Elsevier

The Lancet Neurology

Volume 11, Issue 11, November 2012, Pages 963-972
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(12)70213-2Get rights and content

Summary

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.

Introduction

Multiple sclerosis (MS) is often regarded as an immune-mediated inflammatory demyelinating disorder of the CNS, in which neurodegeneration is a secondary phenomenon.1 Grey-matter degeneration is, however, common in MS and more closely associated with disability than white-matter degeneration.2, 3 Whether grey-matter degeneration in MS occurs only as a result of white-matter injury is unclear.4 Neuronal loss in the retina could occur as a primary process in MS, independent of demyelination or axonal injury.5, 6

The retina, although unmyelinated, is a common site of inflammation, disruption of the blood–retina barrier, and neuronal loss in patients with MS. Retinal perivascular inflammation (periphlebitis), suggesting disruption of the blood–retina barrier, occurs in up to 20% of patients with MS.7 Active retinal periphlebitis tends to occur simultaneously with disruption of the blood–brain barrier in these patients,8 and might be a risk factor for relapses and gadolinium-enhancing lesions.9 Intermediate uveitis, especially pars planitis, also occurs in up to 16% of patients with MS.10 Consistent with clinical observations, post-mortem analyses show retinal inflammation with activated microglia in the eyes of people with MS.11 Collectively, these findings suggest myelin might not be necessary for maintaining or propagating inflammation in MS.

Spectral-domain optical coherence tomography (OCT) renders images with high resolution (<5 μm),12 from which the individual retinal layers can be demarcated, qualitatively assessed, and objectively and precisely quantified.5 These layers include the retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner nuclear layer (INL), and outer nuclear layer (ONL). The RNFL is the innermost layer of the retina and primarily consists of the axons of ganglion cell neurons, which are located distal to the RNFL. These axons coalesce at the optic disc to form the optic nerve, and exit the eye through the lamina cribrosa, where they acquire myelin.6

MS affects the optic nerves both clinically (as optic neuritis) and subclinically, resulting in retrograde degeneration of the axons of the optic nerve, culminating in RNFL and GCL atrophy7, 11, 13 that can be detected and quantified in vivo with OCT.6, 14 Additionally, deeper retinal layer pathology has been shown to occur in MS, although not in all studies.15 Consistent with post-mortem demonstration of INL atrophy in 40% of eyes of patients with MS,11 and the electroretinographic identification of INL and ONL dysfunction,16, 17 we have previously shown using macular segmentation that INL and ONL thicknesses are decreased in eyes of patients with MS, both with optic neuritis (which we have termed mixed retinal pathology phenotype) and without a history of optic neuritis (which we have termed macular thinning predominant phenotype).5, 6 These findings could represent primary retinal neuronal mechanisms of pathology, since atrophy of the INL or ONL has not been shown following optic nerve transection in animals.18 The presence of this deeper retinal neuronal layer pathology in patients with MS was associated with greater disability in a cross-sectional study.5

A recent study using OCT identified microcystic macular oedema (MMO) of the INL in about 5% of patients with MS.19 MMO was thought to represent breakdown of the blood–retina barrier and retinal inflammation, potentially because of subclinical uveitis or retinitis, and was associated with greater disability and visual dysfunction. However, longitudinal data were available for only six patients, and the INL was not quantitatively assessed with OCT segmentation. Therefore, the prevalence of MMO of the INL, and its development over time in patients with MS remains unclear. Since MMO of the INL might be inflammatory, we postulate that some patients with MS could harbour INL inflammation in the absence of visible MMO, resulting in increased thickness of the INL. Indeed, a recent cross-sectional study showed that increased thickness of the INL (measured as the thickness of the combined INL and outer plexiform layer) correlated with higher T2-weighted fluid-attenuated inversion recovery MRI lesion volume in patients with MS, while thicknesses of other retinal layers did not.20 The clinical relevance of MMO of the INL and increased INL thickness (which could both represent myelin-independent neuronal compartment inflammation) remains to be elucidated.

The primary objectives of our retrospective study were: (1) to confirm the occurrence of MMO in patients with MS, ascertain its prevalence, and assess whether MMO occurs in healthy controls (to determine whether MMO in patients with MS represents a pathological process or a normal phenomenon); (2) to determine whether MMO in patients with MS is associated with disease activity and disability; and (3) to determine whether increased thickness of the INL at baseline, measured as thickness of the combined INL and outer plexiform layer, in patients with MS is associated with disease activity or disability progression.

Section snippets

Study design and participants

Two cohorts were recruited: an MS cohort (without acute optic neuritis or evidence of optic disc swelling on fundoscopy within 3 months of baseline assessment; about 40% of this cohort have been included in other cross-sectional studies done by our group) and a healthy control cohort.6, 20 Study participants were recruited between September, 2008, and December, 2010, and studied between September, 2008, and March, 2012.

The MS cohort was recruited by unselected convenience sampling of

Results

164 patients with MS and 60 healthy controls participated in the study (figure 1, table 1). Mean follow-up durations were 25·8 (SD 9·1) months for the MS cohort and 22·4 (11·4) months for the control group.

MMO was identified in ten of 164 patients with MS during the study (6%; four of ten had MMO at baseline), and was bilateral in two patients (figure 2). In one of these patients with bilateral MMO, bilateral epiretinal membranes, without associated retinal traction, were also present

Discussion

Our study confirms the occurrence of MMO (predominantly of the INL) in patients with MS, shows that MMO is a dynamic process, and highlight MMO as a pathological process that does not seem to occur in healthy controls.19 Although only four of the ten patients with MS and MMO at any stage during the study had visible MMO at baseline, baseline INL thickness was higher in the patients with MS and MMO than in patients with MS who did not have MMO. This finding highlights the potential for earlier

References (35)

  • T Engell et al.

    Multiple sclerosis: periphlebitis retinalis et cerebro-spinalis. A correlation between periphlebitis retinalis and abnormal technetium brain scintigraphy

    Acta Neurol Scand

    (1984)
  • J Sepulcre et al.

    Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS

    Neurology

    (2007)
  • MJ Donaldson et al.

    Pars planitis: a 20-year study of incidence, clinical features, and outcomes

    Am J Ophthalmol

    (2007)
  • AJ Green et al.

    Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration

    Brain

    (2010)
  • S Saidha et al.

    Optical coherence tomography as a marker of axonal damage in multiple sclerosis

    CML Multiple Sclerosis

    (2010)
  • LS Talman et al.

    Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis

    Ann Neurol

    (2010)
  • AU Brandt et al.

    Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography

    Brain

    (2011)
  • Cited by (233)

    • Non-vasogenic cystoid maculopathies

      2022, Progress in Retinal and Eye Research
    View all citing articles on Scopus

    These authors contributed equally

    View full text