Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study

Abstract

Background: Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression.

Methods: This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters.

Findings: 164 patients with MS and 60 healthy controls were assessed. Mean follow-up was 25·8 months (SD 9·1) for patients with MS and 22·4 months (11·4) for healthy controls. Ten (6%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5·93 [range 2·44-8·91]) than those who did not have MMO at any time during the study (151 patients; 3·81 [0·13-9·47]; p=0·032), although expanded disability status scale (EDSS) scores were not significantly different (5·2 [1·0-6·5] for patients with MS and MMO vs 2·5 [0·0-8·0] for those without MMO; p=0·097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100% contrast, p=0·017; 2·5% contrast, p=0·031; 1·25% contrast, p=0·014), and increased INL thicknesses (p=0·003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0·007), new T2 lesions (p=0·015), EDSS progression (p=0·034), and relapses in patients with relapsing-remitting MS (p=0·008) during the study. MMO was not associated with disease activity during follow-up.

Interpretation: Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS.

Funding: National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.

Figure 1. Study profile

MS: multiple sclerosis, AON: acute optic neuritis, HCs: healthy controls, OCT: optical coherence tomography, HSV: herpes simplex encephalitis, ERM: epiretinal membrane

Figure 2. Microcystic macular edema (MME) of the inner nuclear layer (INL) as identified by spectral-domain optical coherence tomography, with automated segmentation lines displayed

Panels A–C: All images were acquired from the same patient during a 3-year period of observation, and are presented in chronological order in consecutive panels. Panel A: MME of the INL (red arrows) was present at baseline, as well as a foveal cyst of the outer nuclear layer (ONL). Panels B–C: The ONL cyst progressively resolved during follow-up. Panels D–F: All images were acquired from the same patient during a 2-year period of observation, and are presented in chronological order in consecutive panels. Panel D: A single INL cyst (red arrow) was present at baseline. Panel E: The cyst spontaneously resolved after one year. Panel F: Following fingolimod treatment (initiated after scan E) the patient developed new cystic changes of the INL (red arrow). An epiretinal membrane is noted (white arrow) that had been present on previous scans as well (not illustrated though in either panel D or E). Panels G–I: Three different patients with MME of the INL (red arrows) are presented in each panel. Vessel artifacts (black arrows) are demonstrated for comparison. OCT-segmentation performed in 3D identifies the inner limiting membrane, the outer boundaries of the RNFL, inner plexiform layer, and outer plexiform layer, and the inner boundary of the retinal pigment epithelium. The identification of these retinal boundaries enables the determination of the thicknesses of the following retinal layers – the macular RNFL, GCL+innerplexiform layer (GCIP; labeled 1 in panel A), INL (including the outer plexiform layer; labeled 2 in panel A), and ONL (including the inner and outer photoreceptor segments; labeled 3 in panel A).

Figure 3. Illustration of the retinal layer boundaries identified by automated OCT segmentation in an eye exhibiting microcystic macular edema

OCT-segmentation performed in 3D identifies the inner limiting membrane, the outer boundaries of the RNFL, inner plexiform layer, and outer plexiform layer, and the inner boundary of the retinal pigment epithelium. The identification of these retinal boundaries enables the determination of the thicknesses of the following retinal layers – the macular RNFL, GCL+innerplexiform layer (GCIP; labeled 1), INL (including the outer plexiform layer; labeled 2), and ONL (including the inner and outer photoreceptor segments; labeled 3).

Figure 4. Box and whisker plots of baseline INL thickness

Panel A illustrates that RRMS patients that developed relapses or new Gd-enhancing lesions during study follow-up (n=47 subjects [94 eyes])had higher baseline INL thicknesses, as compared to patients that did not develop relapses or new Gd-enhancing lesions (n=73 subjects [146 eyes]). Panel Billustrates that MS patients exhibiting new T2 lesions during follow-up (n=49 subjects [98 eyes]), as compared to patients that did not (n=109 subjects [218 eyes]), had higher baseline INL thicknesses. P-values were calculated utilizing mixed effects linear regression accounting for within subject inter-eye correlations. The top and bottom of the box represent the 25^th and 75^th percentiles respectively. The line in the center of the box represents the median (50^th percentile). The ends of the whiskers represent the largest value within the 75^th percentile + 1·5 * inter-quartile range (IQR) and the smallest value within the 25^th percentile – 1·5 * IQR. Values outside of the ends of the whiskers are represented with dots.