Association of Retinal Architecture, Intrathecal Immunity, and Clinical Course in Multiple Sclerosis

Abstract

IMPORTANCE Biomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.OBJECTIVE To assess whether retinal layer volumes are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS This observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration [cohort 1] and 240 patients with longer disease duration [cohort 2]) treated at a single German university hospital from April 15, 2013, through November 11, 2015. MAIN OUTCOMES AND MEASURESThe common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.RESULTS A total of 312 patients (212 women [67.9%] and 100 men [32.1%]; median age, 34.0 years [interquartile range (IQR), 28.0-42.0 years]) were available for analysis. In cohort 1 (50 women [69.4%] and 22 men [30.6%]; median age, 31.0 years [IQR,3 years]), with short disease durations (median, 1.0 months [IQR, 1.0-2.0 months]), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% [IQR, 1.45%-4.20%]) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 [IQR,). The INL volumes correlated with the frequencies of intrathecal CD56 bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm 3 ) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women [67.5%] and 78 men [32.5%]; median age, 34.0 years [IQR, 29.0-42.0 years]) consisting of patients with longer disease durations (median, 36.0 months [IQR, 21.0-60.0 months]) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.CONCLUSIONS AND RELEVANCE Retinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.

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

“…In our study, it was found that patients with pRNFL thickness and GCIP volume loss were at higher risk for clinical conversion to MS. 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].…”

“…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].…”

“…For statistical analyses, GraphPad Prism 7 (San Diego, CA, USA) and R v3.5.3 (Vienna, Austria) with the package survival v2.44-1 were used. To account for inter-eye correlations of OCT measurements within each patient, a paired-eye statistical approach was used [21] as previously described [22]. Mean values of both eyes were calculated and used as one individual data point when both eyes were available for longitudinal analysis.…”

Optical coherence tomography in multiple sclerosis

“…Bsteh et al [40] observed that having a RNFL thickness below 88 μm was independently associated with a threefold increased risk of EDSS progression (p < 0.001) and a 2.7-fold increased risk of cognitive decline (p < 0.001) within the following 3 years. A different study observed that MS patients with low GCIPL volumes had a 6.4-fold increased risk of disability worsening within the following three years [11].…”

“…Knier et al observed an association between low GCIPL volumes and increased intrathecal B-cell frequencies and intrathecal IgG synthesis [11].…”