Optic nerve aplasia (ONA) is a rare anomaly characterized by absence of the optic nerve, retinal blood vessels, and retinal ganglion cells.1 Most reported cases occur unilaterally and in association with ipsilateral ocular malformations, including microphthalmos.1 Bilateral cases of ONA, although rare, are often accompanied by central nervous system (CNS) anomalies, including congenital hypopituitarism, posterior pituitary ectopia, hydranencephaly, meningoencephalocele, and septo-optic dysplasia.1,2 Rarely has ONA been reported associated with congenital infection.3 Herein, we describe a case of ONA in the setting of congenital infection with cytomegalovirus (CMV).
A 3-month-old infant from Ecuador was referred for a second opinion with a diagnosis of microcornea and chorioretinitis in the setting of congenital CMV. She was the first child of non-consanguineous parents, born at 38 weeks, birth weight 3.79 kg, following an unremarkable vaginal delivery and pregnancy. She conveyed poor visual development soon after birth. There was no family history of ocular disease.
Workup at 10 weeks of age revealed an elevated CMV immunoglobulin G (IgG) titer (229.8 U/mL). Maternal IgG titers were elevated for CMV (> 250 U/mL), herpes simplex virus (HSV) type 1 (6.80 EU/mL), and Epstein-Barr virus (28.00 U/mL). Titers for Venereal Disease Research Laboratory test, rubella, HSV type 2, and toxoplasmosis were negative in both the mother and infant. The infant demonstrated hypoxemia and elevated liver function enzymes. All other blood work was unremarkable. Abdominal ultrasound and magnetic resonance imaging of the brain were reportedly normal. Audiology testing showed subtle neurosensory hearing loss in the right ear. Flash visual evoked potential (VEP) showed prolonged latent occipital responses with normal amplitudes in the right eye (OD) and no conduction in the left eye (OS). She was treated with intravenous ganciclovir (Zirgan; Bausch + Lomb, Rochester, NY) in Ecuador and referred for further evaluation.
In our office, anthropometric measurements were normal with no dysmorphic features observed other than her ocular findings. She demonstrated no fixation or tracking and a variable esotropia up to 15 prism diopters. Extraocular movements revealed +1 inferior oblique overaction in both eyes (OU), and there was a variable, slow (∼2 Hz), pendular nystagmus. Intraocular pressures were 14 mm Hg OD and 10 mm Hg OS. Red reflex was normal. Pupils were 4 mm and fixed with no reactivity to light. Cycloplegic refraction was −2.00 OD and −2.00 +1.00 × 90° OS.
Exam under anesthesia revealed clear corneas. Corneal diameters were 7.0 mm × 6.0 mm (horizontal × vertical) OD and 7.5 mm × 6.5 mm OS. No anterior chamber cell or flare was detected. There were scattered anterior and posterior synechiae OU, with mid-iris atrophy OD (Figures 1A–1C). The vitreous was hazy, and there was absence of the retinal vessels and optic nerves, and diffuse severe chorioretinal atrophy OU (Figures 2A–2D). Retinal detachment with vitreous hemorrhage was observed inferiorly OS (Figure 2B).
Color external photographs demonstrated scattered posterior synechiae with mid-iris atrophy in the right eye (A) and iris filaments and posterior synechiae in the left eye (B). Gonioscopy in the left eye showed scattered iris processes that were noted in both eyes (C).
Fundus photographs of the right (A) and left (B) eyes demonstrated peripheral areas of large chorioretinal atrophy and absence of the optic nerves and retinal vessels bilaterally. There was hemorrhage and vitreoretinal membranes inferiorly in the left eye (B). C and D highlight the abnormal optic disc region in the right and left eyes, respectively.
Fluorescein angiography (FA) revealed choroidal filling, but absence of retinal vessels OD (Figures 3A to 3E). A vascular tuft originating from the choroidal vasculature was noted coursing back over an area of chorioretinal atrophy that was associated with leakage at 30 seconds (Figures 3B to 3E). There was leakage OS, but no distinctly normal choroidal or retinal vessels were noted (Figure 3F). B-scan ultrasonography revealed globes that were age appropriate in size (axial length: 18.7 mm OD, 18.1 mm OS). There was a temporal staphyloma OD and retinal detachment OS. Narrowing and hyperechogenicity of the optic nerves were observed OU (Figure 4).
Fluorescein angiography of the right eye at 15 seconds after dye injection revealed choroidal filling and absence of fluorescein uptake in the disc area or in retinal vessels (A). At 19 seconds, there was uptake of fluorescein dye in a vascular tuft originating from the choroidal vasculature and surfacing over an area of chorioretinal atrophy (B). Higher magnification is provided in panel (C) to highlight the choroidal neovascularization ridge and choroidal origin of the tuft. At 30 seconds, there was mild leakage at the distal area of the choroidal vascular ridge (D), which was more prominent at 1:01 seconds (E). In the left eye at 1:24 seconds, there was absence of fluorescein uptake in the disc area and in retinal vessels (E).
B-scan ultrasonography demonstrated thinning and hyperechogenicity of the right optic nerve through the transverse plane with the probe in the 3 o'clock position (A). In the left eye, longitudinal plane in the 9 o'clock position, there was thinning and hyperechogenicity of the optic nerve and a hyperechoic structure in the vitreous corresponding to an area of retinal detachment (B).
Systemic manifestations of congenital CMV include fever, jaundice, hepatosplenomegaly, hearing loss, microcephaly, petechiae, and periventricular calcifications.4,5 About 3% of children with congenital CMV have cataracts and 2% have chorioretinitis.6 Chorioretinitis and retinitis can lead to retinal necrosis, retinal breaks, and retinal detachments. CMV spreads to the retina hematogenously, infects the vascular endothelium, and thereby spreads to retinal cells. Of those with at least one systemic manifestation, 13% show severe visual impairment compared with none without systemic signs.4 Visual impairment can be related to corneal clouding, cataract, strabismus, and abnormalities of the cortex, retina, and optic nerve.5,7
To date, there are two reported cases of congenital CMV-associated ONA.3,8 In one bilateral case, maternal serology was also positive for toxoplasmosis and rubella, and VEP showed irregular, not absent, conduction.3 In the second unilateral case, the authors could not definitively associate congenital infection with the ophthalmic findings, as CMV titers were positive at age 2, and there was no evidence of systemic disease. There are three reported cases of optic nerve hypoplasia in the setting of congenital CMV, each with variable severity, although disc margins were discernible in all cases.3,7,9
In our case, although clinical examination conveyed bilateral ONA, VEP suggested otherwise — there was no conduction OS (confirming aplasia), but there were prolonged latent occipital responses OD (suggesting severe hypoplasia). B-scan ultrasonography showed thinning and hyperechogenicity of the optic nerves OU, likely comprised of remnants of optic nerve sheaths and glial tissue, as suggested in a similar case of bilateral ONA in an otherwise healthy 10-month-old child.10 A review of ONA cases demonstrated that the appearance of the orbital optic nerve is variable, ranging from absent to normal.1 MRI was not available in our case for review, although the report from Ecuador read as normal.
These variable presentations suggest that the pathogenesis of ONA is multifactorial. ONA may result from defective formation of the embryonal fissure, failure of the mesenchymal inlay of the hyaloid system to enter the embryonal fissure, or primary agenesis of retinal ganglion cells.11,12 Bilateral cases may be due to failure of the ganglion cell layer to differentiate with subsequent failure of the retina to vascularize.13 Alternatively, ONA may result from failure of the retinal blood vessels to bud from the hyaloid artery, such that subsequent ganglion cell degeneration occurs.13 In the case of congenital infection, severity of optic nerve hypoplasia and aplasia may be linked to the timing of intrauterine infection.
Fundus photographs and FA of the infant's right eye demonstrated a large chorioretinal coloboma with rudimentary vessels originating from the choroid and surfacing over the aplastic retinal surface (Figure 3C). This feature has been noted previously.1 Perhaps the vascular growth and neovascularization observed in these cases is driven by exposure of the rich, vascular supply of the choroid to the hypoxic, avascular retina. Our patient's visual prognosis was poor, and unfortunately there was no intervention that could be offered.
We present the rare case of a 3-month-old child with ONA OS and severe optic nerve hypoplasia OD. The patient and mother's elevated CMV IgG titers, the patient's elevated liver enzymes, respiratory dysfunction, hearing loss, and ocular findings all support intrauterine infection with CMV as the probable cause for ONA. ONA should be considered in cases of microcornea and iris coloboma especially in the setting of intrauterine infections. MRI may be obtained in cases of ONA to evaluate for commonly associated CNS anomalies.
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- Jin HD, Demmler-Harrison GJ, Coats DK, et al. Congenital CMV Longitudinal Study Group. Long-term visual and ocular sequelae in patients with congenital cytomegalovirus infection. Pediatr Infect Dis J. 2017;36(9):877–882. doi:10.1097/INF.0000000000001599 [CrossRef]
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- Mannan R, Chandra P. Rare case of unilateral optic nerve aplasia. BMJ Case Rep. 2015;2015.
- Rochels R, Trevino E, Brand M. Aplasia of retinal vessels in congenital cytomegaly. Klin Monbl Augenheilkd. 1983;182(3):237–240. doi:10.1055/s-2008-1054754 [CrossRef]
- Khandgave TP, Kulkarni VN, Muzumdar DV, Puthran N. Bilateral optic nerve aplasia: A rare isolated central nervous system anomaly. Middle East Afr J Ophthalmol. 2014;21(3):262–264. doi:10.4103/0974-9233.134690 [CrossRef]
- Sanjari MS, Ghasemi Falavarjani K, Parvaresh MM, Kharazi HH, Kashkooli MB. Bilateral aplasia of the optic nerve, chiasm, and tracts in an otherwise healthy infant. Br J Ophthalmol. 2006;90(4):513–514. doi:10.1136/bjo.2005.088229 [CrossRef]
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