According to the US Centers for Disease Control and Prevention, congenital Zika syndrome is characterized by a distinct pattern of birth defects that include microcephaly, decreased brain tissue, eye defects, hypertonia, and congenital contractures. The devastating effects of congenital Zika virus infection (ZVI) on infant development led the World Health Organization in 2016 to designate the Zika virus epidemic a Public Health Emergency of International Concern.

Similar to other neurotropic viruses, the Zika virus targets the central nervous system1 and has been shown to infect peripheral neurons directly and induce cell death.2 Emerging research implicates ZVI in the development of neurologic abnormalities beyond microcephaly, including hydrocephaly, central nervous system calcifications,3 and Guillain-Barré syndrome.4 The authors of  a recent review article suggested that ZVI is a possible risk factor for autism spectrum disorder.5 The rising rates of ZVI globally6 continue to fuel research in this field.

In an interview with Neurology Advisor, Jonathan Miner, MD, PhD, Assistant Professor of Medicine at Washington University in St. Louis, Missouri, and Karin Nielsen-Saines, MD, MPH, Professor of Clinical Pediatrics at the David Geffen School of Medicine at the University of California, Los Angeles, discussed the latest insights about neurologic complications of ZVI and knowledge gaps that still exist in this field.

Neurology Advisor: How does ZVI affect the developing infant brain?

Jonathan Miner, MD, PhD: Zika virus is a neurotropic virus that can infect both mature and immature cells. It has been supported by data that Zika virus preferentially infects and causes death of neural progenitor cells, which has a major impact on infant brain development. The fundamental concept that is important to recognize is that Zika virus damages neural progenitor cells and causes inflammation and pathology in the developing brain.

Neurology Advisor: Which factors influence the severity of neurologic abnormalities resulting from ZVI?

Dr. Miner: Multiple factors affect the severity of abnormalities cause by ZVI, including gestational age, strain of the virus, and severity of the infection, which can in turn influence maternal immunity, placental barrier immunity, and fetal immunity against the virus. Certain studies in animals have suggested that certain antiviral proteins such as type 1 interferon may be pathogenic to the developing fetus during infection and that outcomes in the fetus may be improved in the absence of signaling through the type 1 interferon receptor. Therefore, it is likely that a combination of factors involved in virus-mediated pathology, inflammation, and response to the virus, viral load, viral strain, and host immunity influence the degree of resulting neurologic abnormalities.

Neurology Advisor: In what percent of infants affected by congenital ZVI do neurologic abnormalities develop?

Dr. Miner: As far as we know so far, the majority of pregnancies turn out healthy. In the early epidemiologic studies conducted in Brazil, approximately 40% of infants born to mothers who were infected with Zika during pregnancy had some type of abnormality detected on ultrasound (such as brain calcification, microcephaly, or intrauterine growth restriction); however, not all abnormalities were neurologic.7 Other possible abnormalities associated with ZVI include intrauterine growth restriction, retinal damage and blindness, and feet malformation.

Neurology Advisor: How much is known about the long-term effects of ZVI?

Dr. Miner: A Brazilian study conducted in 24 children with congenital Zika syndrome born with microcephaly found significant neurodevelopmental delay that affected language development, gross and fine motor skills, and social/personal development.8 The children in this study had an average chronologic age of 19.9 months. Not enough time has passed from the recent major outbreaks of ZVI to properly assess the long-term effects of ZVI. I think that longer-term prospective studies are still needed in this area.

Neurology Advisor: In which ways does ZVI affect the neurologic development of affected infants beyond microcephaly?

Karin Nielsen-Saines, MD, MPH: It is well known that Zika virus can cause structural abnormalities of the brain in infants with antenatal exposure to the virus. In its most severe form, Zika virus manifests as congenital Zika virus syndrome, where microcephaly and several other brain abnormalities are noted. These have been well described by several research groups including our own.7,9-12 We have noted, however, that it is not an all-or-nothing phenomenon. There is a spectrum of manifestations that range from highly symptomatic to more subtle clinical findings. There are children who appear to be normal in infancy who do not have microcephaly or other evident serious brain abnormalities, but they can still have neurodevelopmental delays when tested at 1 year of age or older, as we reported in the December 2018 in the New England Journal of Medicine13 and also in a study of general movement assessments and neurodevelopment.14

Conversely, there are children who appeared to be abnormal at birth, having findings such as seizures or abnormal neurologic examinations but who had normal neurodevelopmental testing at 12 months of age or older. There are also the hearing deficits and the ophthalmologic abnormalities that may accompany the clinical picture. In our prospective series, eye abnormalities were present in 6% of children and hearing abnormalities in 13%.13 As children born to women who contracted ZVI during pregnancy age, we learn more about longer-term repercussions of disease. For example, we saw that nearly 15% of children in our prospective cohort had either significant neurodevelopmental delay below -2 standard deviations on Bayley-III testing (a score less than 70 in one of the neurodevelopmental functions assessed), or had hearing or eye abnormalities. In addition, there was a large proportion of children (20% or more) who scored below average, with neurodevelopmental scores between -1 and -2 standard deviations in neurodevelopmental testing conducted between 12 and 18 months. This does not necessarily mean that they are delayed but indicates that they are at risk for future neurodevelopmental delay and should be followed closely, with additional testing performed at later time points. In our studies so far, it was the language domain that appeared to be most affected in antenatally Zika-exposed children compared with motor and cognitive domains, which is what children were tested for.

Neurology Advisor: How much is known about the central nervous system (CNS) targets of Zika?

Dr Nielsen-Saines: We know that Zika affects neural progenitor cells. Microglia which become resident macrophages in the brain also appear to be involved in the pathogenesis of CNS infection. In this sense, Zika is especially tropic for developing brain cells. Microcephaly is a condition that is generally secondary to abnormal neuronal and glial proliferation, which underscores the viral tropism for neural progenitor cells and microglia. Malformations caused by abnormal neuronal migration can also be identified in Zika, such as lissencephaly. Alterations caused by abnormal neuronal post-migrational development have also been identified. Anatomically, posterior fossa alterations are prominent in infants with congenital Zika syndrome. Cerebral calcifications can occur anywhere but the most characteristic finding in Zika is for them to be present in the cortical and subcortical gray/white matter junction or in the basal ganglia.

The timing of maternal infection during pregnancy, which translates into the timing of fetal in utero development, plays a very important role in which pathway is affected and what repercussions, if any, will be seen. In more subtle neurologic manifestations of Zika virus, neuroimaging may appear normal, therefore, neuroimaging won’t always be predictive of subsequent problems, as seen in prospective studies such as our own.

Neurology Advisor: Does ZVI persist throughout childhood? Is there a continual risk for neurologic complications in affected children?

Dr Nielsen-Saines: It has not been demonstrated that the virus necessarily persists throughout childhood; however, repercussions of fetal infection may only become manifest later in a child’s life, particularly in less severe forms of disease. We know for example that children who have congenital rubella or congenital cytomegalovirus infection may later have deafness or have learning disabilities diagnosed during pre-school or school-age years. This does not mean that the virus necessarily persisted, and therefore CNS damage happened later; rather, it is more likely that specific neurodevelopmental functions could only be assessed later in a child’s life, and for this reason, the diagnosis is postponed.  

Neurology Advisor: What types of studies still need to be conducted to obtain a better understanding of neurologic manifestations of ZVI?

Dr Nielsen-Saines: For a better understanding of neurologic manifestations of ZVI in children and neurodevelopmental repercussions, we need long-term follow-up of prospective cohorts of children who had documented antenatal exposure to the Zika virus during pregnancy. These children should receive yearly neurodevelopmental testing until school age and eye and hearing assessments in the first years of life. As this is a newly recognized disease, we need to monitor these children closely and be able to compare them with age-matched uninfected peers living in the same environment.

References

1. Lebov JF, Brown LM, MacDonald PDM, et al. Review: Evidence of neurological sequelae in children with acquired Zika virus infection. Pediatr Neurol. 2018;85:16-20.

2. Oh Y, Zhang F, Wang Y, et al. Zika virus directly infects peripheral neurons and induces cell death. Nat Neurosci. 2017;20(9):1209-1212.

3. Marques VM, Santos CS, Santiago IG, et al. Neurological complications of congenital Zika virus infection. Pediatr Neurol. 2019;91:3-10.

4. Krauer F, Riesen M, Reveiz L, et al. Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: systematic review. PLoS Med. 2017;14(1):e1002203.

5. Vianna P, Gomes JA, Boquett JA, et al. Zika virus as a possible risk factor for autism spectrum disorder: neuroimmunological aspects. Neuroimmunomodulation. 2018;25:320-327.

6. Mittal R, Nguyen D, Debs LH, et al. Zika virus: An emerging global health threat. Front Cell Infect Microbiol. 2017;7:486.

7. Brasil P, Pereira JP, Moreira ME, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016;375(24):2321-2334.

8. Alves LV, Paredes CE, Silva GC, Mello JG, Alves JG. Neurodevelopment of 24 children born in Brazil with congenital Zika syndrome in 2015: A case series study. BMJ Open. 2018;8(7):e021304.

9. Zin AA, Tsui I, Rossetto JD, et al. Screening criteria for ophthalmic manifestations of congenital Zika virus infection. JAMA Pediatr. 2017;171(9):847-854.

10. Tsui I, Moreira MEL, Rossetto JD, et al. Eye Findings in Infants With Suspected or Confirmed Antenatal Zika Virus Exposure. Pediatrics. 2018;142(4):e20181104.

11. Zin AA, Tsui I, Rossetto JD, et al. Visual function in infants with antenatal Zika virus exposure. J AAPOS. 2018;22(6):452-456.

12. Pereira JP Jr, Nielsen-Saines K, Sperling J, et al. Association of prenatal ultrasonographic findings with adverse neonatal outcomes among pregnant women with Zika virus infection in Brazil. JAMA Netw Open. 2018;1(8):e186529.

13. Lopes Moreira ME, Nielsen-Saines K, Brasil P, et al. Neurodevelopment in infants exposed to Zika virus in utero [letter]. N Engl J Med. 2018;379(24):2377-2379.

14. Einspieler C, Utsch F, Brasil P, et al. Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool. JAMA Netw Open. 2019;2(1):e187235.

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This article originally appeared on Neurology Advisor