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Anterior-Segment Ocular Findings and Microphthalmia in Congenital Zika Syndrome
Report Anterior-Segment Ocular Findings and Microphthalmia in Congenital Zika Syndrome The Zika virus (ZIKV) is a neurotropic virus that can attack the central nervous system and cause microcephaly, neurodevelopmental impairment, and severe skeletal, hearing, and ocular abnormalities by vertical transmission.1e4 The wide range of congenital abnormalities associated with the vertical transmission of the ZIKV is referred to as “congenital Zika syndrome” (CZS). Most studies that have addressed the ocular findings in patients with CZS identified posterior segment alterations, such as chorioretinal atrophy, pigment mottling, and optic nerve abnormalities.1e4 However, in early February 2016, our group reported the first case of CZS with anterior-segment findings including lens subluxation and bilateral iris coloboma.1 Subsequently, we described the first case of congenital glaucoma related to CZS.5 The aim of this study was to describe a case series of infants with the congenital ZIKV infection who developed structural ocular malformations, including microphthalmia, iris coloboma, and cataract. While conducting an investigation of the microcephaly outbreak in Salvador, Rio de Janeiro, and Recife, Brazil, we identified infants with ocular anterior-segment findings. All children and their mothers were evaluated at 1 of 3 institutions: the Roberto Santos General Hospital in Salvador, Fernandes Figueira Institute in Rio de Janeiro, or Altino Ventura Foundation in Recife. The children’s parents or caregivers provided written informed consent. The Ethics Committee of the Federal University of São Paulo approved the study protocol, which followed the tenets of the Declaration of Helsinki. Each parent or caregiver provided detailed prenatal and postnatal clinical histories. We identified 6 infants from 3 Brazilian states (Rio de Janeiro, Bahia, and Pernambuco) who had laboratory-confirmed ZIKV infection during gestation, had negative Dengue viruse specific immunoglobulin-M antibody capture enzyme-linked immunosorbent assay, and presented with anterior-segment ocular findings associated or not associated with microphthalmia (Table 1). Infants were excluded if they tested positive for infections such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and human immunodeficiency virus. No mother had a history of alcohol or illicit drug use during pregnancy or a familial history of microcephaly. All mothers and infants underwent external ocular examination, ocular biomicroscopy, and indirect ophthalmoscopy with pupillary dilation. All corneas were measured, and the patients with suspected microphthalmia underwent ocular ultrasonography (DGH 8000 B-Scan Scanmate, DGH Technology, Inc., Exton, PA, or Alcon UltraScan, Alcon Laboratories, Duluth, GA).
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We present 6 patients with CZS from 3 different Brazilian states who presented with microphthalmia or abnormal anterior-segment findings (Table 1). Cases 1, 2, and 3 were from Rio de Janeiro, Rio de Janeiro; cases 4 and 5 were from Salvador, Bahia; and case 6 was from Recife, Pernambuco. Five of the mothers reported signs and symptoms of ZIKV during pregnancy (2 occurred in the first trimester, 2 occurred in the second trimester, and 1 occurred in the third trimester). No mothers had signs of active or previous uveitis, and all had normal findings on the ocular examination. Among the 6 infants, 4 of whom were microcephalic at birth, the most frequent findings were iris coloboma, observed in 5 of 12 eyes, followed by microphthalmia in 4 eyes and cataract in 1 eye. Two patients were affected bilaterally. Four patients had fundus abnormalities. No ocular inflammation was seen in any eye (Fig 1, available at www.aaojournal.org). Despite the fact that fundus abnormalities are the most common ocular findings in newborns with the CZS, ZIKV is associated with other ocular manifestations. The current case series showed that microphthalmia, iris coloboma, and cataract also can be related to the CZS. Iris coloboma and microphthalmia have complex causes that include genetic and gestational-acquired infectious diseases, such as rubella, toxoplasmosis, varicella zoster, and cytomegalovirus. We suspect that the presence of an iris coloboma is a marker for an infection that occurred before the seventh week of gestation, which is generally the limit of the period of closure of the optic fissure. However, case 2 presented with iris colobomas, which were unexpected in a patient who had Zika infection during the third trimester, because the optic fissure generally is closed at this time, but this abnormality could be justified by earlier infection and polymerase chain reaction testing that remained positive in the third trimester. Prolonged detection of ZIKV RNA during pregnancy has been reported.5 Unusual ocular findings were observed in 3 eyes of 2 patients who presented with an atypical superior or temporal iris coloboma, whereas typical iris colobomas are located inferonasally. The current case series, the largest to date to report structural and anterior-segment abnormalities identified in infants with the CZS, suggested that the ZIKV also might mediate and cause anterior-segment damage. The mechanism by which the ZIKV triggers these additional ocular findings remains unknown and might be secondary to direct toxicity or a teratogenic effect. No eyes had any sign of active or previous inactive inflammation. The current study alerts clinicians to the fact that besides ocular posterior lesions and glaucoma, microphthalmia and anteriorsegment findings might be present in babies with the CZS. Thus, infants with a suspected congenital ZIKV infection should undergo a complete ophthalmologic evaluation that includes assessment of the anterior and posterior segments.
Table 1. Characteristics of the Six Patients with Congenital Zika Syndrome
Case
State
Illness during Pregnancy (Trimester)
Microcephaly at Birth
Laboratory Confirmation
Age at Examination/ Sex
Structural/Anterior Findings Microphthalmia (OS) - axial lengths OD: 19 mm/OS: 14.6 mm
Rio de Janeiro
Rash/fever (1)
Yes
qRT-PCR (infant CSF)
30-day-old/female
2
Rio de Janeiro
Rash/fever (3)
No
qRT-PCR (maternal blood and urine)
4-mo-old/female
3
Rio de Janeiro
Rash (2)
No
2-mo-old/male
No
4
Bahia
Rash/fever (1)
Yes
qRT-PCR (maternal urine) Zika IgM MAC-ELISA (infant sera)
6-mo-old/male
Yes (OU: macular retinal pigment mottling)
5
Bahia
NO
Yes
1-mo-old/female
No
6
Pernambuco
Rash/arthralgia/fever/ fatigue/retrobulbar pain (1)
Yes
Zika IgM MAC-ELISA (infant sera) Zika IgM MAC-ELISA (infant CSF)
4-mo-old/female
Yes (OD: tilted optic nerve with discrete retinal vessels dragging superiorly in the right eye. OS: not feasible because of the cataract)
Microphthalmia (OS) - axial lengths OD: 20 mm/OS: 15 mm þ iris coloboma (OU) - inferior complete iris coloboma with a pupillary shape resembling a keyhole was identified in both eyes Microphthalmia (OD) - axial lengths OD: 18.5 mm/OS: 22.5 mm Iris colobma (OU) - incomplete iris coloboma superiorly in the right eye and complete iris coloboma temporally in the left eye Iris coloboma (OS) - complete iris coloboma superotemporally Microphthalmia (OS) - axial lengths OD: 22.1 mm/OS: 17.7 mm þ cataract (OS)
CSF ¼ cerebrospinal fluid; Ig ¼ immunoglobulin; MAC-ELISA ¼ IgM antibody capture enzyme-linked immunosorbent assay; OD ¼ right eye; OS ¼ left eye; OU ¼ both eyes; qRT-PCR ¼ quantitative reverse transcriptase polymerase chain reaction.
Report
Fundus Abnormalities Yes (OD: optic nerve, peripapillary atrophy, and macular colobomatous-like chorioretinal atrophy with perilesional retinal pigmentary mottling in the right eye/OS: not feasible due to poor pupillary dilation) Yes (OD: extensive optic nerve, chorioretinal, and macular colobomatous-like chorioretinal atrophy and perilesional retinal pigment mottling in the right eye. OS: not feasible due to poor pupillary dilation)
1
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Ophthalmology Volume 124, Number 12, December 2017 BRUNO DE PAULA FREITAS, MD1,2 ANDREA ZIN, MD, PHD3 ALBERT KO, MD4,5 MAURÍCIO MAIA, MD, PHD2 CAMILA V. VENTURA, MD2,6 RUBENS BELFORT, JR., MD, PHD2
Correspondence: Rubens Belfort Jr., MD, PhD, Department of Ophthalmology, Federal University of São Paulo, Rua Botucatu, 821, 1st Floor, São Paulo 04023-062, Brazil. E-mail: [email protected].
References
1 Department of Ophthalmology, Hospital Geral Roberto Santos, Salvador, Brazil; 2Vision Institute and Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil; 3Clinical Research Unit, Instituto Fernandes Figueira, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 4Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Brazil; 5Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut; 6Altino Ventura Foundation, Recife, Pernambuco, Brazil
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Author Contributions: Conception and design: de Paula Freitas, Zin, Ventura Data collection: de Paula Freitas, Zin, Ventura, Belfort Analysis and interpretation: de Paula Freitas, Ko, Maia, Belfort Obtained funding: Not applicable Overall responsibility: de Paula Freitas, Zin, Ko, Maia, Ventura, Belfort
1. 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. JAMA Ophthalmol. 2016;134:529-535. 2. Ventura CV, Maia M, Bravo-Filho V, et al. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet. 2016;387:228. 3. Ventura CV, Maia M, Ventura BV, et al. Ophthalmologic findings in infants with microcephaly and presumable intrauterus Zika virus infection. Arq Bras Oftalmol. 2016;79: 1-3. 4. de Paula Freitas B, Ko AI, Khouri R, et al. Glaucoma and congenital Zika syndrome. Ophthalmology. 2017;124:407408. 5. Meaney-Delman D, Oduyebo T, Polen KN, et al. Prolonged detection of Zika virus RNA in pregnant women. Obstet Gynecol. 2016;128:724-730.
Corrigenda The authors of “United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment” (Ophthalmology. 2017;124:1259-1270) would like to issue the following statistical corrections (changes in bold): In the Abstract; under the Results section: “In the treatment group, the maximum keratometry value decreased by 2.0 D or more in 28 eyes (31.5%) and increased by 2.0 D or more in 5 eyes (5.6%)” In the Discussion section, in the first paragraph of the subheading Vision Changes after Corneal Collagen Crosslinking: “Although this finding was statistically significant, the actual clinical significance is demonstrated better in studying the outcomes on an individual basis; among patients undergoing CXL, 23 eyes (28%) gained 2 lines or more of CDVA . .” These changes do not affect the results of the study.
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We present 6 patients with CZS from 3 different Brazilian states who presented with microphthalmia or abnormal anterior-segment findings (Table 1). Cases 1, 2, and 3 were from Rio de Janeiro, Rio de Janeiro; cases 4 and 5 were from Salvador, Bahia; and case 6 was from Recife, Pernambuco. Five of the mothers reported signs and symptoms of ZIKV during pregnancy (2 occurred in the first trimester, 2 occurred in the second trimester, and 1 occurred in the third trimester). No mothers had signs of active or previous uveitis, and all had normal findings on the ocular examination. Among the 6 infants, 4 of whom were microcephalic at birth, the most frequent findings were iris coloboma, observed in 5 of 12 eyes, followed by microphthalmia in 4 eyes and cataract in 1 eye. Two patients were affected bilaterally. Four patients had fundus abnormalities. No ocular inflammation was seen in any eye (Fig 1, available at www.aaojournal.org). Despite the fact that fundus abnormalities are the most common ocular findings in newborns with the CZS, ZIKV is associated with other ocular manifestations. The current case series showed that microphthalmia, iris coloboma, and cataract also can be related to the CZS. Iris coloboma and microphthalmia have complex causes that include genetic and gestational-acquired infectious diseases, such as rubella, toxoplasmosis, varicella zoster, and cytomegalovirus. We suspect that the presence of an iris coloboma is a marker for an infection that occurred before the seventh week of gestation, which is generally the limit of the period of closure of the optic fissure. However, case 2 presented with iris colobomas, which were unexpected in a patient who had Zika infection during the third trimester, because the optic fissure generally is closed at this time, but this abnormality could be justified by earlier infection and polymerase chain reaction testing that remained positive in the third trimester. Prolonged detection of ZIKV RNA during pregnancy has been reported.5 Unusual ocular findings were observed in 3 eyes of 2 patients who presented with an atypical superior or temporal iris coloboma, whereas typical iris colobomas are located inferonasally. The current case series, the largest to date to report structural and anterior-segment abnormalities identified in infants with the CZS, suggested that the ZIKV also might mediate and cause anterior-segment damage. The mechanism by which the ZIKV triggers these additional ocular findings remains unknown and might be secondary to direct toxicity or a teratogenic effect. No eyes had any sign of active or previous inactive inflammation. The current study alerts clinicians to the fact that besides ocular posterior lesions and glaucoma, microphthalmia and anteriorsegment findings might be present in babies with the CZS. Thus, infants with a suspected congenital ZIKV infection should undergo a complete ophthalmologic evaluation that includes assessment of the anterior and posterior segments.
Table 1. Characteristics of the Six Patients with Congenital Zika Syndrome
Case
State
Illness during Pregnancy (Trimester)
Microcephaly at Birth
Laboratory Confirmation
Age at Examination/ Sex
Structural/Anterior Findings Microphthalmia (OS) - axial lengths OD: 19 mm/OS: 14.6 mm
Rio de Janeiro
Rash/fever (1)
Yes
qRT-PCR (infant CSF)
30-day-old/female
2
Rio de Janeiro
Rash/fever (3)
No
qRT-PCR (maternal blood and urine)
4-mo-old/female
3
Rio de Janeiro
Rash (2)
No
2-mo-old/male
No
4
Bahia
Rash/fever (1)
Yes
qRT-PCR (maternal urine) Zika IgM MAC-ELISA (infant sera)
6-mo-old/male
Yes (OU: macular retinal pigment mottling)
5
Bahia
NO
Yes
1-mo-old/female
No
6
Pernambuco
Rash/arthralgia/fever/ fatigue/retrobulbar pain (1)
Yes
Zika IgM MAC-ELISA (infant sera) Zika IgM MAC-ELISA (infant CSF)
4-mo-old/female
Yes (OD: tilted optic nerve with discrete retinal vessels dragging superiorly in the right eye. OS: not feasible because of the cataract)
Microphthalmia (OS) - axial lengths OD: 20 mm/OS: 15 mm þ iris coloboma (OU) - inferior complete iris coloboma with a pupillary shape resembling a keyhole was identified in both eyes Microphthalmia (OD) - axial lengths OD: 18.5 mm/OS: 22.5 mm Iris colobma (OU) - incomplete iris coloboma superiorly in the right eye and complete iris coloboma temporally in the left eye Iris coloboma (OS) - complete iris coloboma superotemporally Microphthalmia (OS) - axial lengths OD: 22.1 mm/OS: 17.7 mm þ cataract (OS)
CSF ¼ cerebrospinal fluid; Ig ¼ immunoglobulin; MAC-ELISA ¼ IgM antibody capture enzyme-linked immunosorbent assay; OD ¼ right eye; OS ¼ left eye; OU ¼ both eyes; qRT-PCR ¼ quantitative reverse transcriptase polymerase chain reaction.
Report
Fundus Abnormalities Yes (OD: optic nerve, peripapillary atrophy, and macular colobomatous-like chorioretinal atrophy with perilesional retinal pigmentary mottling in the right eye/OS: not feasible due to poor pupillary dilation) Yes (OD: extensive optic nerve, chorioretinal, and macular colobomatous-like chorioretinal atrophy and perilesional retinal pigment mottling in the right eye. OS: not feasible due to poor pupillary dilation)
1
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Ophthalmology Volume 124, Number 12, December 2017 BRUNO DE PAULA FREITAS, MD1,2 ANDREA ZIN, MD, PHD3 ALBERT KO, MD4,5 MAURÍCIO MAIA, MD, PHD2 CAMILA V. VENTURA, MD2,6 RUBENS BELFORT, JR., MD, PHD2
Correspondence: Rubens Belfort Jr., MD, PhD, Department of Ophthalmology, Federal University of São Paulo, Rua Botucatu, 821, 1st Floor, São Paulo 04023-062, Brazil. E-mail: [email protected].
References
1 Department of Ophthalmology, Hospital Geral Roberto Santos, Salvador, Brazil; 2Vision Institute and Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil; 3Clinical Research Unit, Instituto Fernandes Figueira, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 4Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Brazil; 5Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut; 6Altino Ventura Foundation, Recife, Pernambuco, Brazil
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Author Contributions: Conception and design: de Paula Freitas, Zin, Ventura Data collection: de Paula Freitas, Zin, Ventura, Belfort Analysis and interpretation: de Paula Freitas, Ko, Maia, Belfort Obtained funding: Not applicable Overall responsibility: de Paula Freitas, Zin, Ko, Maia, Ventura, Belfort
1. 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. JAMA Ophthalmol. 2016;134:529-535. 2. Ventura CV, Maia M, Bravo-Filho V, et al. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet. 2016;387:228. 3. Ventura CV, Maia M, Ventura BV, et al. Ophthalmologic findings in infants with microcephaly and presumable intrauterus Zika virus infection. Arq Bras Oftalmol. 2016;79: 1-3. 4. de Paula Freitas B, Ko AI, Khouri R, et al. Glaucoma and congenital Zika syndrome. Ophthalmology. 2017;124:407408. 5. Meaney-Delman D, Oduyebo T, Polen KN, et al. Prolonged detection of Zika virus RNA in pregnant women. Obstet Gynecol. 2016;128:724-730.
Corrigenda The authors of “United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment” (Ophthalmology. 2017;124:1259-1270) would like to issue the following statistical corrections (changes in bold): In the Abstract; under the Results section: “In the treatment group, the maximum keratometry value decreased by 2.0 D or more in 28 eyes (31.5%) and increased by 2.0 D or more in 5 eyes (5.6%)” In the Discussion section, in the first paragraph of the subheading Vision Changes after Corneal Collagen Crosslinking: “Although this finding was statistically significant, the actual clinical significance is demonstrated better in studying the outcomes on an individual basis; among patients undergoing CXL, 23 eyes (28%) gained 2 lines or more of CDVA . .” These changes do not affect the results of the study.
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