Thickness of Retinal Nerve Fiber Layer Correlates with Disease Duration in Parallel with Corticospinal Tract Dysfunction in Untreated Multiple Sclerosis

INTRODUCTION In multiple sclerosis (MS), both inflammatory demyelination and axonal loss in gray and white matter are observed early, even presymptomatically [1]. These losses lead to central nervous system (CNS) atrophy [2] and functional disability [3]. Standard outcome measures of relapse rate and magnetic resonance imaging (MRI) lesion load neither correlate well with functional decline nor reflect CNS neurodegeneration [4-5]. Optical coherence tomography (OCT) is under evaluation as an outcome measure of axonal degeneration for use in clinical trials and practice [6]. OCT is a noninvasive technique that uses infrared laser light to create cross-sectional images of the retina; this technique provides quantitative analysis of the retinal nerve fiber layer (RNFL) thickness (RNFLt), macular thickness, and macular volume. The mechanism and reliability of OCT are well described [7]. OCT detects changes in the RNFL, which contains unmyelinated axons subject to damage in glaucomatous and ischemic optic neuropathies [8]; more recently, OCT has been applied to optic neuritis (ON) [9]. Short-term follow-up studies after acute ON demonstrate an acute decrement of the peripapillary RNFLt that plateaus by 3 to 6 months [10]. OCT also detects changes in the macula after ON [11]. The calculated macular volume includes the inner macular thickness, which contains the retinal ganglion cells presumably affected after ON by a dying-back axonopathy, as seen in animal models [12]. Alternatively or additionally, primary neuronal degeneration may affect the retinal ganglion cells. OCT has been shown to correlate with functional optic nerve measures such as multifocal visual-evoked potentials [13] and low-contrast visual acuity (LCVA) [14]. As one of the longer white matter tracts in the CNS, the optic nerve is likely to show the effects of both acute inflammation and neurodegeneration early in MS. ON is the presenting symptom of MS in 25 to 50 percent of cases and eventually affects up to 80 percent of patients during the illness, causing significant morbidity [15]. RNFLt in subjects with MS without a history of ON is lower than in control subjects, indicating subclinical axonal loss [9,16]. Thus, OCT is an attractive candidate measure for capturing early changes in MS. The corticospinal tract is another long CNS white matter tract frequently affected in MS. Like the optic nerve, it is subject both to acute inflammation in the form of transverse myelitis and to neurodegeneration as seen by increasing gait dysfunction, MRI atrophy [2], and recently, gray matter demyelination on high-field MRI [17]. The Expanded Disability Status Scale (EDSS) is a standard measure of gait dysfunction and may correlate with other long tract signs, including RNFL loss and cognitive dysfunction [18], although it poorly predicts longterm disability [19] and its validity in relapsing-remitting MS (RRMS) has been recently challenged [20]. OCT may provide a more sensitive research and clinically applicable measure to capture neurodegeneration in MS. Most studies using OCT have not accounted for the effects of disease-modifying therapies (DMTs) on the RNFL, which may be significant if similar to DMT effects in early MS [21]. We studied OCT in subjects with MS of varying disease durations and with no exposure to DMTs to test the hypothesis that in untreated MS, RNFLt loss occurs both over the course of disease and in parallel with corticospinal tract dysfunction reflecting CNS neurodegeneration. METHODS Subjects The institutional review board approved all study procedures, and subjects gave their written informed consent. We recruited subjects over 18 years of age from the Thomas Jefferson University Comprehensive MS Center (Philadelphia, Pennsylvania) and the Neuro-Ophthalmology Service at Wills Eye Institute (Philadelphia, Pennsylvania) with no exposure to DMT. Subjects met revised McDonald criteria for MS [22]. …