Aplasia of the Optic Nerve: A Report of Seven Cases

ABSTRACT

Optic nerve aplasia (ONA) is a rare congenital anomaly with a limited number of published reports. A retrospective review was performed on seven patients with ONA seen during 2004–2017. Patient’s ocular and extraocular manifestations, imaging findings, and clinical course were described. Magnetic resonance imaging (MRI) showed anomalies of the optic chiasm and tracts and other central nervous system involvement. In conclusion, in addition to thorough ophthalmic examinations, MRI is important in evaluating and diagnosing ONA. The patients need to be monitored for both ocular and extraocular concerns.

Introduction

Optic nerve aplasia (ONA) is a rare congenital condition characterised by the absence of optic nerve and disc, central retinal vessels, and retinal ganglion cells.^1,2 There is no unified aetiology to the mechanisms of ONA. Proper proliferation and apoptosis of retinal ganglion cells (RGC) are important for the development of the optic nerve.^3,4 ONA can be a result of primary agenesis or secondary degeneration of RGC during the third to fourth month of gestation due to failure of retinal angiogenesis.^1,5 The optic vesicle starts to invaginate at the early stage of eye development and an optic fissure is formed to allow the hyaloid arteries to enter the retina. Failure of this process disrupts retinal vasculature, which is consistent with retinal abnormalities in ONA.³ It is suggested that the failure of neural retina formation may be responsible for disruption of optic nerve development and disorganisation of other ocular tissues in ONA.⁶ Pax-6 is expressed in the CNS, optic stalk, retinal progenitors, and RGC, and its mutations are likely disruptive to the optic nerve and other ocular structures.⁷

Unilateral ONA comprises the majority of the reported cases. ONA can be associated with other ocular abnormalities, such as microphthalmia, microcornea, strabismus, blepharoptosis, goniodysgenesis, iris hypoplasia, iris coloboma, iris strands, aniridia, retinal dysplasia, persistent fetal vasculature, and cataract.^1,8 Bilateral ONA is reported even more rarely and is more likely to be accompanied by central nervous system (CNS) anomalies.⁸ Hydranencephaly, septo-optic dysplasia, and pituitary malformation have been reported in patients with bilateral ONA^9,10 although there are reported cases of bilateral ONA who appear to be otherwise healthy.^5,7,11

Materials and methods

This case series included seven patients with unilateral or bilateral optic nerve aplasia during 2004–2017. Medical charts of the patients were retrospectively reviewed. All seven patients had undergone dedicated orbital and brain magnetic resonance imaging (MRI) to confirm the diagnosis. This project was approved by the Institutional Review Board of Ann & Robert H. Lurie Children’s Hospital of Chicago.

Case 1

An 11-week-old girl presented with multiple abnormalities of the right eye, including blepharoptosis, microphthalmia, iris coloboma, and lack of light response. Intraocular pressure (IOP) of the right eye was elevated (34–46 mmHg). No optic disc was visible – instead its typical location showed a few chorioretinal colobomata and greyish gliotic tissue with additional retinal pigment epithelial disturbances and abnormal vascular pattern. B-scan OD suggested posterior staphyloma with no visible optic nerve shadow. The patient was initially managed with topical ocular hypotensive agents and used a prosthetic conformer; however, refractory neovascular glaucoma eventually developed. At the age of 16 months, she also underwent levator advancement of the right upper eyelid.

Case 2

A 1-month-old boy came with a microphthalmia OS that had a poor pupillary light response and notable persistent pupillary membrane; however, the cornea was clear without microcornea. There was no identifiable optic disc or macula. Scattered blood vessels without a clear pattern were noted at the posterior pole (Figure 1e). He was managed with a prosthetic conformer and received physical therapy for postural asymmetry and torticollis that was associated with his blindness OS. At 4 years old, the cornea developed neovascularisation and opacification. The fundus was notable for spotty retinal pigment epithelium. Thus, far at 11 years old, he has otherwise been healthy with a sensory esotropia OS.

Figure 1.

Ocular findings associated with optic nerve aplasia. (a-b): External photographs of Case 4 showing posterior synechiae and persistent pupillary membrane partially occluding pupil with poor pharmacologic dilation. (c): External photograph of Case 6 showing microphthalmia and persistent pupillary membrane after pharmacologic dilation. (d): External photograph of Case 7 showing microphthalmia, corneal haze, and inferior iris coloboma after pharmacologic dilation. (e-h): Colour fundus photographs of Cases 2 (e), 5 (f), 6 (g), and 7 (h) showing the absence of optic disc, chorioretinal colobomata, and anomalous retinal vasculature.

Case 3

A 4-month-old girl presented for second opinion regarding microphthalmia and poor vision potential OD. She was noted to have esotropia, blepharophimosis, and no response to light in the right eye. Further evaluation revealed microcornea with iris atrophy, indiscernible optic disc, posterior pole pigmentary mottling, and attenuated retinal vessels forming an abnormal pattern. The patient had an intact pituitary gland and normal neurological function. By 14 months of, the right eye developed a cataract, and at 20 months, there was nystagmus. The patient has otherwise been generally healthy up to 6 years old thus far.

Case 4

A 3-month-old, full-term girl presented with crossed eyes, lack of eye-opening, and absent tracking. Initial exam showed bilateral microphthalmia (OD > OS) and alternating esotropia. Funduscopic view was obstructed by significant anterior segment abnormalities; however, no optic nerve shadow was appreciated on B-scan. An exam under anaesthesia revealed sclerocornea-like haze, pannus, and severe pupillary membrane with posterior synechiae (OD > OS) (Figure 1a-b). Through the small view of the right pupil, a diffuse cataract was noted without visualisation of the posterior segment. The left eye had a clear lens, scattered areas of vitreous haemorrhage and organisation, atrophic retina, and an opaquely white circular area where the optic nerve would be expected. MRI confirmed bilateral ONA (Figure 2d-f), and indicated dysplastic lenses, and nonspecific retrocerebellar fluid with mild prominence of the subarachnoid spaces of uncertain significance. Neurological evaluations indicated mild developmental delay and hypotonia without pituitary dysfunction. At 16 months, she was only able to speak two specific words. Genetic testing revealed chromosomal microarray and no mutations of several microphthalmia related genes (BCOR, OTX2, SOX2, VSX2). She has been doing well with ocular prostheses at her most recent visit of 21 months old.

Figure 2.

Neuroimaging of optic nerve aplasia. (a-c): T2-weighted, fat-saturated magnetic resonance images of the brain in Case 3 demonstrating absence of right optic nerve and right microphthalmia. The white arrows highlight the presence of the left optic nerve. (d-f): T2-weighted, fat-saturated magnetic resonance images of the brain in Case 4 demonstrating bilateral absence of optic nerves and chiasm as well as right microphthalmia.

Case 5

An 8-month-old girl presented for concerns of poor eye-opening and eye-rolling`. Her father had ophthalmic surgery as a child but was a poor historian as to his condition. The patient displayed bilateral ptosis and lack of light perception. An exam under anaesthesia showed microcornea (OD > OS), shallow anterior chamber OD, a persistent pupillary membrane with posterior synechiae (OD > OS) associated with a lenticular polar opacity, moderate cortical cataract, and dense posterior plaque OD, inferonasal cataract with lens and iris coloboma OS. Anterior segment anomalies precluded funduscopy in the right eye. The left eye had no discernible nerve head or foveal reflex in a milieu of retinal atrophy, prominent choroidal vasculature, and chorioretinal coloboma inferiorly (Figure 1f). A-/B-scan showed microphthalmia OD and absence of optic nerve shadow OU. There was no evidence of persistent fetal vasculature. Unfortunately, the patient never returned for follow up.

Case 6

A 2-month-old boy presented with bilateral microphthalmia and infrequent opening of the eyes. Two of his great-aunts were born blind with an unknown diagnosis. He had bilateral tearing and greenish white discharge. During a planned procedure to address the dacryostenosis, an exam under anaesthesia indicated intact nasolacrimal duct system, but clinical anophthalmia OS. The right eye had persistent pupillary membrane, posterior synechiae (Figure 1c), posterior polar cataract, and retinal dysgenesis with anomalous vasculature and no definable optic disc aside from a scleral outline (Figure 1g). The patient underwent left orbital dermis fat graft and obtained an orbital hydrogel expander. He was otherwise noted to be healthy until last follow up at the age of 27 months.

Case 7

A 2-month-old, full-term girl presented with irregular pupils and asymmetric eyes. Pregnancy was notable for maternal smoking during the second and third trimesters. Bilaterally, there was a glial opacity with abnormal vessels around the rim in the typical location of the optic nerve head. The fundus also displayed scattered, lacunae-like chorioretinal coloboma (Figure 1h). Both eyes were microphthalmic with microcornea with associated haze and thick pachymetry (Figure 1d). On the MRI, there was a small pars intermedia cyst, favoured to be incidental, and a hypoplastic dorsal C1 arch with associated craniovertebral junction stenosis. She underwent posterior fossa decompression at the age of 10 months. Surveillance showed an unchanged pituitary cyst size, and she has had no endocrinologic dysfunction. Aicardi syndrome was ruled out due to the patient’s normal chromosomal microarray and absence of dermatological findings and seizures. Neurologic evaluation noted delays in visual-dependent skills. At the time of this report, the patient was healthy at 5 years old and has had subsequent imaging demonstrating an unremarkable skull base.

Discussion

Optic nerve aplasia is a rare condition with a limited number of reports in the literature, and most of the reports contain a single case. We present a series of seven patients – four of them with bilateral involvement. The mean patient age of initial presentation was 13 weeks (range 4 weeks to 32 weeks). Aside from Case 5 who was only evaluated at presentation (8 months old), follow-up ranged from 16 months to 11 years. Although limited in scope due to the retrospective nature of this series, these latter six cases did not exhibit any general health or developmental problems with the appropriate therapies in place during the known follow-up time. A prosthetic conformer or expander were used in four patients to promote orbital growth (n = 4, 57%). The only patient that required neurosurgical intervention was Case 7 (n = 1, 14%).

ONA is typically associated with other ocular abnormalities¹ as seen here, too (Table 1). All of our patients clinically demonstrated microphthalmia and various involvements of both anterior and posterior segments in their affected eye(s) (n = 7, 100%). Microphthalmia usually indicates anatomic alterations of the eye and is a feature of many ocular diseases.¹² In Case 4, no pathogenic variant was detected in four genes known to cause microphthalmia, indicating that other genes, epigenetic, or environmental factors may be contributory.⁶ It has been suggested that ONA may be underdiagnosed in the setting of severe microphthalmia due to difficulties of examining the eyes via funduscopy.¹³ Anomalous retina, as seen in all of our patients (n = 7, 100%), is another prominent feature of ONA, which indicates a close relationship between the optic nerve and retinal development. Neovascularization of the posterior segment has been reported, which was attributed to retinal ischaemia.¹⁴ In contrast, the neovascularization of our patients occurred in the anterior segment (n = 2, 29%). Other common ocular features in our patients included persistent pupillary membrane (n = 4, 57%), coloboma (n = 3, 43%), cataract (n = 3, 43%), posterior synechiae (n = 3, 43%), corneal abnormalities (n = 2, 29%), and elevated IOP (n = 2, 29%).

Table 1.

Summary of clinical findings in seven patients with optic nerve aplasia.

Case	Age of diagnosis	Laterality	Transverse optic canal diameter (mm)		Optic tract width (mm)		Ocular Anomalies	MRI Findings
			R	L	R	L
1	11 weeks	Unilateral (Right)	1	2.7	1.3	<1	Right Microphthalmia Ptosis Iris coloboma Elevated IOP Anterior iris stromal neovascularisation Chorioretinal coloboma Retinal pigment epithelial disturbances Anomalous retinal vascular pattern	Right-sided chiasmal hypoplasia
2	1 month	Unilateral (Left)	2.9	1.1	0.5	0.7	Left Microphthalmia Corneal opacification and neovascularisation Persistent pupillary membrane Retinal pigment epithelial disturbances Anomalous retinal vascular pattern	Non-specific chiasmal abnormality Bilateral optic tract hypoplasia
3	4 months	Unilateral (Right)	1	2.3	1.4	0.9	Right Microphthalmia Blepharophimosis Iris atrophy Diffuse cataract Pigmentary mottling of posterior pole Anomalous retinal vascular pattern	Right-sided chiasmal hypoplasia Left optic tract hypoplasia
4	3 months	Bilateral	1	1	NDa	ND	Bilateral Microphthalmia Posterior synechiae (right > left) Lens dysplasia Right Persistent pupillary membrane Left Vitreous haemorrhage/organisation Atrophic retina with anomalous retinal vascular pattern	Aplasia of optic chiasm Fluid collection within posterior fossa
5	8 months	Bilateral	1	1.4	ND	ND	Bilateral Microphthalmia Ptosis Right Persistent pupillary membrane Posterior synechiae Persistent fetal vasculature and tunica vasculosa lentis Cortical cataract Left Iris coloboma Lens coloboma Inferonasal sectoral cataract Fundus coloboma	Aplasia of optic chiasma
6	2 months	Bilateral	1.3	1.3	ND	ND	Bilateral Microphthalmia (left > right) Dacryostenosis Right Persistent pupillary membrane Posterior synechiae Posterior polar cataract Atrophic retina with calcified lesion at inferonasal periphery Left Clinical anophthalmia	Aplasia of optic chiasm
7	2 months	Bilateral	1.1	1.1	ND	ND	Bilateral Microphthalmia Increased corneal thickness and haze Elevated IOP Iris coloboma Chorioretinal coloboma/lacunae Anomalous retinal vascular pattern	Aplasia of optic chiasm Hypoplastic corpus callosum, pars intermedia cyst, foramen magnum stenosis

^aND = non-detectable

MRI confirms the diagnosis and can provide information on other CNS abnormalities (Figure 2). In our review, the contralateral optic nerve appears unremarkable in unilateral ONA. The optic chiasm is either abnormal or hypoplastic in all cases (n = 7, 100%). The measurements of the optic canal and optic tracts are shown in Table 1. There may be small margins of error when measuring these small structures, as the MRI slice thickness is 2–3 mm, even though dedicated orbital images were used. In unilateral ONA, the ipsilaterally involved optic canal is smaller. The optic tracts are not detectable in bilateral ONA and are asymmetric in unilateral ONA. Interestingly in all cases of unilateral ONA (3 of 3, 100%), the optic tracts are larger on the side ipsilateral to the ONA. Such asymmetry was also reported in one previous study.⁵ On the other hand, the patient from another case report of unilateral ONA had symmetrical optic tracts.¹⁵ Due to the small sample size of our study and previous studies, it is difficult to conclude whether and how the size of the optic tract is related to the laterality of ONA, especially considering that there is partial decussation of the contralateral optic nerve at the optic chiasm.

Most of the published literature regarding ONA indicated that MRI was used in the diagnostic approach. As MRI shows excellent details of soft tissues, it is often used to evaluate the visual pathway.¹⁶ Just as in previous studies, our patients’ lateral geniculate nucleus (LGN) or optic radiation could not be visualized clearly on MRI. Recent advances in MRI, though, include higher field strengths and an increased number of coils, which produce slices as thin as 1 mm, and greatly improve the image resolution.^16,17 Nowadays, MRI likely would be able to evaluate the visual pathway in a more detailed fashion beyond confirming the absence of optic nerves in ONA. A better understanding of what structural components are lacking along the pathway may inform the process that leads to ONA and how this is associated with other neurological maldevelopment.

ONA tends to occur sporadically. Thus far, there has been only one familial case reported: an autosomal dominant inheritance of CYP26A1 and CYP26C1 gene deletion, which was found in a father with unilateral ONA and his dizygotic twins with bilateral ONA.⁵ Our cases seem to be non-hereditary. None of our cases of unilateral ONA had extraocular anomalies, while two of the bilateral ONA patients case 4 and 7 (2 of 3, 67%) had CNS involvement which were shown on their MRI (Table 1). Interestingly, though, the extraocular anomalies are relatively unimpressive to those previously described as enlarged subarachnoid spaces and hypoplastic dorsal C1 arches can be common findings. It is difficult to study the environmental impact on ONA development. Among our cases, only Case 7 had a clear history of intrauterine exposure to tobacco smoking Although a definitive correlation between smoking during pregnancy and development of ONA cannot be made, it may be considered a potential risk factor.¹⁸ Moreover, smoking during pregnancy is thought to be contributive to the development of optic nerve hypoplasia, which is a related entity to ONA, and a number of other congenital ophthalmic conditions.¹⁹

Conclusions

The variation in clinical features of ONA makes the initial diagnosis sometimes challenging. MRI is a useful diagnostic tool to detect the absence of optic nerve and optic chiasm, which ensures an accurate diagnosis of ONA. In such patients, ophthalmologists should utilize advanced MRI protocols to help better characterize the state of the visual pathway and evaluate for any additional CNS anomalies. The clinical variation of ocular and extraocular manifestations presented in the study will further our understanding of ONA and its impact on patients’ lives. Although the eye with ONA has no visual potential, affected patients may require management for other complications such as ocular hypertension, poor orbital growth, and of course the effect of blindness on other aspects of development. A multidisciplinary approach is important to address extraocular concerns and provide support for congenital blindness.

Declaration of interest statement

The authors report no conflict of interest.