Microcystic macular oedema in multiple sclerosis is associated with disease severity

Abstract

Macular oedema typically results from blood-retinal barrier disruption. It has recently been reported that patients with multiple sclerosis treated with FTY-720 (fingolimod) may exhibit macular oedema. Multiple sclerosis is not otherwise thought to be associated with macular oedema except in the context of comorbid clinical uveitis. Despite a lack of myelin, the retina is a site of inflammation and microglial activation in multiple sclerosis and demonstrates significant neuronal and axonal loss. We unexpectedly observed microcystic macular oedema using spectral domain optical coherence tomography in patients with multiple sclerosis who did not have another reason for macular oedema. We therefore evaluated spectral domain optical coherence tomography images in consecutive patients with multiple sclerosis for microcystic macular oedema and examined correlations between macular oedema and visual and ambulatory disability in a cross-sectional analysis. Participants were excluded if there was a comorbidity that could account for the presence of macular oedema, such as uveitis, diabetes or other retinal disease. A microcystic pattern of macular oedema was observed on optical coherence tomography in 15 of 318 (4.7%) patients with multiple sclerosis. No macular oedema was identified in 52 healthy controls assessed over the same period. The microcystic oedema predominantly involved the inner nuclear layer of the retina and tended to occur in small, discrete patches. Patients with multiple sclerosis with microcystic macular oedema had significantly worse disability [median Expanded Disability Score Scale 4 (interquartile range 3-6)] than patients without macular oedema [median Expanded Disability Score Scale 2 (interquartile range 1.5-3.5)], P = 0.0002. Patients with multiple sclerosis with microcystic macular oedema also had higher Multiple Sclerosis Severity Scores, a measure of disease progression, than those without oedema [median of 6.47 (interquartile range 4.96-7.98) versus 3.65 (interquartile range 1.92-5.87), P = 0.0009]. Microcystic macular oedema occurred more commonly in eyes with prior optic neuritis than eyes without prior optic neuritis (50 versus 27%) and was associated with lower visual acuity (median logMAR acuity of 0.17 versus -0.1) and a thinner retinal nerve fibre layer. The presence of microcystic macular oedema in multiple sclerosis suggests that there may be breakdown of the blood-retinal barrier and tight junction integrity in a part of the nervous system that lacks myelin. Microcystic macular oedema may also contribute to visual dysfunction beyond that explained by nerve fibre layer loss. Microcystic changes need to be assessed, and potentially adjusted for, in clinical trials that evaluate macular volume as a marker of retinal ganglion cell survival. These findings also have implications for clinical monitoring in patients with multiple sclerosis on sphingosine 1-phosphate receptor modulating agents.

Figure 1

Microcystic macular oedema on spectral domain optical coherence tomography in multiple sclerosis. (A–H) Seven different patients with multiple sclerosis; B is a magnified view of A. The microcysts predominantly involved the inner nuclear layer of the retina (asterisks). For comparison purposes, I is a representative scan without macular oedema in a patient with relapsing-remitting multiple sclerosis and J is a representative scan from an unaffected control. Note that the retinal nerve fibre layer (short arrow) is thinner in the patient with multiple sclerosis (I) than in the control participant (J). An epiretinal membrane is noted in H (wide arrow).

Figure 2

Microcystic macular oedema in multiple sclerosis is associated with greater disability (EDSS). The P-value was calculated by the Wilcoxon Rank Sum test. The line in the centre of the box indicates the median and the shaded box denotes the IQR. The whiskers denote minimum and maximum values, excluding outliers (defined as >1.5 times the lower and upper quartile values).

Figure 3

Microcystic macular oedema worsened at 5 months of follow-up in one patient (A and B), with an increase in macular volume from 3.14 to 3.19 mm³, while improving at 12 months of follow-up in another patient (C and D), with a decrease in macular volume from 3.01 to 2.99 mm³. In A and B, the automatic real-time was 70 and quality was 26 and 22, respectively. In C and D, the automatic real-time was 30 and the quality was 29 and 22, respectively.