Date Presented 04/01/2022
Understanding the full spectrum of deficits and early predictors associated with Zika virus (ZIKV) is important for OTs to provide early intervention therapy to maximize long-term child functional outcomes. Using a rhesus macaque model, we examined the impact of ZIKV on gait development. Compared with controls, macaques with prenatal exposure to ZIKV demonstrated less balance over the first month of life, potentially identifying an early predictor of late-onset functional motor deficits.
Primary Author and Speaker: Sabrina Kabakov
Additional Authors and Speakers: Karla Ausderau
Contributing Authors: Natalie Dulaney, Jack Drew, Madison Stumpf, Kristen A. Pickett, Emma Mohr
PURPOSE: The purpose of this study is to understand early developmental deficits in gait when a mother transmits the Zika virus (ZIKV) to a fetus during pregnancy. About 10% of exposed infants are born with severe birth defects and an additional, 40% of infants born without severe birth defects developed late-onset developmental delays, including motor deficits. Understanding the full spectrum of deficits associated with ZIKV is important for occupational therapists to provide early intervention therapy to children exposed to ZIKV to maximize child functional outcomes. It is critical to utilize a model system of rhesus macaques to understand the range of deficits associated with in utero exposure to ZIKV because they share 93% of the human genome and develop 3-4 times faster than humans. We hypothesize that prenatal exposure to ZIKV in infant rhesus macaques will impact motor development as evidenced by decreased balance and coordination in early gait development compared to the mock injection control group.
DESIGN: A controlled longitudinal experimental design with rhesus macaques was utilized to conduct comprehensive assessments to identify early subtle motor deficits associated with prenatal ZIKV exposure. Pregnant female rhesus macaques were inoculated with Puerto Rican ZIKV (n = 16) or a mock injection (n = 7) at day 30-45 gestation. Mothers were followed throughout pregnancy and infants were studied for the first three years of life. Researchers were blinded to the groups to prevent observer bias.
METHOD: Infants were placed in the Noldus CatWalk XT for highly sensitive quantification of gross motor skills and gait development at 14, 21, and 28 (+/- 1) days of life. At each time point, we collected 3 useable runs as defined by at least two consecutive footfalls per limb. The data was analyzed for duty-factor, percent of time each limb (right front, left front, right hind, and left hind) was on the ground over the total step cycle. A linear mixed-effects model with animal-specific random effects was used to determine significance between groups (p<0.05).
RESULTS: ZIKV exposed infants approached significance of spending more time on their left front at day 21 (p = .0514, effect size = -1.143) and day 28 (p = .0511, effect size = -1.072), and on their right front at day 14 (p = 0763, effect size = -1.012), and day 21 (p = .0573, effect size = -1.120) compared to the control group. There were no differences between groups in their hind limb usage. There was also widespread variability within the ZIKV group for duty-factor. Additional observations were found of six animals using an uncoordinated walking pattern with difficulty lifting their limb when ambulating.
CONCLUSION: Infants prenatally exposed to ZIKV have less balance and coordination requiring additional support from their front limbs when ambulating. Moreover, the range of deficits experienced by human infants is highlighted by overall heterogeneity in the ZIKV group. Understanding the balance and coordination of rhesus macaques is essential to develop early predictors of later functional movement pattern differences in humans. Future research is still needed to better understand motor deficits associated with prenatal ZIKV exposure that may become more apparent later in development.
IMPACT STATEMENT: A future Zika virus pandemic is probable which may lead to many children being born with late-onset developmental deficits. Occupational therapists are well situated to support the identification of young children who are at risk. OTs will play a critical role in early intervention to improve outcomes in the context of the child’s occupations: play, school, and daily activities.
Nielsen-Saines, K., Brasil, P., Kerin, T., Vasconcelos, Z., Gabaglia, C. R., Damasceno, L., … Moreira, M. E. (2019). Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nature Medicine, 25(8), 1213–1217. https://doi.org/10.1038/s41591-019-0496-1
Reynolds, M. R., Jones, A. M., Petersen, E. E., Lee, E. H., Rice, M. E., Bingham, A., … Zaki, S. (2017). Vital Signs: Update on Zika Virus–Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure — U.S. Zika Pregnancy Registry, 2016. MMWR. Morbidity and Mortality Weekly Report, 66(13), 366–373. https://doi.org/10.15585/mmwr.mm6613e1
Dudley, D. M., Aliota, M. T., Mohr, E. L., Newman, C. M., Golos, T. G., Friedrich, T. C., & O’Connor, D. H. (2019). Using Macaques to Address Critical Questions in Zika Virus Research. Annual Review of Virology, 6(1), 481–500. https://doi.org/10.1146/annurev-virology-092818-015732
Einspieler, C., Utsch, F., Brasil, P., Panvequio Aizawa, C. Y., Peyton, C., Hydee Hasue, R., …Nielsen-Saines, K.; GM Zika Working Group. (2019). Association of Infants Exposed to Prenatal Zika Virus Infection With Their Clinical, Neurologic, and Developmental Status Evaluated via the General Movement Assessment Tool. JAMA Network Open, 2(1), e187235. https://doi.org/10.1001/jamanetworkopen.2018.7235