutic Intervention and Treatment Mechanisms in Congenital Central Hypoventilation Syndrome (CCHS): A Multi-Site Study Using The NIH Toolbox

CCHS is a genetic autonomic nervous system disorder caused by heterozygous mutations in the PHOX2B gene. 90-92% are caused by polyalanine repeat expansion mutations (PARMs) with 4 to 13 additional alanines on the affected allele in the 20 alanine repeat region of exon 3 (resulting genotype is 20/24-20/33). The remaining 8-10% of PHOX2B mutations are non-PARMs including missense, nonsense, frameshift or stop codon mutations. And less than 1% of CCHS patients are heterozygous for a large deletion eliminating the entire PHOX2B gene and potentially other neighboring genes. Different causative mutations vary in the level of associated protein dysfunction, leading to variability in the severity of the CCHS phenotype, and potentially in the severity and frequency of resulting neurocognitive insult. Severe cyanotic breath-holding spells and prolonged sinus pauses are two phenotypic features of CCHS known to alter regional blood flow/oxygen saturation to the brain (near-infrared spectroscopy; personal communication 2018). The fact that both of these phenotypic presentations are associated with particular PHOX2B genotypes suggests that genetic factors, intrinsic to CCHS pathology, might influence neurocognitive outcomes.

A recent report suggests that a number of extrinsic factors might also affect neurocognitive performance in patients with CCHS with later identification and less than conservative management in terms of artificial ventilation. While all cases of CCHS require assisted ventilation during sleep, some more severe cases require 24-hour/day artificial ventilation. Methods of assisted ventilation differ case-by-case and are chosen based on several factors, including the patient's level of alveolar hypoventilation, physician recommendation, and a family's ability to provide the recommended support. While these mechanisms are all meant to ensure optimal ventilation, the level of physiological oxygen stability and the stability of carbon dioxide levels provided with each varies. Thus, methods of respiratory assistance are likely to influence neurocognitive outcomes.

Currently, there is no standard mechanism for examining the neurocognitive impact that intrinsic pathology (PHOX2B genotype) and extrinsic factors (age of diagnosis and method of respiratory assistance) have on CCHS patients across age groups and between sites. In order to establish such a standard, this study aims to use a brief and reliable cognitive battery called the NIH Toolbox at multiple sites. The NIH Toolbox was developed to standardize evaluations in specific clinical populations for investigations of neurological development and change, disease recovery, and therapeutic interventions. The Toolbox consists of a series of cognitive assessments of executive function, attention, memory, and language designed for broad use across age groups from childhood to adulthood.

Participants in this study will initially be recruited during clinical visits at the Ann & Robert H. Lurie Children's Hospital of Chicago, Seattle Children's Hospital, and Children's Hospital Los Angeles as well as at meetings of the CCHS Family Network. All participants will complete a 45-minute NIH Toolbox cognitive assessment that is administered on an iPad by trained study staff. Additionally, parents (or adult participants) will complete a simple, 15-minute, electronic REDCap questionnaire designed to obtain basic information including PHOX2B genotype, age of CCHS diagnosis, past and present artificial ventilation interface (example mask, tracheostomy, etc.), past and present mode of artificial ventilation (positive pressure ventilator, negative pressure ventilator, phrenic nerve-diaphragm pacers), phenotype, and disease history. After initial participation, study subjects will complete the Toolbox and questionnaire at annual clinic visits or potentially at CCHS Family Network meetings to allow for longitudinal data collection.

The study will validate the NIH Toolbox as an assessment of cognitive performance and longitudinal cognitive outcomes in CCHS patients. Additionally, the study will characterize the effect of intrinsic and extrinsic disease factors on the neurocognitive outcomes of affected individuals in order optimize care for CCHS patients.