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Zika Virus Infection and the Eye

Zika Virus Infection and the Eye Human and insect travel between continents has resulted in the dissemination of previously remote infections to more populated parts of the world. West Nile virus apparently moved from Israel to New York, where it decimated bird populations, and subsequently moved across the United States, producing human neurologic disease and retinal lesions. Now, a related virus—Zika virus—has been implicated as the cause of an epidemic of microcephaly, first in Brazil and now spreading into other parts of the western hemisphere. Zika virus was identified by reverse transcription–polymerase chain reaction in the amniotic fluid of 2 women in Brazil whose fetuses had been found to have microcephaly by prenatal ultrasonography,1 and the Centers for Disease Control and Prevention have confirmed that a microcephalic baby born in Hawaii to a mother from Brazil had been infected with the virus.2 Ongoing registry studies are under way to confirm the causative association between the viral infection and microcephaly. Millions of people in Brazil are believed to have been infected with the virus, which has rapidly spread throughout the Americas. It is transmitted primarily by the Aedes aegypti mosquito, although sexual transmission has been very rarely noted. The infection itself is rarely life threatening, manifesting typically as short-lived fever, nonspecific rash, and joint pain, or it may be completely asymptomatic. The mild nature of the infection makes ascertainment of a relationship between maternal infection and subsequent fetal anomalies difficult, as the illness is often unnoticed or unreported. Ophthalmologic manifestations of congenital Zika virus infection are not yet well described. A report earlier this year described 3 babies from Brazil with microcephaly and presumed Zika virus intrauterine infection who had macular pigment mottling and loss of foveal reflex, with 1 manifesting well-defined macular atrophy.3 The report by de Paula Freitas et al4 in this issue of JAMA Ophthalmology implicates this infection as the cause of chorioretinal scarring and possibly other ocular abnormalities in infants with microcephaly recently born in Brazil. Microcephaly can be genetic, metabolic, drug related, or due to perinatal insults such as hypoxia, malnutrition, or infection. The present 20-fold reported increase of microcephaly in parts of Brazil is temporally associated with the outbreak of Zika virus. However, this association is still presumptive because definitive serologic testing for Zika virus was not available in Brazil at the time of the outbreak and confusion may occur with other causes of microcephaly.5 Similarly, the currently described eye lesions are presumptively associated with the virus. Zika virus is a flavivirus transmitted by Aedes mosquitoes and is related to yellow fever virus, dengue virus, and West Nile virus. Zika virus was first identified in Uganda in 1947 in macaques and then in humans as early as 1968.6 It has also been identified in French Polynesia, where an epidemic was associated with perinatal transmission and fetal abnormalities. The virus presently in Brazil appears to have originated from Polynesia. The clinical findings of primary infection mimic both dengue virus and chikungunya virus, also present in Brazil and carried by the same mosquito. Testing for Zika virus is not readily available, making the diagnosis challenging; however, the Centers for Disease Control and Prevention in Atlanta, Georgia, can perform serologic testing (IgM and plaque-reduction neutralization), and polymerase chain reaction testing is available. The infection causing microcephaly and retinal lesions typically occurs during the first or second trimester of pregnancy. In the series described by de Paula Freitas and colleagues, almost 80% of mothers reported symptoms consistent with Zika virus infection, most in the first trimester.4 Ocular abnormalities were present in 10 of the 29 infants examined (35%) and were bilateral in 7 of the 10. The characteristic lesions included posterior pole pigmentary clumping and areas of sharply circumscribed chorioretinal atrophy. In addition, 1 baby showed iris colobomas and lens subluxation (although it is not clear whether this was related to Zika virus). It is likely with further experience that the spectrum of ocular lesions will increase. At the present time it has been suggested that women in the areas of the epidemic consider not getting pregnant and it is recommended that pregnant women, especially during their first 2 trimesters, not travel to areas where the disease is epidemic. As West Nile virus spread across the United States and then became endemic, uveitis and chorioretinitis were seen. Interestingly, West Nile virus was reported to have transplacental transmission, producing lesions somewhat similar to the current cases.7 The differential diagnosis of chorioretinal lesions such as those reported in this series includes many other infections, including toxoplasmosis, cytomegalovirus, rubella, herpes simplex virus, and syphilis, although these can easily be ruled out with neonatal testing. Based on current information, in our opinion, clinicians in areas where Zika virus is present should perform ophthalmologic examinations on all microcephalic babies. Because it is still unclear whether the eye lesions occur in the absence of microcephaly, it is premature to suggest ophthalmic screening of all babies born in epidemic areas. As yet, there is no vaccine for Zika virus. Efforts to eradicate mosquitos are critical and will also reduce infection rates with other mosquito-borne illnesses such as malaria, dengue fever, chikungunya, and West Nile virus. These efforts are already under way globally and rely primarily on environmental modifications. Genetic manipulation of mosquito populations, such as the recently described gene-drive system that can introduce female sterility into a target vector population,8 may enhance these efforts. Back to top Article Information Corresponding Author: Lee M. Jampol, MD, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, 645 N Michigan Ave, Ste 440, Chicago, IL 60611 (l-jampol@northwestern.edu). Published Online: February 9, 2016. doi:10.1001/jamaophthalmol.2016.0284. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al; Brazilian Medical Genetics Society–Zika Embryopathy Task Force. Possible association between Zika virus infection and microcephaly: Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(3):59-62.PubMedGoogle ScholarCrossref 2. Centers for Disease Control and Prevention. Zika virus. http://www.cdc.gov/zika. Accessed January 31, 2016. 3. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R Jr. Zika virus in Brazil and macular atrophy in a child with microcephaly [published online January 7, 2016]. Lancet. doi:10.1016/S0140-6736(16)00006-4.PubMedGoogle Scholar 4. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil [published online February 9, 2016]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2016.0267.Google Scholar 5. Lucey DR, Gostin LO. The emerging Zika pandemic: enhancing preparedness [published online January 27, 2016]. JAMA. doi:10.1001/jama.2016.0904.PubMedGoogle Scholar 6. Boze B; Vector Disease Control International. Zika virus: an emerging mosquito-borne infection in the Americas. http://www.vdci.net/blog/zika-what-every-parent-needs-to-know. Accessed January 31, 2016. 7. Alpert SG, Fergerson J, Noël LP. Intrauterine West Nile virus: ocular and systemic findings. Am J Ophthalmol. 2003;136(4):733-735.PubMedGoogle ScholarCrossref 8. Hammond A, Galizi R, Kyrou K, et al. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nat Biotechnol. 2016;34(1):78-83.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

Zika Virus Infection and the Eye

Jampol, Lee M.; Goldstein, Debra A.
JAMA Ophthalmology , Volume 134 (5) – May 1, 2016
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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/jamaophthalmol.2016.0284
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Abstract

Human and insect travel between continents has resulted in the dissemination of previously remote infections to more populated parts of the world. West Nile virus apparently moved from Israel to New York, where it decimated bird populations, and subsequently moved across the United States, producing human neurologic disease and retinal lesions. Now, a related virus—Zika virus—has been implicated as the cause of an epidemic of microcephaly, first in Brazil and now spreading into other parts of the western hemisphere. Zika virus was identified by reverse transcription–polymerase chain reaction in the amniotic fluid of 2 women in Brazil whose fetuses had been found to have microcephaly by prenatal ultrasonography,1 and the Centers for Disease Control and Prevention have confirmed that a microcephalic baby born in Hawaii to a mother from Brazil had been infected with the virus.2 Ongoing registry studies are under way to confirm the causative association between the viral infection and microcephaly. Millions of people in Brazil are believed to have been infected with the virus, which has rapidly spread throughout the Americas. It is transmitted primarily by the Aedes aegypti mosquito, although sexual transmission has been very rarely noted. The infection itself is rarely life threatening, manifesting typically as short-lived fever, nonspecific rash, and joint pain, or it may be completely asymptomatic. The mild nature of the infection makes ascertainment of a relationship between maternal infection and subsequent fetal anomalies difficult, as the illness is often unnoticed or unreported. Ophthalmologic manifestations of congenital Zika virus infection are not yet well described. A report earlier this year described 3 babies from Brazil with microcephaly and presumed Zika virus intrauterine infection who had macular pigment mottling and loss of foveal reflex, with 1 manifesting well-defined macular atrophy.3 The report by de Paula Freitas et al4 in this issue of JAMA Ophthalmology implicates this infection as the cause of chorioretinal scarring and possibly other ocular abnormalities in infants with microcephaly recently born in Brazil. Microcephaly can be genetic, metabolic, drug related, or due to perinatal insults such as hypoxia, malnutrition, or infection. The present 20-fold reported increase of microcephaly in parts of Brazil is temporally associated with the outbreak of Zika virus. However, this association is still presumptive because definitive serologic testing for Zika virus was not available in Brazil at the time of the outbreak and confusion may occur with other causes of microcephaly.5 Similarly, the currently described eye lesions are presumptively associated with the virus. Zika virus is a flavivirus transmitted by Aedes mosquitoes and is related to yellow fever virus, dengue virus, and West Nile virus. Zika virus was first identified in Uganda in 1947 in macaques and then in humans as early as 1968.6 It has also been identified in French Polynesia, where an epidemic was associated with perinatal transmission and fetal abnormalities. The virus presently in Brazil appears to have originated from Polynesia. The clinical findings of primary infection mimic both dengue virus and chikungunya virus, also present in Brazil and carried by the same mosquito. Testing for Zika virus is not readily available, making the diagnosis challenging; however, the Centers for Disease Control and Prevention in Atlanta, Georgia, can perform serologic testing (IgM and plaque-reduction neutralization), and polymerase chain reaction testing is available. The infection causing microcephaly and retinal lesions typically occurs during the first or second trimester of pregnancy. In the series described by de Paula Freitas and colleagues, almost 80% of mothers reported symptoms consistent with Zika virus infection, most in the first trimester.4 Ocular abnormalities were present in 10 of the 29 infants examined (35%) and were bilateral in 7 of the 10. The characteristic lesions included posterior pole pigmentary clumping and areas of sharply circumscribed chorioretinal atrophy. In addition, 1 baby showed iris colobomas and lens subluxation (although it is not clear whether this was related to Zika virus). It is likely with further experience that the spectrum of ocular lesions will increase. At the present time it has been suggested that women in the areas of the epidemic consider not getting pregnant and it is recommended that pregnant women, especially during their first 2 trimesters, not travel to areas where the disease is epidemic. As West Nile virus spread across the United States and then became endemic, uveitis and chorioretinitis were seen. Interestingly, West Nile virus was reported to have transplacental transmission, producing lesions somewhat similar to the current cases.7 The differential diagnosis of chorioretinal lesions such as those reported in this series includes many other infections, including toxoplasmosis, cytomegalovirus, rubella, herpes simplex virus, and syphilis, although these can easily be ruled out with neonatal testing. Based on current information, in our opinion, clinicians in areas where Zika virus is present should perform ophthalmologic examinations on all microcephalic babies. Because it is still unclear whether the eye lesions occur in the absence of microcephaly, it is premature to suggest ophthalmic screening of all babies born in epidemic areas. As yet, there is no vaccine for Zika virus. Efforts to eradicate mosquitos are critical and will also reduce infection rates with other mosquito-borne illnesses such as malaria, dengue fever, chikungunya, and West Nile virus. These efforts are already under way globally and rely primarily on environmental modifications. Genetic manipulation of mosquito populations, such as the recently described gene-drive system that can introduce female sterility into a target vector population,8 may enhance these efforts. Back to top Article Information Corresponding Author: Lee M. Jampol, MD, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, 645 N Michigan Ave, Ste 440, Chicago, IL 60611 (l-jampol@northwestern.edu). Published Online: February 9, 2016. doi:10.1001/jamaophthalmol.2016.0284. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al; Brazilian Medical Genetics Society–Zika Embryopathy Task Force. Possible association between Zika virus infection and microcephaly: Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(3):59-62.PubMedGoogle ScholarCrossref 2. Centers for Disease Control and Prevention. Zika virus. http://www.cdc.gov/zika. Accessed January 31, 2016. 3. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R Jr. Zika virus in Brazil and macular atrophy in a child with microcephaly [published online January 7, 2016]. Lancet. doi:10.1016/S0140-6736(16)00006-4.PubMedGoogle Scholar 4. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil [published online February 9, 2016]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2016.0267.Google Scholar 5. Lucey DR, Gostin LO. The emerging Zika pandemic: enhancing preparedness [published online January 27, 2016]. JAMA. doi:10.1001/jama.2016.0904.PubMedGoogle Scholar 6. Boze B; Vector Disease Control International. Zika virus: an emerging mosquito-borne infection in the Americas. http://www.vdci.net/blog/zika-what-every-parent-needs-to-know. Accessed January 31, 2016. 7. Alpert SG, Fergerson J, Noël LP. Intrauterine West Nile virus: ocular and systemic findings. Am J Ophthalmol. 2003;136(4):733-735.PubMedGoogle ScholarCrossref 8. Hammond A, Galizi R, Kyrou K, et al. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nat Biotechnol. 2016;34(1):78-83.PubMedGoogle ScholarCrossref

Journal

JAMA Ophthalmology – American Medical Association

Published: May 1, 2016

Keywords: chorioretinitis,disease outbreaks,eye abnormalities,newborn,microcephaly,pregnancy complications, infectious,retinal diseases,congenital anomaly of retina,viral infections congenital,zika virus infections

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