Novel ophthalmological assessments for detection of optic pathway gliomas in children

Abstract

Optic pathway gliomas (OPGs) are vision-threatening brain lesions that are extremely important to detect at young age for appropriate medical intervention. Children with neurofibromatosis type 1 (NF1) are particularly at increased risk of developing OPG. The gold standard in detection is magnetic resonance imaging of the brain and orbits. Nevertheless, neuroimaging escalates both costs and parental anxiety and exposes the patient for the risks of repeated sedation. Magnetic resonance imaging for screening of OPG in children with NF1 is not indicated as the detection of these tumors rarely changes management in the absence of clinical symptoms or signs. The most common symptom is visual loss and therefore, there is an established screening procedure for ophthalmological follow-up of children with NF1. Two important visual parameters are the visual acuity (VA) and visual field (VF), both psychophysical tests that require a high level of participation to provide reliable results. In addition, visual maturation must be taken into the account. Therefore, different testing methods are used depending on the age of the patient. Sometimes there is also a difficulty of differentiating true pathology from behavior changes that are common among patients with NF1. These factors reduce the sensitivity in detection of early pathological changes. Thus, there may be a role for additional imaging screening in children whom reliable visual assessment cannot be performed. Optical coherence tomography (OCT) is a well-established, patient-friendly, high-resolution imaging modality that may complement ophthalmological examination and facilitate the indication for magnetic resonance imaging. It has shown promising results in several studies in detection of early signs of neural tissue destruction in adults. However, studies in children have been limited due to lack of normative values.

Paper I evaluated ganglion cell and inner plexiform layer (GC-IPL) thickness as assessed by Cirrus High-Definition OCT (Carl Zeiss Meditec, Dublin, CA, USA) in 92 healthy 6.5-year-old children. Intraocular analysis showed that average GC-IPL values below 76 μm (fifth percentile) and/or GC‐IPL asymmetry defined as a difference between the thickest and thinnest sector of > 10 μm (values above 95th percentile) may be considered abnormal. The GC-IPL topography was evenly distributed around the fovea without any larger thickness variations between superior and inferior hemispheres or between combined nasal and temporal sectors. The interocular difference in average GC-IPL thickness was 1.5 μm (SD ±1.3, range 0 to 6 μm). A statistically significant increase in average GC-IPL thickness was found with increasing hyperopia (p = 0.031, Spearman’s ρ 0.23). The most frequently occurring image artefacts were identified and their impact on the measurements were estimated. However, even if reduced fixation resulted in artefacts that led to false thickening of the superior macular segment as well as average thickness the difference was not statistically significant and most importantly, none of the sectors were statistically significantly thinner among scans with artefacts (Uncomplete Scans) in comparison to scans without artefacts (Complete Scans). Inclusion of Uncomplete Scans in the total analysis did not change the mean values of any OCT variable significantly.

Paper II aimed to evaluate the relation between ocular structure (GC-IPL) and function (VA, VF) in children with NF1-associated or sporadic OPG (n = 51). We confirmed that GC-IPL thinning and/or large differences in segmental thickness within an eye and between eye pairs were sensitive markers of damage to the visual pathway in children with OPG. Average GC- IPL distinguished well between eyes with and without OPG (p < 0.001). The GC-IPL pattern loss corresponded in 95% to VF defects and in 92% to neuroimaging. Significant correlations were found between GC-IPL thickness and function (VF and VA) (p < 0.001).

Paper III evaluated longitudinal changes over a period of three years including four parameters (GC-IPL, VA, VF index and peripapillary retinal nerve fiber layer) in 25 children with known OPG (NF1-associated or sporadic) and in 57 children with NF1 without symptomatic OPG. The study showed that GC-IPL measurements were easy to obtain, acquired at a similar young age as VA measurements and considerably earlier than both VF examinations as well as reliable peripapillary retinal nerve fiber layer measurements. Unlike VA, GC-IPL was not affected by age in young children, highlighting the importance and reliability of GC-IPL measurement in the detection and follow-up of OPG.

In conclusion, our findings suggest that thinning of GC-IPL as assessed with OCT enables early diagnosis of underlying OPG and should therefore be included in the ophthalmological screening protocol of children with NF1.