Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis

Abstract

IMPORTANCE Multiple sclerosis (MS) is characterized by demyelination, axonal degeneration, and inflammation. Corneal confocal microscopy has been used to identify axonal degeneration in several peripheral neuropathies.OBJECTIVE To assess corneal subbasal nerve plexus morphologic features, corneal dendritic cell (DC) density, and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with MS. DESIGN, SETTING, AND PARTICIPANTSThis single-center, cross-sectional comparative study was conducted at a tertiary referral university hospital between May 27, 2016, and January 30, 2017. Fifty-seven consecutive patients with relapsing-remitting MS and 30 healthy, age-matched control participants were enrolled in the study. Corneal subbasal nerve plexus measures and DC density were quantified in images acquired with the laser scanning in vivo corneal confocal microscope, and peripapillary RNFL thickness was measured with spectral-domain optical coherence tomography. MAIN OUTCOMES AND MEASURESCorneal nerve fiber density, nerve branch density, nerve fiber length, DC density, peripapillary RNFL thickness, and association with the severity of neurologic disability as assessed by the Kurtzke Expanded Disability Status Scale (score range, 0-10; higher scores indicate greater disability) and Multiple Sclerosis Severity Score (score range, 0.01-9.99; higher scores indicate greater severity). RESULTSOf the 57 participants with MS, 42 (74%) were female and the mean (SD) age was 35.4 (8.9) years; of the 30 healthy controls, 19 (63%) were female and the mean (SD) age was 34.8 (10.2) years. Corneal nerve fiber density (mean [SE] difference, −6.78 [2.14] fibers/mm 2 ; 95% CI, −11.04 to −2.52; P = .002), nerve branch density (mean [SE] difference, branches/mm 2 ; 95% CI, −28.77 to −7.10; P = .001), nerve fiber length (mean [SE] difference, −3.03 [0.89] mm/mm 2 ; 95% CI, −4.81 to −1.25; P = .001), and the mean peripapillary RNFL thickness (mean [SE] difference, −17.06 [3.14] μm; 95% CI, −23.29 to −10.82; P < .001) were reduced in patients with MS compared with healthy controls. The DC density was increased (median [interquartile range], 27.7 [12.4-66.8] vs 17.3 [0-28.2] cells/mm 2 ; P = .03), independent of a patient's history of optic neuritis. Nerve fiber density and RNFL thickness showed inverse associations with the Expanded Disability Status Scale (ρ = −0.295; P = .03 for nerve fiber density and ρ = −0.374; P = .004 for RNFL thickness) and the Multiple Sclerosis Severity Score (R = −0.354; P = .007 for nerve fiber density and R = −0.283; P = .03 for RNFL thickness), whereas other study measures did not.CONCLUSIONS AND RELEVANCE These data suggest that corneal confocal microscopy demonstrates axonal loss and increased DC density in patients with MS. Additional longitudinal studies are needed to confirm the use of corneal confocal microscopy as an imaging biomarker in patients with MS.

Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome

“…The number of immune cell infiltrates was also higher in CIDP patients compared to controls and decreased with disease duration; further, cell counts positively correlated with the degree of motor impairment . In patients with multiple sclerosis, CNFD, CNFL, and CNBD were lower than in healthy controls, whereas the density of dendritic cells was higher in the patient group . Examining patients with diabetes mellitus with and without neuropathy in comparison to healthy controls, lower CNFD, CNFL, and CNBD, and higher nerve fiber tortuosity and LC density were found .…”

“…The impact of small nerve fiber impairment on FMS symptoms remains elusive. Reduction of corneal innervation was found in patients with painful (ie, herpes zoster ophthalmicus) and painless (ie, inflammatory and diabetic neuropathy, multiple sclerosis) neurological diseases paralleled by an increase in corneal Langerhans cell (LC) density and LC‐nerve fiber contact. Integrity of the corneal sub‐basal nerve plexus is regulated by interactions between immune cells and nerve fiber endings .…”

Small‐fiber neuropathy: Expanding the clinical pain universe

“…64 CCM has been used to detect small-fiber damage in other neurological diseases, such as Fabry disease, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth type 1A, and multiple sclerosis. [65][66][67][68] Conversely, research on patients with Parkinson showed an increase in CNBD and CNFL. 41 2.5 | Assessment of the function of small nerve fibers 2.5.1 | Quantitative sensory testing QST is a non-invasive psychophysical method that quantifies the thresholds of sensory perception carried by large and small nerve fibers.…”

“…CCM has been used to detect small‐fiber damage in other neurological diseases, such as Fabry disease, chronic inflammatory demyelinating polyneuropathy, Charcot‐Marie‐Tooth type 1A, and multiple sclerosis . Conversely, research on patients with Parkinson showed an increase in CNBD and CNFL …”

Ocular Biomarkers of Alzheimer's Disease: The Role of Anterior Eye and Potential Future Directions

“…A more recent study also revealed even preclinical small nerve neuropathy in newly diagnosed PD patients. 75 Significant reduction in total corneal nerve fiber density, which was associated with clinical severity 76 and reduced corneal nerve measures and increased dendritic cell density in patients with multiple sclerosis, 77 has been described in recent CCM studies.…”