Corneal axonal loss as an imaging biomarker of neurodegeneration in multiple sclerosis: a longitudinal study

Abstract

Background: Resourceful endpoints of axonal loss are needed to predict the course of multiple sclerosis (MS). Corneal confocal microscopy (CCM) can detect axonal loss in patients with clinically isolated syndrome and established MS, which relates to neurological disability. Objective: To assess corneal axonal loss over time in relation to retinal atrophy, and neurological and radiological abnormalities in MS. Methods: Patients with relapsing-remitting (RRMS) ( n = 68) or secondary progressive MS (SPMS) ( n = 15) underwent CCM and optical coherence tomography. Corneal nerve fibre density (CNFD-fibres/mm2), corneal nerve branch density (CNBD-branches/mm2), corneal nerve fibre length (CNFL-mm/mm2) and retinal nerve fibre layer (RNFL-μm) thickness were quantified along with neurological and radiological assessments at baseline and after 2 years of follow-up. Age-matched, healthy controls ( n = 20) were also assessed. Results: In patients with RRMS compared with controls at baseline, CNFD ( p = 0.004) and RNFL thickness ( p < 0.001) were lower, and CNBD ( p = 0.003) was higher. In patients with SPMS compared with controls, CNFD ( p < 0.001), CNFL ( p = 0.04) and RNFL thickness ( p < 0.001) were lower. For identifying RRMS, CNBD had the highest area under the receiver operating characteristic (AUROC) curve (0.99); and for SPMS, CNFD had the highest AUROC (0.95). At follow-up, there was a further significant decrease in CNFD ( p = 0.04), CNBD ( p = 0.001), CNFL ( p = 0.008) and RNFL ( p = 0.002) in RRMS; in CNFD ( p = 0.04) and CNBD ( p = 0.002) in SPMS; and in CNBD ( p = 0.01) in SPMS compared with RRMS. Follow-up corneal nerve loss was greater in patients with new enhancing lesions and optic neuritis history. Conclusion: Progressive corneal and retinal axonal loss was identified in patients with MS, especially those with more active disease. CCM may serve as an imaging biomarker of axonal loss in MS.

Corneal immune cells as a biomarker of inflammation in multiple sclerosis: a longitudinal study

“…This study was originally powered to detect differences in corneal nerve morphology in patients with MS compared to controls. 28 Post hoc power calculation using univariate analysis of variance with…”

“…38 We and others previously demonstrated significant corneal axonal loss in MS, [15][16][17][18][19][20][21] which correlated with neurological disability and progressed over time. 16,28 Apart from axons, the cornea also contains corneal ICs, which are immature dendritic cells (MHC-class II, CD80 negative, and/or CD86 negative). These cells act as antigen-presenting cells and form part of the innate immune system.…”

“…This study was originally powered to detect differences in corneal nerve morphology in patients with MS compared to controls. 28 Post hoc power calculation using univariate analysis of variance with baseline DCP as the dependent variable and patient status as the fixed factor showed that a sample of n = 80 participants (effect size = 0.17, p < 0.001) provides 97.8% power with alpha = 0.05. Continuous data were tested for normality using a Shapiro–Wilk test ( p > 0.05) and relevant histograms (Q–Q plots).…”

“… 27 In MS, Bitirgen et al first showed increased dendritic cell density in patients with relapsing-remitting MS (RRMS), 15 with a significant increase in patients with worsening disability at follow-up. 16 , 28 Khan et al 29 demonstrated increased corneal IC density in patients with RRMS, to a lesser extent in secondary progressive MS (SPMS) and clinically isolated syndrome, and showed an association with cognitive function and neurological disability. In the present study, we have prospectively assessed alterations in corneal IC density in relation to corneal and retinal axonal morphology, disease-modifying treatment, MRI abnormality, and neurological disability.…”

Spinal muscular atrophy: are small sensory fibres involved?

“…In Parkinson's disease corneal nerve loss is associated with autonomic and motor disability, and more rapid motor deterioration at follow‐up [3]. In multiple sclerosis reduced corneal nerve density underpins both relapsing–remitting and primary and secondary progressive subtypes and has been associated with neurological disability and central inflammatory activity [4]. Corneal nerve loss occurs in patients with mild cognitive impairment and dementia, is related to cognitive dysfunction and functional independence and predicts conversion to dementia in subjects with mild cognitive impairment [5].…”