Children with zika-associated microcephaly display heterogeneous neurological development, study shows

Assessment of two- and three-year-olds can help health professionals design personalized treatment. The study involved scientists in Brazil and the United States, and is published in PLOS ONE.

By Luciana Constantino  |  Agência FAPESP – A study conducted in Salvador, the capital of Bahia state in Brazil, shows that children with microcephaly caused by zika virus display very different neurological development profiles at 2-3 years of age. The significant variation can be detected by neurological assessment tests, allowing for a personalized approach to treatment.

The study, published in the journal PLOS ONE, involved 42 infants aged between 24 and 40 months with congenital zika syndrome, a group of birth defects associated with infection by zika virus during pregnancy.

In general, these children had severe cerebral palsy (Level 5, the highest in the Gross Motor Function Classification System, involving bilateral spasticity, characterized by muscle stiffness, contraction and spasms, typically requiring use of a wheelchair) and significant cognitive, linguistic and neurological impairment. However, the researchers captured clear differences in neurological development, such as varying ability to respond to external stimuli, using two assessments: the Hammersmith Infant Neurological Examination (HINE), considered quick and easy to perform; and the third edition of the Bayley Scale of Infant Development (Bayley-III). The best HINE scores correlated with more positive results in the Bayley-III assessment, but scores varied significantly even among the most severe cases, evidencing heterogeneity.

The study also showed that larger head circumference was associated with higher cognitive and motor scores. The infants in the study sample had head circumferences under 31.9 cm for boys and 31.5 cm for girls. These are the parameters established by the World Health Organization (WHO) to detect suspected cases of microcephaly.

“Most studies compare children exposed to zika virus in the womb and divide them into those with and without microcephaly. The former have a worse prognosis, with low neurological development, and the latter risk suffering from the same problems but more moderately. Our study included only children with congenital zika syndrome, and evaluated the varying degrees of neurological impairment to understand individual differences, not as a group with the same development and follow-up analysis,” Juan Pablo Aguilar Ticona, first author of the article, told Agência FAPESP. Aguilar Ticona is a researcher affiliated with the Institute of Collective Health at the Federal University of Bahia (UFBA).

The study was supported by FAPESP as part of the Thematic Project “Antigen discovery and development of serological diagnostic methods and vaccine approaches against zika virus”, for which the principal investigators are Luís Carlos de Souza Ferreira and Edison Luiz Durigon, professors at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP). 

Albert Ko, a professor at Yale School of Public Health (USA), and Federico Costa, a professor at UFBA, supervised the study and are the last two authors of the article.

According to Aguilar Ticona, previous studies used the HINE to evaluate babies with zika-associated microcephaly, but this was one of the first to link HINE scores to cognitive and motor development, offering an important neurological assessment tool for early diagnosis.

Although the study sample was small, he added, it provided a good opportunity to investigate the evolution of microcephaly a few years after birth. “Our analysis of the test results and neurological delays highlighted significant developmental differences. An aspect that we didn’t evaluate in the study but that may have effects was the possible association between development and social context, such as education and family,” he said. 

In another study reported by the same group in July 2021 in PLOS Neglected Tropical Diseases, food insecurity and low levels of educational attainment were influential social factors affecting the risk of zika infection for pregnant women. The study, which was also supported by FAPESP, involved 469 pregnant women, 61% of whom tested positive for zika during the 2015-16 outbreak in Salvador. The researchers analyzed demographic, socio-economic and clinical data for the subjects, and measured exposure to zika by means of a virus neutralization test. The findings help identify risk factors that can be targeted by future interventions to reduce the impact of zika on vulnerable members of society.

Sample

The latest study involved children treated in Salvador at the microcephaly outpatient clinic of Roberto Santos General Hospital (HGRS). The infants were born during the peak of the zika outbreak, between October 2015 and January 2016.

Brazil was then one of the countries with the most zika cases, largely because of the widespread presence of the vector, the mosquito Aedes aegypti, which also transmits dengue. The symptoms of both diseases are similar, including fever, headache, red eyes, rash, and joint pain.

Although zika is usually asymptomatic, research has shown a link between this disease and the development of neurological complications such as Guillain-Barré syndrome and meningitis in adults, and congenital malformations such as microcephaly in newborns.

However, cases of zika and congenital zika syndrome did not spread throughout Brazil, but were reported mostly in the Northeast region. According to the Ministry of Health, 3,423 babies were born with congenital zika syndrome between 2015 and 2020, and about 2,900 were still alive last year, but only 56.4% were receiving specialized treatment.

The children analyzed in the study were treated by a multidisciplinary team comprising physical therapists, speech therapists, nurses and physicians, including an ophthalmologist and a neurologist. Data was collected on the mothers and babies by means of interviews, clinical records and examinations.

The HINE scores covered 26 items, including posture, movements, tone, and cranial nerve functions. In subjects aged more than 18 months, the ideal HINE score for this section is 74 and over. A large proportion of the sample scored less than 40, reflecting severe motor impairment.

The Bayley-III scores referred to cognition, expressive and receptive language, and fine and gross motor development. Other tests included visual acuity and contact, sensitivity to light, ocular fixation, stability, object tracking, social smile response, and facial responses to visual stimuli.

“To glean a better understanding of the differences between these children and identify early interventions which will reduce the disease burden, it is first necessary to develop either new evaluative tools or standardized adjustments to existing ones, which reflect this heterogeneity and can be used to follow and evaluate the progression of the disease. Health professionals need easy, practical and reliable tests which can predict the longer-term outcomes of their patients and help design plans for their treatment,” the article concludes.

Zika cases continue to be reported in Brazil even though more than five years have passed since the outbreak began. In 2020 alone, 1,007 cases were notified: 35 were confirmed, and 597 were still under investigation in February 2021, when the ministry issued its last bulletin.

The article “Heterogeneous development of children with congenital zika syndrome-associated microcephaly” is at: journals.plos.org/plosone/article?id=10.1371/journal.pone.0256444.