Hot Topics in Neuroscience: Zika Microcephaly

This ongoing column explores off-label or emerging treatment options, drug development trends, and theoretical concepts in the field of neuroscience.

by Rajashekar Reddy Yeruva, MD; Hema Madhuri Mekala, MD; Priyanga Jayakumar, MD; Steven Lippmann, MD

Funding: No funding was provided for the preparation of this article.

Financial Disclosures: The authors have no conflicts of interest relevant to the

Innov Clin Neurosci. 2017;14(9–10):11–12.

Concerns

Zika virus has caused worldwide apprehension following recent epidemics in Brazil and Florida.¹ The easy transmission of the virus, primarily by the major vectors Aedes aegypti and Aedes albopictus, has caused epidemics in subtropical and tropical areas. Clinical manifestations of a zika infection can vary from asymptomatic to flu-like symptoms and can also include Guillain-Barré syndrome.

Embryo and/or fetal exposure to zika during gestation can result in serious neurological sequelae; this risk exists throughout all stages of pregnancy.² It can be a part of the congenital zika syndrome. Although the greatest danger is during the first trimester, the pathologic changes include brain abnormalities that might be noted in fetuses infected at as late as 27 weeks of gestation.³ Fetal death is sometimes documented between 36 and 38 weeks. Brain anomalies like microcephaly can result in a lifetime of retardation.³

Even infants with normal head circumference at birth might develop microcephaly in early infancy because of deceleration in head growth. Thus, in infants with prenatal exposure to zika virus, the absence of microcephaly at birth does not preclude the risk of brain pathology. Regular developmental follow-up is indicated.⁴

Pathology

Zika virus is identified prenatally in the amniotic fluid of women whose fetuses had microcephaly detected on ultrasonography; it is also observed in fetal brains of those with congenital microcephaly.² A zika infection activates inflammatory signals within affected neural progenitor cells that are important in immune responses. This might result in abnormal cell cycle dynamics and neuronal apoptosis.⁴ Several genes related to neuropathology are up-regulated by zika infections; infection results in down-regulation of cell cycle genes, impaired cell cycle progression, and decreased proliferation. When zika down-regulates genes, chromosome segregation occurs; this is similar to other genetic causes of abnormal brain development with microcephaly.⁵

Imaging

Ultrasonography of zika-positive pregnant women documents congenital abnormalities of fetuses.³ The findings include growth restriction with or without microcephaly, posterior ocular deformities, ventricular calcifications, various other brain pathologies, low amniotic fluid volumes, and impaired cerebral or umbilical artery flow.³

Computerized tomography of affected infants with microcephaly reveals intracranial calcifications mainly in the frontal and parietal lobes at the corticomedullary junction, cerebral hypogyration, cerebellar hypoplasia, and ventriculomegaly.⁶ Hypodensity of the white matter exists diffusely.

Reporting

According to the Centers for Disease Control and Prevention (CDC), symptomatic and asymptomatic pregnant women with laboratory evidence of zika virus infection, while also diagnosed with complications of pregnancy, should be reported to the National Arboviral Surveillance System (ArboNET).⁷ Asymptomatic zika cases of pregnant women without known gestational complications are not mandated to be reported.⁷ As of March 16, 2017, the CDC identified 5,139 pregnant women in the United States with verified zika diagnoses.⁷ Among them, 47 delivered live infants with birth defects, including microcephaly and intracranial calcifications; five other pregnancies resulted in miscarriage, stillbirth, or termination, all with similar anomalies.⁷ Yet, there have been infants without known neurological deficits reportedly born to mothers with zika infections.⁸

Discussion

Zika virus can be detected in almost all body fluids. Its various methods of transmission and sequelae have created global public health concerns. The virus can negatively affect neurologic outcomes of development at all stages of pregnancy; there is evidence to substantiate a significant association between zika infections during gestation and microcephaly.^1–8 Despite the World Health Organization and CDC having developed guidelines for pregnant women, there is no proven link to fully verify the confirmed or potential neurological risks during a concurrent zika virus infection.⁷ It has recently been demonstrated that a combination of intrinsic antiviral responses and the quick type I interferon production by astrocytes has an important role in self-protection of astrocytes and suppression of flavivirus replication in the brain.⁹

Since the safety profile remains unclarified, everyone should be up to date about zika prevention and gestational concerns. Zika-induced microcephaly can yield a life-long disability. Current CDC guidelines recommend that men should abstain from any direct sexual contact for at least six months and women should not become pregnant for at least eight weeks after a potential and/or proven zika exposure.¹⁰ Whether this is a long enough interval for safety from developmental anomalies of the brain remains to be verified.

 

References

1. Centers for Disease Control and Prevention. Microcephaly & other birth defects. Zika Virus website. https://www.cdc.gov/zika/healtheffects/birth_defects.html. Accessed March 16, 2017.
2. Rasmussen SA, Jamieson DJ, Honein MA, et al. Zika virus and birth defects-reviewing the evidence for causality. N Engl J Med. 2016;374(20):1981–1987.
3. Brasil P, Pereira JP Jr, Moreira ME, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016;375(24):2321–2334.
4. van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 2016;65(47):1343–1348. https://www.cdc.gov/mmwr/volumes/65/wr/mm6547e2.htm. Accessed March 16, 2017.
5. Rolfe AJ, Bosco DB, Wang J, et al. Bioinformatic analysis reveals the expression of unique transcriptomic signatures in Zika virus infected human neural stem cells. Cell Biosci. 2016;6:42. Doi: 10.1186/s13578-016-0110-x.
6. Hazin AN, Poretti A, Martelli CMT, et al. Computed tomographic findings in microcephaly associated with zika virus. N Engl J Med. 2016;374(22):2193­–2195.
7. Centers for Disease Control and Prevention. Outcomes of pregnancies with laboratory evidence of possible zika virus infection, 2015–2017. Zika Virus website. https://www.cdc.gov/zika/geo/pregnancy-outcomes.html. Accessed March 16, 2017.
8. Centers for Disease Control and Prevention. CDC concludes zika causes microcephaly and other birth defects. CDC Newsroom website. http://www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html. Accessed March 16, 2017.
9. Lindqvist R, Mundt F, Gilthorpe JD, et al. Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. J Neuroinflammation. 2016;13(1):277.
10. Centers for Disease Control and Prevention (CDC). Women & their partners trying to become pregnant. Zika Virus website. http://www.cdc.gov/zika/pregnancy/thinking-about-pregnancy.html. Accessed March 16, 2017.

Tags: microcephaly, neuroscience, zika

Category: Hot Topics in Neuroscience, Medical Issues, Neuro infections, Neurology, Past Articles, Trial Methodology