Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities

Kalteniece, Alise; Ferdousi, Maryam; Adam, Safwaan; Schofield, Jonathan; Azmi, Shazli; Petropoulos, Ioannis N.; Soran, Handrean; Malik, Rayaz A.

doi:10.1371/journal.pone.0183040

Cited by 99 publications

(89 citation statements)

References 22 publications

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“…To assess this, we used in vivo corneal confocal microscopy (CCM) to quantify corneal nerve morphology as an objective imaging end point for the extent of neurologic disease in FRDA. [12][13][14][15][16][17][18] The data demonstrate that quantification of corneal nerve morphology using CCM correlates well with the GAA repeat length, and SARA and FARS scores, supporting the concept that CCM can be used as a noninvasive, objective imaging biomarker to quantify neurologic deficits in FRDA.…”

supporting

confidence: 53%

“…Healthy matched subjects were identified by advertisements. Written informed consent was obtained under Age at 1st symptom, yr N/A 11.5 ± 5.0 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) Age at diagnosis, yr N/A 14.7 ± 6.5 Duration from 1st symptom, yr N/A 13.0 ± 5.2 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) Duration from diagnosis, yr N/A 10.0 ± 5.4 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)…”

Section: Study Populationmentioning

confidence: 99%

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Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Pagovich

Zhao

et al. 2018

Annals of Neurology

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Objective: Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding for the mitochondrial protein frataxin, is characterized by ataxia and gait instability, immobility, and eventual death. We evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, noninvasive, in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. Methods: Corneal nerve fiber density, branch density, and fiber length were quantified in individuals with FRDA (n = 23) and healthy age-matched controls (n = 14). All individuals underwent genetic testing and a detailed neurological assessment with the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich's Ataxia Rating Scale (FARS). A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment. Results: CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameter-generated equations that predict the neurologic severity of FRDA. Interpretation: Together, the data suggest that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA. ANN NEUROL 2018;84:893-904 F riedreich ataxia (FRDA), an inherited autosomal recessive disorder with an incidence of 1:50,000 in the Caucasian population, is characterized by progressive ataxia, gait instability, immobility, and eventual death. 1,2 FRDA is caused by a guanine-adenine-adenine (GAA) trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which causes epigenetic silencing of the FXN gene and decreases levels of FXN mRNA. 2 The resulting deficiency of FXN protein causes an imbalance of iron homeostasis in the mitochondria, with increased oxygen radical production and oxidative stress. 3 FRDA is characterized by spinocerebellar ataxia, dysarthria, pyramidal weakness, sensory loss, optic atrophy, hypertrophic cardiomyopathy, and diabetes mellitus. 1,4 The onset of FRDA is usually between the ages of 10 and 15 years, leading to wheelchair dependence and premature death by the 4th decade. 4,5 The recent focus on disease-modifying therapies for FRDA has highlighted the need for validated biomarkers of disease progression. 6,7 The current standards to assess FRDA disease severity are the two clinical scales Friedreich's Ataxia Rating Scale (FARS) 8,9 and Scale for the Assessment and Rating of Ataxia (SARA). 10 Based on a body of literature demonstrating the presence of a distal axonopathy and abnormal quantitative sensory thresholds in FRDA, indicative of unmyelinated nerve fiber pathology, 11 we hypothesized that quantification of View this article online at wileyonlinelibrary.com.

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confidence: 53%

Section: Study Populationmentioning

confidence: 99%

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Pagovich

Zhao

et al. 2018

Annals of Neurology

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“…51 Additionally, the application of a standardized approach as in the current study has recently been shown to have high intra-and interobserver reproducibility for all corneal nerve parameters. 52 We observed that there are focal losses in GCC volume (GCC FLV) in the macular area in very mild and mild NPDR in the presence of comparatively normal GCC and RNFL thickness. GCC FLV is similar in concept to pattern standard deviation of the Humphrey visual fields test, which indicates the local depressions and potholes in the entire GCC map after correcting for the overall depression of the topography of GCC thickness map.…”

Section: Discussionmentioning

confidence: 67%

Corneal and Retinal Neuronal Degeneration in Early Stages of Diabetic Retinopathy

Srinivasan

Dehghani

Pritchard

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To examine the neuronal structural integrity of cornea and retina as markers for neuronal degeneration in nonproliferative diabetic retinopathy (NPDR).METHODS. Participants were recruited from the broader Brisbane community, Queensland, Australia. Two hundred forty-one participants (187 with diabetes and 54 nondiabetic controls) were examined. Diabetic retinopathy (DR) was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), corneal nerve fiber tortuosity (CNFT), full retinal thickness, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), focal (FLV) and global loss volumes (GLV), hemoglobin A 1c (HbA 1c ), nephropathy, neuropathy, and cardiovascular measures were examined.RESULTS. The central zone (P ¼ 0.174), parafoveal thickness (P ¼ 0.090), perifovea (P ¼ 0.592), RNFL (P ¼ 0.866), GCC (P ¼ 0.798), and GCC GLV (P ¼ 0.338) did not differ significantly between the groups. In comparison to the control group, those with very mild NPDR and those with mild NPDR had significantly higher focal loss in GCC volume (P ¼ 0.036). CNFL was significantly lower in those with mild NPDR (P ¼ 0.004) in comparison to the control group and those with no DR. The CNBD (P ¼ 0.094) and CNFT (P ¼ 0.458) did not differ between the groups.CONCLUSIONS. Both corneal and retinal neuronal degeneration may occur in early stages of diabetic retinopathy. Further studies are required to examine these potential markers for neuronal degeneration in the absence of clinical signs of DR.

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“…Images were selected by a single expert in a masked fashion taking into account the quality, depth, and variability using an established protocol. 10,19 We quantified five corneal nerve parameters: corneal nerve fiber density (CNFD: total number of main nerves per square millimeter) (no./mm 2 ), corneal nerve branch density (CNBD: total number of branches per square millimeter) (mm/mm 2 ), corneal nerve fiber length (CNFL: total length of main nerves and nerve branches per square millimeter) (mm/mm 2 ), inferior whorl length (IWL: total length of nerves per square millimeter) (mm/mm 2 ), and average nerve fiber length (ANFL = CNFL + IWL/2) (mm/mm 2 ).…”

Section: Corneal Nervesmentioning

confidence: 99%

Diabetic Neuropathy Is Characterized by Progressive Corneal Nerve Fiber Loss in the Central and Inferior Whorl Regions

Ferdousi

Kalteniece

Petropoulos

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose We hypothesized that longitudinal changes in corneal nerve morphology would differ between the central cornea and inferior whorl in relation to other measures of diabetic neuropathy. Methods Thirty patients with diabetes (age: 54.08 ± 15.86, duration: 23.95 ± 14.2, HbA1c: 7.51 ± 1.37) and 19 age-matched healthy controls (age: 49.47 ± 13.25) underwent assessment of neuropathy disability score (NDS), vibration perception threshold (VPT), cold (CPT) and warm (WPT) perception thresholds, peroneal motor nerve conduction velocity (PMNCV), corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), inferior whorl length (IWL), and the average of CNFL and IWL (ANFL) at baseline and after 1 to 8 years. Results In patients with diabetes, between baseline and follow-up, there was a significant reduction in CNBD (57.72 ± 30.08 vs. 44.04 ± 23.69; P = 0.02), CNFL (21.77 ± 5.19 vs. 15.65 ± 4.7; P < 0.0001), IWL (24.69 ± 8.67 vs. 14.23 ± 6.13; P < 0.0001), ANFL (23.26 ± 5.53 vs. 15.09 ± 4.48; P < 0.0001), and WPT (43.56 ± 4.43 vs. 40.78 ± 4.93; P = 0.01), and an increase in VPT (12.9 ± 8.96 vs. 13.78 ± 8.99; P = 0.02). There was no significant change in CNFD (27.12 ± 8.2 vs. 25.43 ± 7.11; P = 0.2), NDS (3.38 ± 3.35 vs. 2.61 ± 2.8; P = 0.08), CPT (17.7 ± 10.59 vs. 22.45 ± 9.23; P = 0.06), or PMNCV (42.4 ± 4.21 vs. 42.16 ± 6.3; P = 0.2). Conclusions There is evidence of corneal nerve loss in patients with diabetes, particularly at the inferior whorl during follow-up.

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Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities

Cited by 99 publications

References 22 publications

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Corneal and Retinal Neuronal Degeneration in Early Stages of Diabetic Retinopathy

Diabetic Neuropathy Is Characterized by Progressive Corneal Nerve Fiber Loss in the Central and Inferior Whorl Regions

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