Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis

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Abstract

Multiple sclerosis is characterized by the dual pathological processes of inflammation and neurodegeneration. Conventional MRI techniques are considered the best tools for assessing and monitoring lesion burden and inflammation but are limited in their ability to assess axonal loss. Optical coherence tomography (OCT) is a simple high-resolution technique that uses near infrared light to quantify the thickness of the retinal nerve fiber layer (RNFL), which contains only non-myelinated axons. RNFL thickness (RNFLT) was measured using OCT on thirty consecutive MS patients (60 eyes). Eighteen patients underwent quantitative MRI analysis including T1- and T2-lesion volumes (LV), normalized brain volume (NBV), normalized cortical, white and gray matter volumes (NCV, NWMV, and NGMV), and mean whole brain diffusivity (MD). There was a strong association between NBV and average RNFL thickness (p < 0.001, partial rp = 0.77). The T2-LV and NWMV were significantly associated with average RNFL thickness (p = 0.002, partial rp =  0.76 and p = 0.005, partial rp = 0.68, respectively) and there were trends toward association with T1-LV (p = 0.041) and NGMV (p = 0.067). There was negative correlation between average RNFL thickness (average of both eyes) and disability as assessed by EDSS (p = 0.02). The results support potential usefulness of OCT for MS patient monitoring and research applications.

Introduction

Multiple sclerosis (MS) is a degenerative, chronic inflammatory disease of the central nervous system (CNS) that causes demyelination, sclerotic plaque formation and CNS atrophy. Relapsing remitting multiple sclerosis is characterized by an early inflammatory component. Recent histopathological findings have demonstrated that MS is associated with a significant neurodegenerative component and progressive neuronal loss secondary to the initial inflammatory process [1], [2]. A mechanistic framework consistent with the associations between inflammatory processes (i.e., T2-LV) and RNFLT is suggested by recent reports that found significant loss of retinal ganglion cells secondary to inflammation in PLP-induced EAE and in oligodendrocyte glycoprotein (MOG)-specific TCR transgenic mice with spontaneous optic neuritis [3], [4]. In the chronic MOG-induced rat EAE however, retinal ganglion cell loss precedes inflammation [5]. These EAE studies suggest that mechanisms of retinal ganglion cell loss in MS can be heterogeneous with contributions from inflammation-dependent and inflammation-independent neurodegenerative pathways [4]. Neurodegeneration is prominent in the progressive phases of MS and is only partially affected by current MS therapies. Currently, one of the pressing research challenges in MS is the development of a sensitive surrogate marker for neurodegeneration suitable for use as an outcome measure in clinical trials of neuroprotective and reparative therapies.

Optical coherence tomography (OCT) is a simple, non-invasive, high-resolution technique that uses near infrared light to quantify the retinal nerve fiber layer thickness [6]. The RNFL contains non-myelinated ganglion cell axons that comprise the optic nerves, chiasm, and optic tracts. OCT is a reliable and objective technique for capturing loss of retinal ganglion cell axons in early glaucoma and in other forms of optic neuropathy [7], [8].

Axonal densities are reduced in the optic nerves and optic tracts of MS patients compared with age-matched control subjects at autopsy (30–45% fewer axons in MS) [9]. Losses of axons in the pregeniculate afferent visual pathways, however, are generally not well captured by conventional biological markers of atrophy, such as MRI [10]. Several studies have applied OCT assessment of the RNFLT to patients with optic neuritis and MS. OCT is able to detect axonal changes in the affected eye three to six months following an episode of acute optic neuritis [11]. In a small pilot study (n = 14), reductions in overall peripapillary RNFLT were noted in eyes with a history of acute optic neuritis, but were also present in contralateral non-optic neuritis eyes of MS patients [12]. RNFLT measurements in MS patients without any history of optic neuritis in either eye were also reduced compared to disease free controls [13], suggesting sub-clinical disease activity. In MS patients, a decrease in RNFLT has been correlated with low whole field visual evoked potential amplitude, which measures axonal loss [14]. Higher EDSS scores also are significantly associated with reduction of overall RNFLT [13]. In patients with a history of an isolated episode of ON, with or without MS, Trip et al. demonstrated that decreased RNFLT is correlated with atrophy of the optic nerve on MRI [15]. A decrease in RNFLT has been correlated with clinical measures of lower visual function scores using low-contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli–Robson charts). Worse scores on low-contrast letter acuity and contrast sensitivity have also been associated with greater degrees of abnormality on magnetization transfer MRI imaging [16]. These studies suggest potential future utility of visual function and ocular imaging techniques as surrogate markers in MS.

MRI is currently the standard tool for disease activity, inflammation and neurodegeneration in MS [17], [18]. However, MRI is costly and time consuming for frequent disease monitoring. The purpose of this study was to delineate the relationships between RNFLT obtained by OCT and brain MRI parameters of inflammation and atrophy in MS patients and to further confirm the usefulness of OCT as a surrogate marker of disease activity in MS.

Section snippets

Study population

A retrospective review of data was performed for thirty consecutive patients with a confirmed history of clinically definite (CD) MS diagnosed according to McDonald criteria [19] from the Baird Multiple Sclerosis Center, Buffalo, NY, evaluated during a 9-month period by the same neuro-ophthalmologist (NL). All the patients had relapsing MS; patients with Devic's neuromyelitis optica and vasculitis were excluded. The EDSS was scored by a neurologist with expertise in MS at the time of a routine

Patient characteristics

The demographic and clinical characteristics of our patient population are summarized in Table 1. Thirty patients with CD MS underwent OCT exams; 21 of these patients also had a history of optic neuritis, 13 unilateral and 8 bilateral. The demographic and clinical characteristics of the cohort are summarized in Table 1. The clinical, demographic, OCT and history of optic neuritis characteristics of the subset of patients with MRI were similar to the larger group. The visual acuity and RNFLT

Discussion

In this report, we have presented data that suggest that RNFLT assessed by OCT is strongly associated with the brain atrophy (NBV and NWMV) and lesion MRI parameters (T2-LV). These promising findings highlight the potential usefulness of RNFLT in MS.

Our study was limited by its small sample size and retrospective study design but despite these significant constraints, strong associations between RNFLT and key MRI measures were observed. Based on the absence of myelination in the retinal nerve

Acknowledgement

Barbara Teter Ph.D., MPH for statistical review. Director of Clinical Research and Development, New York State Multiple Sclerosis Consortium, Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203.

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