Association of Retinal Ganglion Cell Layer Thickness With Future Disease Activity in Patients With Clinically Isolated Syndrome

Abstract

IMPORTANCE Clinically isolated syndrome (CIS) describes a first clinical incident suggestive of multiple sclerosis (MS). Identifying patients with CIS who have a high risk of future disease activity and subsequent MS diagnosis is crucial for patient monitoring and the initiation of disease-modifying therapy. OBJECTIVE To investigate the association of retinal optical coherence tomography (OCT) results with future disease activity in patients with CIS. DESIGN, SETTING, AND PARTICIPANTS This prospective, longitudinal cohort study took place between January 2011 and May 2017 at 2 German tertiary referral centers. A total of 179 patients with CIS were screened (80 in Berlin and 99 in Munich). Patients underwent neurological examination, magnetic resonance imaging (MRI), and OCT. Only eyes with no previous optic neuritis were considered for OCT analysis. MAIN OUTCOMES AND MEASURES The primary outcome was not meeting the no evidence of disease activity (NEDA-3) criteria; secondary outcomes were MS diagnosis (by the 2010 McDonald criteria) and worsening of disability. The primary measure was OCT-derived ganglion cell and inner plexiform layer thickness; the secondary measures included peripapillary retinal nerve fiber layer thickness, inner nuclear layer thickness, and MRI-derived T2-weighted lesions. RESULTS A total of 97 of the 179 screened patients (54.2%) were enrolled in the study at a median of 93 (interquartile range [IQR], 62-161) days after a first demyelinating event. The median follow-up duration (Kaplan-Meier survival time) was 729 (IQR, 664-903) days. Of 97 patients with CIS (mean age 33.6 [7.9] years; 61 [62.9%] female), 58 (59%) did not meet NEDA-3 criteria during the follow-up period. A Kaplan-Meier analysis showed a significant probability difference in not meeting NEDA-3 criteria by ganglion cell and inner plexiform later thickness (thinnest vs thickest tertile: hazard ratio [HR], 3.33 [95% CI, 1.70-6.55; P < .001; log-rank P = .001). A follow-up diagnosis of MS was more likely for patients with low ganglion cell and inner plexiform layer thickness (thinnest vs thickest tertile: HR, 4.05 [95% CI, 1.93-8.50]; P < .001). Low peripapillary retinal nerve fiber layer thickness likewise indicated risk of not meeting NEDA-3 criteria (thinnest vs thickest tertile: HR, 2.46 [95% CI, 1.29-4.66]; P = .01; log-rank P = .02). Inner nuclear layer thickness and T2-weighted lesion count were not associated with not meeting NEDA-3 criteria. CONCLUSIONS AND RELEVANCE Retinal ganglion cell and inner plexiform layer thickness might prove a valuable imaging marker for anticipating future disease activity and diagnosis of MS in patients with CIS, which can potentially support patient monitoring and initiation of disease-modifying therapy.

Inner retinal layer thinning in radiologically isolated syndrome predicts conversion to multiple sclerosis

“…Inner retinal layer thinning occurs early in the course of demyelinating CNS autoimmunity [25] and is most probably driven by retrograde trans-synaptic neurodegeneration [26] due to intrathecal inflammatory processes [22] and subsequent brain atrophy [14]. It has already been shown that reduced pRNFL and GCIP measures are risk factors for clinical progression with sustained disability worsening in both CIS and MS [13,16,22,27]. The decreased likelihood of achieving the status of no evidence of disease activity (NEDA-3) in individuals with low GCIP volumes argues for the predictive power of retinal layer alterations during the course of MS and its 'precursor stages' CIS and RIS [13].…”

“…Optical coherence tomography (OCT) is a non-invasive high-resolution imaging technique of the retina. Distinct changes in the retinal architecture may reflect neurodegenerative and inflammatory processes within the CNS during MS [13][14][15][16] and might be associated with paraclinical disease activity in individuals with RIS [17]. The aim of the current study was to assess whether retinal alterations in individuals with RIS can be used as prognostic markers for conversion to MS.…”

Visualizing the Central Nervous System: Imaging Tools for Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

“…Also in a clinically isolated syndrome (CIS) scenario OCT may be helpful to assess the risk of further disease activity. A bicenter study from Germany grouped 89 patients with a CIS as a qualifying event into three groups according to their baseline GCIPL values in NON eyes (168). Patients in the lowest tertile (ranging from 58.7 to 69.2 µm) had a hazard ratio of 3.43 for not meeting NEDA status within the follow-up period (max 2.5 years) as compared to patients in the highest GCIPL tertile (ranging from 74.2 to 84.8 µm).…”

Retinal thinning and brain atrophy in early MS and CIS

“…Thinning of GCIPL, and their axons in the peripapillary RNFL are assumed to be associated with clinical disability 15 and brain atrophy 7,16 . However, the usefulness of OCT in diagnosing and monitoring MS remains somewhat controversial and is still under evaluation 17‐19 …”