Zika Virus Infection in the Eye

The Zika virus (ZIKV) is a mosquito-borne flavivirus that is closely related with yellow fever, the dengue, and West Nile viruses [1]. It was first identified in rhesus monkeys in Uganda in 1947, and in human beings from Uganda and Tanzania in 1952 [2,3]. Until the early 2000s, no epidemic outbreaks of ZIKV were reported. However, in 2007, the first ZIKV outbreak occurred in Micronesia [4]. Then another epidemic occurred in French Polynesia from 2013 to 2014, where the first case of Guillain-Barre Syndrome (GBS) was identified [5,6]. ZIKV autochthonous transmission was first confirmed in Brazil in April 2015 [7]. Since then, over 1 million Brazilians have had ZIKV infections, and the epidemic has spread to America and Singapore [8]. The rapid geographical expansion reflected the ZIKV capacity to cause worldwide scale outbreaks where the primary mosquito vectors (Aedes species) were endemic [9].

Besides vector transmission from mosquito to human, other forms of transmission have also been reported, such as vertical transmission from mother to fetus, sexual transmission from infected men to their partners, and blood transfusion [10-12]. Since the RNA of ZIKV has been detected in urine, amniotic fluid, breast milk and saliva, other modes of person-to-person transmission may also exist [5,13-15].

It is estimated that around 80% of cases of ZIKV disease are asymptomatic or oligo-symptomatic [16]. When symptoms appear, they usually develop within 3 to 12 days after the bite of a vector mosquito [17]. The clinical presentations are described as “influenzalike”, which include fever, headache, arthralgia, myalgia, retro-orbital pain, non-purulent conjunctivitis and a maculopapular rash [18].

ZIKV infection has also been associated with neurologic complications. It was reported that an unusual increase of microcephaly cases was coincidently observed six months after ZIKV outbreak in Brazil [19]. In addition to microcephaly, other abnormalities related with congenital ZIKV intrauterine infection were reported as the congenital Zika syndrome (CZS) subsequently, which included hearing deficits, arthrogryposis, and ocular lesions [16,20-22]. In adults with ZIKV infection, GBS was identified in a small portion of patients, in which the immune system attacked the peripheral neurons, leading to muscle weakness and paralysis [23].

In January 2016, the first cases of ophthalmic abnormalities in infants with microcephaly and presumed ZIKV intrauterine infection were reported in Brazil after the outbreak. Macular pigment mottling and foveal reflex loss were detected unilaterally in all three cases, with one showing well-delineated macular atrophy [20]. Subsequently, the same group reported 10 other cases with microcephaly which manifested similar chorioretinal atrophy and optic nerve alternations [21]. In February 2016, de Paula Freitas et al. reported 10 of 29 infants with ZIKV-related microcephaly from Salvador, Bahia and Brazil, had significant ocular lesions including focal pigment clumping, chorioretinal atrophy, optic nerve changes, bilateral iris coloboma and lens subluxation [16]. In August 2016, Miranda HA et al. described vascular changes and hemorrhagic retinopathy in three cases of maculopathy along with microcephaly [24]. Since microcephaly was found in all of these cases, it was considered that the microcephaly may be a causative agent or at least a risk factor in the development of ophthalmic abnormalities [16,20,25]. However, Ventura CV et al. defined neurological and ocular findings in an infant without microcephaly but was positive for IgM antibody capture (MAC)- ELISA of ZIKV in the cerebral spinal fluid [26]. Therefore, it is still debatable whether the eye lesions are directly caused by ZIKV infection or secondary to microcephaly [27]. In this way, microcephaly should not be set as a criterion in the diagnosis of ZIKV infection in infants [26].

Manifestations of eye diseases were also reported in adults infected by ZIKV [28-31]. Unilateral acute idiopathic maculopathy (UAIM) was found in a 64-year-old white man with strongly indicative of recent ZIKV infection according to the serum plaque reduction neutralization technique (PRNT) assay performed by Centers for Disease Control and Prevention (CDC). He did not receive any treatment for the maculopathy, and the vision improved to 20/20 within 6 weeks [28]. A case of bilateral hypertensive iridocyclitis was described in a 39-year-old man diagnosed with ZIKV infection clinically [31]. Furtado JM et al. identified bilateral anterior uveitis in a man in his early 40s with positive result for ZIKV on RT-PCR from the aqueous sample [29]. In another 26-year-old white man with bilateral posterior uveitis, both eyes had mild vitreous inflammation, and one of them showed retinal pigment epithelium and chorioretinal lesions on optical coherence tomography (OCT) imaging and indocyanine green dye (ICG) angiography [30]. In these three cases, the patients received topical glucocorticoid therapy for at least one week. Resolutions of visual acuity, lowering of intraocular pressure, as well as complete remission of symptoms were achieved [29-31].

Confirmation of ZIKV infection is based on serology for ZIKV, which include the Zika IgM antibody capture enzyme-linked immunosorbent assay (Zika MAC-ELISA) and the PRNT assay [28,32]. Real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay is used for molecular test in serum specimen [30]. Since ZIKV infection shows nonspecific “influenza-like” manifestations which resemble other flavivirus infections, particularly, Dengue and Chikungunya viruses share the same geographic distribution with ZIKV, differential diagnosis are required [10]. Moreover, the chorioretinal lesions shown in ZIKV infection are nonspecific as well; serology tests for toxoplasmosis, syphilis, cytomegalovirus, rubella, herpes simplex virus are also required [33].

ZIKV infection is becoming one of the greatest concerns nowadays globally. Its rapid geographic spread and the damage to the CNS both in infants and adults emerge as serious public health care threats. To control the epidemic of this new emerging pathogen, new strategies are needed to prevent vertical, sexual and other forms of transmission. Microcephaly, GBS and ocular anomalies have been associated with ZIKV infection since its first outbreak in Brazil. As to eye lesions, it is still unclear whether they are the results of microcephaly or caused by ZIKV infection directly. Since ZIKV can penetrate the blood-brain and blood-retina barriers, many other ophthalmic manifestations might be defined in the future [31]. Clinicians should encourage all newborns and adults with suspected infection, especially those have ocular complaints, to undergo a complete ophthalmologic examination.