Optimal Image Sample Size for Corneal Nerve Morphometry

Vagenas, Dimitrios; Pritchard, Nicola; Edwards, Katie; Shahidi, Ayda M.; Sampson, Geoff P.; Russell, Anthony; Malik, Rayaz A.; Efron, Nathan

doi:10.1097/opx.0b013e31824ee8c9

Cited by 116 publications

(108 citation statements)

References 15 publications

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“…38 They found that the average value of eight standard images would provide a mean that would be approximately within 20% of true mean of the 16-image value 80% of the time and that 5 images were within 30% of true mean of the 16-image value 95% of the time. 38 Therefore, although there is a regional variation in subbasal nerve distribution, 25,39 it does not hinder the use of three-set standard images for measuring the nerve density. In contrast, the higher relative variation in measuring DC density in standard images in our study may reflect a more uneven distribution of DCs across the central cornea, possibly due to regional variation in corneal immune responses.…”

Section: Discussionmentioning

confidence: 98%

“…In a recent study on 20 subjects with diabetes, Vagenas and colleagues 38 compared the accuracy of the nerve density calculated from 2 to 15 randomly selected standard IVCM images from the central cornea to that of 16 standard images. 38 They found that the average value of eight standard images would provide a mean that would be approximately within 20% of true mean of the 16-image value 80% of the time and that 5 images were within 30% of true mean of the 16-image value 95% of the time. 38 Therefore, although there is a regional variation in subbasal nerve distribution, 25,39 it does not hinder the use of three-set standard images for measuring the nerve density.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy

Kheirkhah

Müller

Mikolajczak

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To evaluate whether the densities of corneal subbasal nerves and epithelial immune dendritiform cells (DCs) are comparable between a set of three representative standard images of in vivo confocal microscopy (IVCM) and the wide-field mapped composite IVCM images.METHODS. This prospective, cross-sectional, and masked study included 110 eyes of 58 patients seen in a neurology clinic who underwent laser-scanning IVCM (Heidelberg Retina Tomograph 3) of the central cornea. Densities of subbasal corneal nerves and DCs were compared between the average of three representative standard images and the wide-field mapped composite images, which were reconstructed by automated mapping.RESULTS. There were no statistically significant differences between the average of three representative standard images (0.16 mm 2 each) and the wide-field composite images (1.29 6 0.64 mm 2 ) in terms of mean subbasal nerve density (17.10 6 6.10 vs. 17.17 6 5.60 mm/mm 2 , respectively, P ¼ 0.87) and mean subbasal DC density (53.2 6 67.8 vs. 49.0 6 54.3 cells/mm 2 , respectively, P ¼ 0.43). However, there were notable differences in subbasal nerve and DC densities between these two methods in eyes with very low nerve density or very high DC density.CONCLUSIONS. There are no significant differences in the mean subbasal nerve and DC densities between the average values of three representative standard IVCM images and wide-field mapped composite images. Therefore, these standard images can be used in clinical studies to accurately measure cellular structures in the subbasal layer.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy

Kheirkhah

Müller

Mikolajczak

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Images of the central corneal subbasal nerve plexus were captured using a CCM (Heidelberg Retinal Tomograph III with Rostock Cornea Module; Heidelberg Engineering GmbH, Heidelberg, Germany), after anesthetizing the cornea. CNFL was determined by analyzing eight of the clearest images using semiautomated software (19). The corneal sensation threshold was measured using a custom-made NCCE (6).…”

Section: Methodsmentioning

confidence: 99%

Corneal Confocal Microscopy Predicts 4-Year Incident Peripheral Neuropathy in Type 1 Diabetes

et al. 2015

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OBJECTIVEThis study determined if deficits in corneal nerve fiber length (CNFL) assessed using corneal confocal microscopy (CCM) can predict future onset of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODSCNFL and a range of other baseline measures were compared between 90 nonneuropathic patients with type 1 diabetes who did or did not develop DPN after 4 years. The receiver operator characteristic (ROC) curve was used to determine the capability of single and combined measures of neuropathy to predict DPN. RESULTSDPN developed in 16 participants (18%) after 4 years. Factors predictive of 4-year incident DPN were lower CNFL (P = 0.041); longer duration of diabetes (P = 0.002); higher triglycerides (P = 0.023); retinopathy (higher on the Early Treatment of Diabetic Retinopathy Study scale) (P = 0.008); nephropathy (higher albumin-tocreatinine ratio) (P = 0.001); higher neuropathy disability score (P = 0.037); lower cold sensation (P = 0.001) and cold pain (P = 0.027) thresholds; higher warm sensation (P = 0.008), warm pain (P = 0.024), and vibration (P = 0.003) thresholds; impaired monofilament response (P = 0.003); and slower peroneal (P = 0.013) and sural (P = 0.002) nerve conduction velocity. CCM could predict the 4-year incident DPN with 63% sensitivity and 74% specificity for a CNFL threshold cutoff of 14.1 mm/mm 2 (area under ROC curve = 0.66, P = 0.041). Combining neuropathy measures did not improve predictive capability. CONCLUSIONS DPN can be predicted by various demographic, metabolic, and conventional neuropathy measures. The ability of CCM to predict DPN broadens the already impressive diagnostic capabilities of this novel ophthalmic marker.Diabetic peripheral neuropathy (DPN) can result in pain, foot ulceration, and lower extremity amputation (1). Unmyelinated nerve fibers can now be examined at approximately original magnification 3500 using a laser scanning corneal confocal microscope (CCM) to image the subbasal nerve plexus of the human cornea in vivo (2). This approach has been validated as a viable alternative for assessing DPN (3-5). Increased severity of DPN is associated with reduced corneal nerve fiber length (CNFL) (4,5) and corneal sensitivity (6,7), assessed using CCM and noncontact corneal esthesiometry (NCCE), respectively.

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“…Previous works have also looked at its sensitivity and specificity for the diagnosis of DSPN (10,11), including comparison with IENFD (12). However, the vast majority of previous studies using CCM in diabetic patients have analyzed relatively small image frames of 0.15 mm 2 , which may not be representative of larger corneal areas (13). As possible solutions, multiple nonoverlapping image frames per patient or larger mosaic images generated from image sequences have both been proposed (13,14).…”

Section: Diagnosis Of Diabetic Sensorimotor Polyneuropathy (Dspn)mentioning

confidence: 99%

“…However, the vast majority of previous studies using CCM in diabetic patients have analyzed relatively small image frames of 0.15 mm 2 , which may not be representative of larger corneal areas (13). As possible solutions, multiple nonoverlapping image frames per patient or larger mosaic images generated from image sequences have both been proposed (13,14). Moreover, image assessment has been hampered by the presence of ridge-like tissue deformations in the neighborhood of the SNP and image distortions.…”

Section: Diagnosis Of Diabetic Sensorimotor Polyneuropathy (Dspn)mentioning

confidence: 99%

Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

et al. 2014

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We sought to determine whether early nerve damage may be detected by corneal confocal microscopy (CCM), skin biopsy, and neurophysiological tests in 86 recently diagnosed type 2 diabetic patients compared with 48 control subjects. CCM analysis using novel algorithms to reconstruct nerve fiber images was performed for all fibers and major nerve fibers (MNF) only. Intraepidermal nerve fiber density (IENFD) was assessed in skin specimens. Neurophysiological measures included nerve conduction studies (NCS), quantitative sensory testing (QST), and cardiovascular autonomic function tests (AFTs). Compared with control subjects, diabetic patients exhibited significantly reduced corneal nerve fiber length (CNFL-MNF), fiber density (CNFD-MNF), branch density (CNBD-MNF), connecting points (CNCP), IENFD, NCS, QST, and AFTs. CNFD-MNF and IENFD were reduced below the 2.5th percentile in 21% and 14% of the diabetic patients, respectively. However, the vast majority of patients with abnormal CNFD showed concomitantly normal IENFD and vice versa. In conclusion, CCM and skin biopsy both detect nerve fiber loss in recently diagnosed type 2 diabetes, but largely in different patients, suggesting a patchy manifestation pattern of small fiber neuropathy. Concomitant NCS impairment points to an early parallel involvement of small and large fibers, but the precise temporal sequence should be clarified in prospective studies.

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Optimal Image Sample Size for Corneal Nerve Morphometry

Abstract: The "sample combination analysis" presented here can be used to determine the sample size required for a desired level of accuracy of quantification of corneal subbasal nerve parameters. This technique may have applications in other biological sampling studies.

Cited by 116 publications

References 15 publications

Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy

Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy

Corneal Confocal Microscopy Predicts 4-Year Incident Peripheral Neuropathy in Type 1 Diabetes

Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

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