Early Macular Ganglion Cell Loss in Leber Hereditary Optic Neuropathy, an Optical Coherence Tomography Biomarker to Differentiate Optic Neuritis

Abstract

Background/Objectives: Leber hereditary optic neuropathy (LHON) is often misdiagnosed in its early stages as idiopathic single isolated optic neuritis (SION) or multiple-sclerosis-associated optic neuritis (MS-ON) due to the young age of the patients, the subacute vision loss, and the central visual field defect. The aim of this retrospective study was to evaluate changes in the peripapillary RNFL and GCLT over time in patients with early LHON, MS-ON, and SION in order to differentiate Leber hereditary optic neuropathy (LHON) from optic neuritis (ON) in the early stages of the disease. Methods: Patients with LHON and ON (either idiopathic single isolated optic neuritis (SION) or ON as the first symptom of relapsing-remitting multiple sclerosis (MS-ON) were included. Optical coherence tomography (OCT) scans were reviewed. The inclusion criteria were at least one follow-up OCT examination and a definite diagnosis after examination. Changes in the peripapillary retinal nerve fibre layer (RNFL) and macular ganglion cell layer thickness (GCLT) in both groups were evaluated over time and compared with normative data. The analysis focused on the early phase (0-45 days) after symptom onset. Results: Nine LHON patients with early OCT scans and twenty patients with ON were included. Quantitative OCT analysis showed greater RNFL swelling in LHON compared to ON during the first 60 days after symptom onset. Between day 61 and day 120, subnormal RNFL values were observed in both groups compared to controls. Thereafter, the RNFL decreased continuously and severely in the LHON group. The RNFL of ON patients did not show a clear progression after day 120. The GCLT in five LHON eyes showed a strong and solid decrease from day 0 to day 45, which was stronger than the moderate atrophy measured in ON eyes. Continuous GCL atrophy was measured until day 121 in LHON, after which a floor effect was reached. The GCLT in the inner nasal and inner inferior sectors was significantly smaller in LHON compared to ON patients on days 0-45. Conclusions: Thinning of the GCLT occurs at an early stage in LHON patients. Thus, GCLT may become a diagnostic tool to differentiate LHON from ON in the early phase of disease.

Keywords: Leber hereditary optic neuropathy; macular ganglion cells; neuro-ophthalmology; optic disc; optic neuritis; retinal nerve fibre layer.

Figure 1

Early Treatment Diabetic Retinopathy Study (ETDRS) grid projected over the segmented macular ganglion cell layer of a healthy individual in spectral-domain optical coherence tomography (SD-OCT). Note the thick doughnut-shaped region of ganglion cells surrounding the fovea. The inner circle ganglion cell layer thickness (GCLTi) value contains the mean thickness (in µm) of the four inner sectors (in: inner nasal; is: inner superior; it: inner temporal; ii: inner inferior). The GCLT distribution per sector over the entire horizontal grid was focused on in the very early post-symptomatic phase, including the sectors on: outer nasal; f: foveal; and ot: outer temporal.

Figure 2

Imaging and visual field of the left eye of a 25-year-old Leber hereditary optic neuropathy (LHON) patient with m.11778G→A mutation during the first year after the onset of symptoms. Analysis of retinal nerve fibre layer (RNFL) and macular ganglion cell layer thickness (GCLT) by spectral-domain optical coherence tomography (SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and Humphrey visual field (30-2, Analyser 3, Zeiss, Jena, Germany) are shown from left to right for three time points. (A) Two weeks after symptom onset, there was subtle swelling of the peripapillary RNFL, but already reduced GCLT in all sectors, particularly in the nasal foveal region. Centrocecal scotoma was present, and the visual acuity was 0.80 log MAR at this time. (B) At four months, the RNFL was partially reduced, especially in the temporal region, but there were hardly any ganglion cells visible in the colour image of the GCLT analysis. Almost complete loss of the central visual field was observed over the months. (C) One year after the onset of symptoms, circular atrophy of the RNFL and further reduction in the GCLT were observed with visual field depression, showing enlarged fenestration in the upper visual field.

Figure 3

(A,C) Development of global retinal nerve fibre layer thickness (RNFL, red dots) and inner ring macular ganglion layer thickness (GCLTi, black triangles) in patients with Leber hereditary optic neuropathy (LHON, (A)) or optic neuritis (idiopathic single isolated ON (SION) and MS-associated ON, (C)). Comparison with healthy subjects (green symbols) was conducted using spectral-domain optical coherence tomography (SD-OCT, Heidelberg Engineering, Heidelberg, Germany). RNFL swelling was observed in LHON patients during the first 90 days after symptom onset. Subsequently, RNFL thickness decreased during the first year. Already in the first 45 days after symptom onset, the GCLTi is significantly reduced compared to healthy subjects (A). Substantial thinning of the RNFL occurs after 91–120 days in ON patients. The GCLTi is less reduced over time compared to LHON but is also noticeable in the very early phase 0–45 days (C). (B,D) The five horizontal GCLT sectors at 0–45 days are shown for four LHON eyes (B) and 13 ON eyes (D) (black triangles) compared to healthy subjects (green triangles). The GCLT is prematurely thinned in all LHON eyes, especially with a large delta to normative values in the inner nasal segment of the ETDRS grid (B). There are variable differences in ON patients compared to healthy controls (D). (A–D) The underlying normative values for the thickness of the global RNFL, the GCLTi, and the five horizontal sectors are taken from the study by Storp et al. based on data from 501 eyes of healthy subjects [18]. Values are presented as the median and interquartile range.

Figure 4

Macular ganglion layer thickness (GCLT) in the nasal, temporal, superior, and inferior inner sectors (from left to right) of the inner ring (1–3 mm diameter) of the Early Treatment Diabetic Retinopathy Study (ETDRS) macular grid in patients with Leber’s hereditary optic neuropathy (LHON), optic neuritis (ON), and healthy controls within the first 45 days after symptom onset. Compared to ON patients, there was a significant reduction in LHON eyes nasally and inferiorly. p value < 0.05 (*); p value <0.01 (**); p value < 0.001 (***); p value <0.0001 (****); not significant (ns).