Congenital optic disc malformations : prevalence, clinical and oct findings, long-term follow-up and quality of life

Congenital optic disc malformations are structural anomalies of the optic nerve that can cause different grades of visual impairment and even blindness. Correct diagnosis and early intervention are crucial to optimising visual function and providing the patient and their family with appropriate care, as these conditions can sometimes be associated with systemic diseases. This thesis is about the most common ones: optic nerve hypoplasia (ONH) and optic disc coloboma (ODC).

In Study I, the prevalence of ODC was reported as 8.9/100,000 children, and the ocular, neurological, and behavioural problems of a population-based ODC cohort were described. Thirty-one (18 with unilateral) ODC patients, aged 2.4-18 years (median 10 years), with median best corrected visual acuity (BCVA) of 0.3 (range 0-1.3), were included. Nystagmus presented more often in patients with bilateral ODC (p=0.04). Median BCVA was better (0.82) in eyes with isolated ODC compared to eyes with concurrent macular involvement (0.15). Twenty-one patients underwent behavioural/psychological screening, and a deeper analysis revealed severe deficits in six of them. Intellectual disability was present in seven patients, while eight patients had neurological deficiencies. All these patients had already received a systemic disease diagnosis before the ODC diagnosis. This indicates that the child health care screening system in Sweden excels in identifying extraocular comorbidities.

In Study II, we included 37 eyes with ONH from 20 patients (17 bilateral cases), with a median age of 10.5 years (range 2.8-18.9). We recruited a control group of 140 eyes from 70 healthy individuals. The OCT exam showed that the disc diameter as measured by the Bruch's membrane opening (BMO) was shorter (mean 1030um vs mean 1737um, p<0.001), the peripapillary retinal nerve fibre layer (pRNFL) was thinner (mean 53.9 um vs mean 109.6 um, p<0.001), and the macular ganglion cell complex (GCC) was thinner (mean 71.7 um vs mean 110.4 um, p<0.001) in ONH eyes compared to the control group. BCVA showed a strong/moderate correlation to the pRNFL and the GCC. BCVA correlated strongly to BMO (r=0.709, p<0.001) and moderately to the Zeki ratio (r =- 0.524, p<0.001). Visual fields correlated strongly to pRNFL (r=0.702) and GCC thickness (r=0.722). The presence and location of visual field defects corresponded to the topography of the thinning of the GCC. The best estimated cut-off value for the BMO was 1328um with sensitivity 74.2% and specificity 97.9% for the diagnosis of ONH.

In Study III, we used different methodology to examine 52 ONH eyes and 17 fellow eyes from 36 patients, aged median 15.0 years (range 5-24), with Spectral Domain OCT. The images were analysed semi-manually using a MATLAB program. ONH eyes had shorter disc diameter (1061+375um vs. 1751+221 um, p<0.001), shallower mean cup depth (427+171um vs. 551+152um, p=0.01), thinner GCC perifoveally (44.7+12.6um, 60.8+6.0um, p<0.001), and reduced foveal depth (61+36um, 119+19um, p<0.001) compared to control eyes. Qualitative analysis revealed that 1/3 of ONH eyes lacked an optic cup, while 2/3 had a reduced or absent foveal pit. Fellow eyes, in presumed unilateral cases, had shorter disc diameter (1446+404um vs. 1751+221um, p=0.004) and reduced foveal depth (98+26um vs. 119+19um, p<0.001) but similar GCC thickness (60.8+7.1um vs. 60.8+6.0um, p=0.738) compared to controls, suggesting the possibility of bilateral subclinical disease. Disc diameter showed the best correlation to BCVA in ONH eyes (r=0.517, p<0.001).

Study IV was a long-term retrospective follow-up study of patients with ONH. Median age at the first and last visit was 7.8 (0.4 to 19.2) and 16.3 years (range 9.0 to 28.3) respectively. Median follow-up was 8.5 years (range 5.1-12.6). BCVA was unchanged but a myopic refractive shift was observed during follow-up. Quality of life scores were low compared to other chronic extraocular diseases and correlated strongly to BCVA.

In conclusion, infants and toddlers with colobomas should be referred to paediatricians for a work-up to exclude syndromic ODC, while healthy teenagers do not need to be referred if they are otherwise healthy. Visual acuity in ODC eyes depends more on the involvement of the fovea. OCT can aid in the diagnosis of ONH, while pRNFL, GCC, and BMO can forecast visual acuity. GCC and pRNFL thinning can reveal the location and severity of visual field defects. Optic disc parameters such as the BMO and Zeki's ratio had a stronger correlation to visual acuity than macular parameters. We recommend using OCT in all patients with suspected ONH. However, in equivocal cases, confirming the diagnosis may require a thorough ophthalmological examination, which may involve multimodal imaging, electrophysiologic testing, an endocrinological and neurological evaluation, including neuroimaging, a genetic analysis in selected cases, and critical medical skepsis.

Keywords: optic disc coloboma; optic nerve hypoplasia; behaviour; cognition; neurology; visual outcome; prevalence; optical coherence tomography; foveal hypoplasia; ganglion cell complex; retinal nerve fibre layer; long-term follow-up; quality of life.

List of scientific papers

This thesis is based on the following papers which will be referred to by their Roman numerals:

I. Optic Disc Coloboma in children - prevalence, clinical characteristics and associated morbidity. Skriapa-Manta, A., Olsson, M., Ek, U., Wickström, R. and Teär Fahnehjelm, K. (2019), Acta Ophthalmol, 97: 478-485. https://doi.org/10.1111/aos.13999

II. Optical Coherence Tomography Can Predict Visual Acuity in Children with Optic Nerve Hypoplasia. Skriapa-Manta A, Nilsson M, Svoboda J, Olsson M, Nilsson M, Teär Fahnehjelm K. Clin Ophthalmol. 2022 Nov 17; 16:3785-3794. PMID: 36419566; PMCID: PMC9677923. https://doi.org/10.2147/OPTH.S387084

III. Characteristic deviations of the optic disc and macula in optic nerve hypoplasia based on OCT. Skriapa-Manta, A., Venkataraman AP, Olsson M, Nilsson M, Teär Fahnehjelm K. Acta Ophthalmol. 2024 May 23. Epub ahead of print. PMID: 38782817. https://doi.org/10.1111/aos.16722

IV. Quality of life and long-term follow-up of patients with optic nerve hypoplasia. Skriapa-Manta, A., Olsson M, Nilsson M, Britt-Marie Anderlid, TeärFahnehjelm K. [Manuscript]