Free
Cornea  |   July 2013
Effect of Panretinal Photocoagulation on Corneal Sensation and the Corneal Subbasal Nerve Plexus in Diabetes Mellitus
Author Notes
  • Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 
  • Correspondence: Charles N. J. McGhee, Department of Ophthalmology, Private Bag 92019, University of Auckland, Auckland, New Zealand; c.mcghee@auckland.ac.nz
Investigative Ophthalmology & Visual Science July 2013, Vol.54, 4485-4490. doi:10.1167/iovs.12-10571
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Stuti Misra, Ha Na Ahn, Jennifer P. Craig, Monika Pradhan, Dipika V. Patel, Charles N. J. McGhee; Effect of Panretinal Photocoagulation on Corneal Sensation and the Corneal Subbasal Nerve Plexus in Diabetes Mellitus. Invest. Ophthalmol. Vis. Sci. 2013;54(7):4485-4490. doi: 10.1167/iovs.12-10571.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose.: To assess the effects of panretinal photocoagulation (PRP) for diabetic retinopathy (DR) on the human corneal subbasal nerve plexus (SBNP) and to investigate correlations between corneal subbasal nerve (SBN) density, corneal sensitivity, and diabetic peripheral neuropathy.

Methods.: Thirty-eight subjects with at least a 10-year history of diabetes mellitus (DM) or DR were included. Subjects were assigned to a PRP group (n = 19), having undergone a treatment of retinopathy in at least one eye or a non-PRP group (n = 19), with no history of PRP. The Michigan Neuropathy Screening Instrument (MNSI) was administered to enable quantification of neuropathic symptoms. Laser scanning in vivo confocal microscopy was performed to capture images of the corneal SBNP to allow determination of SBNP density. Central corneal sensitivity (CST) was evaluated by noncontact aesthesiometry and peripheral vibration perception threshold was measured with a biothesiometer.

Results.: Mean SBNP densities were 12.27 ± 4.28 mm/mm2 in the PRP group and 12.75 ± 3.59 mm/mm2 in the non-PRP group. There were no significant differences in SBNP density (P = 0.71), CST (P = 0.84), MNSI score (P = 0.19), and biothesiometry (P = 0.77) between the PRP and non-PRP groups. When data from both groups (n = 38) were combined, corneal sensitivity was modestly correlated with SBNP density (r = 0.30, P = 0.06), and peripheral biothesiometry (r = 0.26, P = 0.11).

Conclusions.: In DM correlation of corneal sensitivity, SBNP density, and peripheral biothesiometry may have a potential role in estimating the severity of peripheral neuropathy. Corneal SBNP density and sensitivity appear to be unaffected by PRP laser treatment compared with non-PRP diabetic eyes.

Introduction
The prevalence of diabetes mellitus (DM) is expected to increase from the 2010 global estimate of 220 million, to approximately 366 million by the year 2030, as projected by the World Health Organization (WHO) Global Burden of Disease Study. 1,2 In the United States alone, DM costs the government approximately $174 billion annually and, thus, diabetes will increasingly burden health care systems throughout the world. 3 Poorly controlled diabetes may lead to a range of systemic complications including nephropathy, cardiomyopathy, and peripheral neuropathy. 4 The ocular complications of DM are numerous and range from the minor to the visually debilitating, including: dry eye, diabetic keratopathy, orbital cellulitis, early onset cataract, rubeosis iridis, and diabetic retinopathy (DR). 510  
DR is one of the leading causes of blindness worldwide. 11 Important therapeutic measures in the management of DR include optimizing glycaemic, lipid, and hypertensive control. However, in cases of proliferative or severe preproliferative DR, laser panretinal photocoagulation (PRP) is indicated with the aim of preventing progression of DR and vision loss. 12 Although “sight-saving” and effective in the treatment of advanced diabetic retinal disease, PRP is fundamentally associated with extensive tissue destruction and underlying anatomical changes. 13,14  
Diabetic keratopathy can be associated with significant ocular complications 9 and decreased corneal sensitivity has been reported following PRP in diabetes. This has been attributed to direct thermal injury to ciliary nerves running between the choroid and sclera. 15,16 However, only one study has directly investigated the effects of PRP on corneal nerve microstructure. 17 The aim of this current study was to utilize in vivo confocal microscopy (IVCM) to investigate the effect of PRP on the subbasal nerve plexus (SBNP) in patients with DM, and to evaluate the relationship between corneal subbasal (SBN) nerve density, corneal sensitivity, and peripheral neuropathy. 
Materials and Methods
The study was conducted in the University of Auckland Research Unit, Department of Ophthalmology, Greenlane Clinical Centre, Auckland, New Zealand with ethical approval granted by the Regional Ethics Committee (NTX/09/12/122) and adhered to the tenets of the Declaration of Helsinki. Inclusion criteria were: a 10 or more year history of DM or the presence of any DR subjects with a history of ocular surgery or trauma; contact lens wear, or a history of corneal disease or systemic disease that may affect the cornea (other than DM) were excluded. The study was explained in detail and written consent to participate was obtained. 
Subjects were categorized into two groups according to their treatment history; the PRP group with a history of PRP at least 6 months previously, and the non-PRP group with no history of PRP. Subjects with recent PRP (<6 months) were excluded from the study. 
A detailed medical history was obtained from all subjects regarding duration of DM, known diabetic complications, comorbidities, medications, and smoking and alcohol history. A validated questionnaire (Michigan Neuropathy Screening Instrument [MNSI]) was administered to calculate the severity score of neuropathic symptoms. 18,19 The results of recent glycated hemoglobin (HbA1c) blood tests, performed within the preceding 3 months, were also recorded. Although fasting glucose remains a useful diagnostic criterion for DM, it only provides an instantaneous, single point, indication of glucose control. In contrast HbA1c gives an indication of the degree of control over the previous 3 months and is considered to be a major diagnostic criterion of DM. 20,21  
Central corneal sensitivity threshold (CST) was measured with a noncontact corneal aesthesiometer (NCCA). 22 After the stimulus was presented to the patient at a suprathreshold pressure for demonstration purposes, CST was determined by following a forced-choice double-staircase protocol. 23 Vibration perception threshold (VPT) of the feet was measured by biothesiometery (Bio-Medical Instrument Co., Newbury, OH), and VPT was also determined by forced-choice double-staircase technique. 24 The examination was performed at the medial malleolus, at the plantar and dorsal aspects of the distal interphalangeal (DIP) joint of the great toe of the foot ipsilateral to the examined eye. Digital images of the central and peripheral retina were captured with a nonmydriatic retinal camera (Non-Mydriatic Retinal Camera DR-DGi; Canon, Inc., Melville, NY) for DR grading. All retinal images were graded by a fellowship-trained medical retina specialist (MP). 
In vivo confocal microscopy using the corneal module of the Heidelberg Retina Tomograph (HRT II; Heidelberg Engineering GmbH, Heidelberg, Germany) was performed in the selected eye of each patient. 17 A drop of local anesthetic (Oxybuprocaine hydrochloride 0.4%; Chauvin Pharmaceuticals Ltd., Kingston, UK) was administered to both eyes and lubricating gel (Viscotears Carbomer; Novartis Pharmaceuticals Ltd., Surrey, UK) applied to the nonexamined eye to protect the ocular surface from drying during the examination. The participant was asked to fixate on a distant target aligned to enable examination of the central cornea, while images of the corneal SBNP were captured with the aid of the device's “section mode.” 
The examination took approximately 5 minutes to perform in each case and none of the participants experienced any visual or corneal sequelae as a result of examination. All examinations were performed by a single experienced examiner (SM). 
From the images showing well-focused nerves from the central cornea, six were randomly selected for each subject and the SBN density calculated in terms of length of nerves per millimeters squared of image area. 23 SBN density was analyzed by an independent observer (HA) using computer software (analySIS 3.1; Soft Imaging System, Münster, Germany). 23  
Statistical analysis was performed with SPSS 19.0 for Windows (Chicago, IL). On the basis of previously reported nerve fibre density data, a power calculation for this study (Statistical Solutions, LLC, Clearwater, FL) determined a minimum sample size of 10 in each group in order to detect a 5% difference in nerve density between the PRP and non-PRP groups, with 80% power and 95% confidence. An independent samples t-test was applied to compare patient characteristics of the PRP and non-PRP groups, and one-way ANOVA was performed to compare ocular and peripheral neuropathy features between the two groups. Bivariate Pearson correlation (two-tailed) was used to determine the correlations between a number of different factors. A P value of less than 0.05 was considered significant. A correlation coefficient (Pearson's r) of less than ±0.3 was considered weak; ±0.3 to ±0.6, was moderate; and greater than ±0.6, was strong. 25  
Results
Thirty-eight eyes of 38 participants with DM were enrolled for this study, of which 20 eyes had previously undergone PRP. Fifteen left eyes and 23 right eyes were assessed. There was no significant difference in the mean age, body mass index (BMI), current severity of retinopathy, and smoking and alcohol history between the PRP and non-PRP groups (Table 1). The mean duration of DM and HbA1c values were not significantly different between the two groups (Table 2). 
Table 1. 
 
Demographics Including Male:Female Ratio, Age, BMI, Smoking History, Alcohol Score, Ethnicity, Duration of DM (Years), and Type of DR (Subject Percentage Included) in Subjects With Retinopathy Treated by PRP and Untreated Retinopathy (Non-PRP) Group
Table 1. 
 
Demographics Including Male:Female Ratio, Age, BMI, Smoking History, Alcohol Score, Ethnicity, Duration of DM (Years), and Type of DR (Subject Percentage Included) in Subjects With Retinopathy Treated by PRP and Untreated Retinopathy (Non-PRP) Group
Groups t-test, P Values
PRP Non-PRP
Subjects, n 19 19
Male:female ratio 13:06 14:05
Age, y 57.0 ± 7.9 59.5 ± 14.2 0.50
BMI, kg/m2 29.6 ± 4.0 29.2 ± 5.1 0.78
Smoking history,
pack y
5.8 ± 12.1 4.4 ± 9.75 0.70
Alcohol score 2.20 ± 2.3 2.0 ± 2.6 0.75
Type 1:type 2 1:18 1:18
Mean DM duration, y 18.0 ± 10.4 13.6 ± 7.2
<10 2 4
10–20 11 13
>20 6 2
No active DR 0 (0%) 1 (5.3%)
Mild NPDR 0 (0%) 10 (52.6%)
Moderate NPDR 3 (15.8%) 2 (10.5%)
Severe NPDR 4 (21.1%) 5 (26.3%)
PDR 12 (63.2%) 1 (5.3%) -
Table 2. 
 
Comparison of SBN Density, HbA1c, Corneal Sensitivity, Michigan Neuropathy Symptomatic Score, and Beiothesiometry for Medial Malleolus (MM), Great Toe Plantar (GTP), and Great Toe Dorsal (GTD) of Patients With (n = 19) and Without (n = 19) a History of PRP
Table 2. 
 
Comparison of SBN Density, HbA1c, Corneal Sensitivity, Michigan Neuropathy Symptomatic Score, and Beiothesiometry for Medial Malleolus (MM), Great Toe Plantar (GTP), and Great Toe Dorsal (GTD) of Patients With (n = 19) and Without (n = 19) a History of PRP
PRP, Mean ± SD Non-PRP, Mean ± SD ANOVA, P Values
SBN density, mm/mm2 12.27 ± 4.28 12.75 ± 3.59 0.71
HbA1c, % 9.12 ± 1.89 8.56 ± 1.64 0.33
Corneal sensitivity, mBar 2.32 ± 2.23 2.46 ± 1.76 0.84
MNSI score 3.00 ± 2.60 2.10 ± 1.37 0.19
Biothesiometry - MM, V 27.15 ± 10.04 26.670 ± 8.89 0.77
Biothesiometry - GTP, V 20.21 ± 10.50 20.94 ± 8.62 0.81
Biothesiometry - GTD, V 19.630 ± 10.11 20.63 ± 8.59 0.71
The mean SBN densities were 12.27 ± 4.28 mm/mm2 in the PRP group and 12.75 ± 3.59 mm/mm2 in the non-PRP group. Representative subbasal nerve plexus images of the central cornea are illustrated in Figure 1. There were no significant differences between the PRP and the non-PRP groups in terms of SBN density (P = 0.71), CST (P = 0.84), MNSI score (P = 0.19), and biothesiometry (P = 0.77, Table 2). 
Figure 1
 
(a) A representative laser scanning in vivo confocal image of the central cornea showing SBNs in a healthy eye. (b) Visibly reduced SBN density in a subject with DM without a history of PRP. (c) SBNs in a subject with DR treated with PRP. Scale bar: 100 μm.
Figure 1
 
(a) A representative laser scanning in vivo confocal image of the central cornea showing SBNs in a healthy eye. (b) Visibly reduced SBN density in a subject with DM without a history of PRP. (c) SBNs in a subject with DR treated with PRP. Scale bar: 100 μm.
The variables included from both groups in the correlation analysis were SBN density, HbA1c, CST, and biothesiometry (medial malleolus, great toe plantar, and great toe dorsal) and MNSI score (Table 3). HbA1c showed no significant correlations with nerve density, corneal sensitivity, biothesiometry, or neuropathy symptoms score. SBN density showed a modest correlation with CST (Pearson's correlation r = 0.30, P = 0.06), and corneal sensitivity was poorly correlated with biothesiometry (medial malleolus) (r = 0.26, P = 0.11, Fig. 2). All three biothesiometry measurements were strongly correlated with each other (Table 3). Symptomatic MNSI scores were also significantly correlated with the biothesiometry measurements (r = 0.83, P < 0.001). 
Figure 2. 
 
Scatter plot graph showing a modest positive correlation between corneal sensitivity and biothesiometry of medial malleolus.
Figure 2. 
 
Scatter plot graph showing a modest positive correlation between corneal sensitivity and biothesiometry of medial malleolus.
Table 3. 
 
Correlations Between SBN Density (mm/mm2), HbA1c (%), Corneal Sensitivity (mBAR), Michigan Neuropathy Symptomatic Score, and Biothesiometry (V) for MM, GTP, and GTD of All Subjects With DM (N = 38)
Table 3. 
 
Correlations Between SBN Density (mm/mm2), HbA1c (%), Corneal Sensitivity (mBAR), Michigan Neuropathy Symptomatic Score, and Biothesiometry (V) for MM, GTP, and GTD of All Subjects With DM (N = 38)
SBN Density, μm/mm2 HbA1c, % CST, mBar VPT - MM, V VPT - GTP, V VPT - GTD, V MNSI Score
SBN density, μm/mm2
 Pearson correlation 1 0.098 0.302* 0.028 0.015 −0.051 0.000
 Significance, two-tailed 0.557 0.065 0.907 0.929 0.763 0.998
HbA1c, %
 Pearson correlation 1 0.084 −0.154 −0.094 −0.041 −0.043
 Significance, two-tailed 0.617 0.356 0.574 0.807 0.797
CST, mBar
 Pearson correlation 1 0.263 0.155 0.285 0.148
 Significance, two-tailed 0.110 0.353 0.082 0.374
VPT - MM, V
 Pearson correlation 1 0.811† 0.753† 0.240
 Significance, two-tailed 0.000 0.000 0.147
VPT - GTP, V
 Pearson correlation 1 0.836† 0.528†
 Significance, two-tailed 0.000 0.001
VPT - GTD, V
 Pearson correlation 1 0.586†
 Significance, two-tailed 0.000
Discussion
The corneal SBNP lies between the basal epithelium and Bowman's layer. 26  
The SBN density in diabetic corneas has been widely reported to be reduced, particularly in patients with associated DR and neuropathy. 2729 Messmer et al. reported mean SBN density of 16.1 mm/mm2 in patients with a mean of 14.8-year history of type 2 DM as compared with 12.2 and 12.7 mm/ mm2 in PRP and non-PRP patients in the current study, using the same IVCM. 30 Importantly, a recent global study showed that the patients with a less than 10-year history of DM had only a 21.0% prevalence of any degree of DR as compared with 54.2% in patients with a 10- to 20-year history of DM. 31 Additionally, only 1.2% of the former group developed proliferative retinopathy compared with 9.0%, possibly requiring treatment, in the latter group. 31 The normal SBN density has been reported to be between 21.6 and 45.9 mm/mm2 as measured by in vivo and ex vivo studies. 3234 The reduction in nerve density is associated with a loss of corneal sensitivity in these eyes. 35 The corneal sensitivity threshold in the healthy population is noted to be significantly lower than that found in the diabetic subjects of the current study, at 0.38 millibars (mBAR). 23 A number of previous studies have investigated the corneal nerve changes in DM patients compared with healthy controls, 30,3638 but there has been little exploration of the possible effects of PRP on corneal nerves. 17  
Interestingly, De Cilla et al. reported lower SBN density in patients with proliferative diabetic retinopathy (PDR) treated by PRP when compared with untreated PDR. 17 However, it is important to note that the extent of DR, per se, has been shown to correlate with reduced corneal sensitivity irrespective of the treatment. 39 The presence of basement membrane abnormalities in the corneal epithelium and retinal blood vessels in DM has been put forward as a possible explanation for this correlation. 40,41 A recent study highlighted differences in corneal sensitivity between the diabetic participants and control subjects, but identified no differences in corneal sensitivity threshold between PRP treated and PRP untreated diabetic participants. 42  
The current study identified no significant differences between the PRP and non-PRP groups with respect to: corneal SBNP density, corneal sensitivity, biothesiometry, and subjective neuropathy score. Thus, PRP did not appear to have any adverse effect on the corneal SBNP density or corneal sensitivity in this study when compared with comparable, non-PRP treated, diabetic eyes. Therefore, these data suggest the reduction in corneal SBN density observed in the PRP group appear to be attributable to the effect of diabetes itself rather than laser treatment. The current study has confirmed that SBNP density is unaffected by PRP in the long term. However, further studies comparing preoperative and 6-month postoperative SBN density would be useful to determine if these nerves are affected in the short term following PRP. 
Reflectivity and tortuosity are two other parameters that have been commonly used to quantify IVCM SBNs in previous studies. Some studies have simply used a subjective grading system for SBN tortuosity. 17,29 More complex objective mathematical methods have also been used to define a tortuosity coefficient in DM using a measure of nerve fibre curvature with the observer selecting nerve branches for calculation. 36,43,44 Unfortunately, these subjective and objective measurements of nerve tortuosity are not directly comparable. Furthermore, in the absence of a repeatable method for analyzing tortuosity, 44 this technique was deemed unsuitable for evaluation of subjects in this study. In the context of reflectivity, the laser scanning in vivo confocal microscope used in the current study automatically adjusts the illuminating brightness to maximize image quality, whilst generally producing higher quality images than white light IVCM, this automatic adjustment leads to inconsistent reflectivity of highly reflective structures, such as corneal SBNs. 45 Another means of measurement is nerve branching analysis, however, this has been reported to be unreliable due to the potential for a single branching fibre to be interpreted as two fibers without branches. 44 Additionally, beading frequency comparison of SBN was not evaluated, as, in order to be comparable, all the images should be captured using fixed illumination intensity. 46 For these reasons, corneal nerve density was chosen as the most reliable parameter for comparison between the groups in this study. 
The current study suggests that PRP does not compromise the integrity of the corneal SBNP and purely from the corneal perspective remains a relatively safe treatment modality in the treatment of DR. The contradictory results to the De Cilla et al. 17 study could relate to our strict exclusion criteria. We only included patients who had undergone PRP more than 6 months previously, but no other previous ocular surgery. 17 De Cilla et al. 17 included subjects with a history of cataract surgery, an intraocular procedure known to cause reduction in corneal sensitivity and innervation. 47 Another possible explanation could be a difference in the severity of thermal injury to underlying nerves related to the number of laser burns applied to treated subjects within in the two studies. These data were not available for comparison. 
Peripheral neuropathy causes early damage to Aδ and unmyelinated C-class small nerve fibers leading to hyperesthesia, paraesthesia, and loss of pain and temperature. 48 Arguably, small corneal nerve fibers are also affected at this early stage. Previous studies have demonstrated that SBN density and corneal sensitivity correlate significantly with the severity of diabetic peripheral neuropathy. 36,37 Biothesiometry (to measure VPT) is a noninvasive and practical technique that can be easily performed in a clinical setting and is recognized as a reliable predictor of diabetic peripheral neuropathy. 49,50 Therefore, a trend in correlation between SBN density and corneal sensitivity; between nerve density and biothesiometry; and between MNSI score and biothesiometry might be anticipated in this study. Indeed, both of the correlation pairs: CST and, MNSI score and VPT, showed a positive correlation with each other. The correlation between MNSI score and VPT suggests that severe peripheral neuropathy is associated with increased symptoms and vice versa. Therefore, in agreement with other studies, these data suggest that noninvasive clinical tools, such as corneal aesthesiometry and the MNSI questionnaire, have the potential to rapidly predict peripheral neuropathy severity in lower limbs. Other studies have also shown positive correlation of peripheral neuropathy with corneal sensitivity 51 and the MNSI questionnaire. 28  
In conclusion, the current study has shown that PRP treatment does not have any significant effect on corneal SBN density or corneal sensitivity in patients with DM compared with subjects with diabetes who have not undergone PRP. 
Acknowledgments
Supported by Save Sight Society, Inc., New Zealand and New Zealand Society for the Study of Diabetes (NZSSD). 
Disclosure: S. Misra, None; H.N. Ahn, None; J.P. Craig, None; M. Pradhan, None; D.V. Patel, None; C.N.J. McGhee, None 
References
Zimmet P Alberti KG Global Shaw J. Global and societal implications of the diabetes epidemic. Nature . 2001; 414: 782–787. [CrossRef] [PubMed]
Wild S Roglic G Green A Sicree R King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care . 2004; 27: 1047–1053. [CrossRef] [PubMed]
Centers for Disease Control and Prevention. Diabetes successes and opportunities for population-based prevention and control: at a glance. 2011. Available at: http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm. Accessed June 27, 2012.
World Health Organization-Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. 1999. Available at: http://whqlibdoc.who.int/hq/1999/who_ncd_ncs_99.2.pdf. Accessed October 20, 2011.
Herse PR. A review of manifestations of diabetes mellitus in the anterior eye and cornea. Am J Optom Physiol Opt . 1988; 65: 224–230. [CrossRef] [PubMed]
Kaiserman I Kaiserman N Nakar S Vinker S. Dry eye in diabetic patients. Am J Ophthalmol . 2005; 139: 498–503. [CrossRef] [PubMed]
Kim J Kim CS Kim H Jeong IH Sohn E Kim JS. Protection against advanced glycation end products and oxidative stress during the development of diabetic keratopathy by KIOM-79. J Pharm Pharmacol . 2011; 63: 524–530. [CrossRef] [PubMed]
Rowe NG Mitchell PG Cumming RG Wans JJ. Diabetes, fasting blood glucose and age-related cataract: the Blue Mountains Eye Study. Ophthalmic Epidemiol . 2000; 7: 103–114. [CrossRef] [PubMed]
Skarbez K Priestley Y Hoepf M Koevary SB. Comprehensive review of the effects of diabetes on ocular health. Expert Rev Ophthalmol . 2010; 5: 557–577. [CrossRef] [PubMed]
Kalesnykiene V Sorri I Voutilainen R Uusitupa M Niskanen L Uusitalo H. The effect of glycaemic control on the quantitative characteristics of retinopathy lesions in patients with type 2 diabetes mellitus: 10-year follow-up study. Graefes Arch Clin Exp Ophthalmol . 2009; 247: 335–341. [CrossRef] [PubMed]
Mohamed Q Gillies MC Wong TY. Management of diabetic retinopathy: a systematic review. JAMA . 2007; 298: 902–916. [CrossRef] [PubMed]
Kollias AN Ulbig MW. Diabetic retinopathy: early diagnosis and effective treatment. Dtsch Arztebl Int . 2010; 107: 75–83. quiz 84. [PubMed]
Buckley SA Parmar DN Jackson H McHugh JD Hunter PA. Anterior segment complications of indirect diode laser in diabetic patients. Br J Ophthalmol . 1998; 82: 1447–1448. [CrossRef] [PubMed]
Kaufman PL Rohen JW Gabelt BT Eichhorn M Wallow IH Polansky JR. Parasympathetic denervation of the ciliary muscle following panretinal photocoagulation. Curr Eye Res . 1991; 10: 437–455. [CrossRef] [PubMed]
Menchini U Scialdone A Pietroni C Carones F Brancato R. Argon versus krypton panretinal photocoagulation side effects on the anterior segment. Ophthalmologica . 1990; 201: 66–70. [CrossRef] [PubMed]
Schiodte SN. Effects on choroidal nerves after panretinal xenon arc and argon laser photocoagulation. Acta Ophthalmol (Copenh) . 1984; 62: 244–255. [CrossRef] [PubMed]
De Cilla S Ranno S Carini E Corneal subbasal nerves changes in patients with diabetic retinopathy: an in vivo confocal study. Invest Ophthalmol Vis Sci . 2009; 50: 5155–5158. [CrossRef] [PubMed]
Moghtaderi A Bakhshipour A Rashidi H. Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg . 2006; 108: 477–481. [CrossRef] [PubMed]
Rahman M Griffin SJ Rathmann W Wareham NJ. How should peripheral neuropathy be assessed in people with diabetes in primary care? A population-based comparison of four measures. Diabet Med . 2003; 20: 368–374. [CrossRef] [PubMed]
Sacks DB Arnold M Bakris GL Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem . 2011; 57: e1–e47. [CrossRef] [PubMed]
Sundell J Janatuinen T Ronnemaa T Lifetime glycaemic exposure predicts reduced coronary vasoreactivity in type 1 diabetic subjects. Diabet Med . 2005; 22: 45–51. [CrossRef] [PubMed]
Murphy PJ Patel S Marshall J. A new non-contact corneal aesthesiometer (NCCA). Ophthalmic Physiol Opt . 1996; 16: 101–107. [CrossRef] [PubMed]
Patel DV Tavakoli M Craig JP Efron N McGhee CN. Corneal sensitivity and slit scanning in vivo confocal microscopy of the subbasal nerve plexus of the normal central and peripheral human cornea. Cornea . 2009; 28: 735–740. [CrossRef] [PubMed]
Bril V Perkins BA. Comparison of vibration perception thresholds obtained with the Neurothesiometer and the CASE IV and relationship to nerve conduction studies. Diabet Med . 2002; 19: 661–666. [CrossRef] [PubMed]
Brace N Kemp R Snelgar R. SPSS for Psychologists: A Guide to Data Analysis Using SPSS for Windows: Versions 12 and 13. 3rd ed. Basingstoke: Palgrave Macmillan; 2006.
Auran JD Koester CJ Kleiman NJ Scanning slit confocal microscopic observation of cell morphology and movement within the normal human anterior cornea. Ophthalmology . 1995; 102: 33–41. [CrossRef] [PubMed]
Chang PY Carrel H Huang JS Decreased density of corneal basal epithelium and subbasal corneal nerve bundle changes in patients with diabetic retinopathy. Am J Ophthalmol . 2006; 142: 488–490. [CrossRef] [PubMed]
Malik RA Kallinikos P Abbott CA Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia . 2003; 46: 683–688. [PubMed]
Mocan MC Durukan I Irkec M Orhan M. Morphologic alterations of both the stromal and subbasal nerves in the corneas of patients with diabetes. Cornea . 2006; 25: 769–773. [CrossRef] [PubMed]
Messmer EM Schmid-Tannwald C Zapp D Kampik A. In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol . 2010; 248: 1307–1312. [CrossRef] [PubMed]
Yau JW Rogers SL Kawasaki R Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care . 2012; 35: 556–564. [CrossRef] [PubMed]
Marfurt CF Cox J Deek S Dvorscak L. Anatomy of the human corneal innervation. Exp Eye Res . 2010; 90: 478–492. [CrossRef] [PubMed]
Misra S Craig JP McGhee CN Patel DV. Interocular comparison by in vivo confocal microscopy of the 2-dimensional architecture of the normal human corneal subbasal nerve plexus. Cornea . 2012; 31: 1376–1380. [CrossRef] [PubMed]
Patel DV McGhee CN. Mapping of the normal human corneal sub-basal nerve plexus by in vivo laser scanning confocal microscopy. Invest Ophthalmol Vis Sci . 2005; 46: 4485–4488. [CrossRef] [PubMed]
Rosenberg ME Tervo TMT Immonen IJ Muller LJ Gronhagen-riska C Vesaluoma MH. Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci . 2000; 41: 2915–2921. [PubMed]
Kallinikos P Berhanu M O'Donnell C Boulton AJ Efron N Malik RA. Corneal nerve tortuosity in diabetic patients with neuropathy. Invest Ophthalmol Vis Sci . 2004; 45: 418–422. [CrossRef] [PubMed]
Tavakoli M Quattrini C Abbott C Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care . 2010; 33: 1792–1797. [CrossRef] [PubMed]
Quattrini C Tavakoli M Jeziorska M Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes . 2007; 56: 2148–2154. [CrossRef] [PubMed]
Saito J Enoki M Hara M Morishige N Chikama T Nishida T. Correlation of corneal sensation, but not of basal or reflex tear secretion, with the stage of diabetic retinopathy. Cornea . 2003; 22: 15–18. [CrossRef] [PubMed]
Azar DT Spurr-Michaud SJ Tisdale AS Gipson IK. Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol . 1992; 110: 537–540. [CrossRef] [PubMed]
Ljubimov AV Burgeson RE Butkowski RJ Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem . 1996; 44: 1469–1479. [CrossRef] [PubMed]
Neira-Zalentein W Holopainen JM Tervo TM Corneal sensitivity in diabetic patients subjected to retinal laser photocoagulation. Invest Ophthalmol Vis Sci . 2011; 52: 6043–6049. [CrossRef] [PubMed]
Tavakoli M Kallinikos P Iqbal A Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med . 2011; 28: 1261–1267. [CrossRef] [PubMed]
Hertz P Bril V Orszag A Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy. Diabet Med . 2011; 28: 1253–1260. [CrossRef] [PubMed]
Patel DV McGhee CN. In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review. Br J Ophthalmol . 2009; 93: 853–860. [CrossRef] [PubMed]
Patel DV McGhee CN. Quantitative analysis of in vivo confocal microscopy images: a review [published online ahead of print February 28, 2013]. Surv Ophthalmol . doi:10.1016/j.survophthal.2012.12.003 .
Kohlhaas M. Corneal sensation after cataract and refractive surgery. J Cataract Refract Surg . 1998; 24: 1399–1409. [CrossRef] [PubMed]
Hossain P Sachdev A Malik RA. Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet . 2005; 366: 1340–1343. [CrossRef] [PubMed]
Garrow AP Boulton AJ. Vibration perception threshold–a valuable assessment of neural dysfunction in people with diabetes. Diabetes Metab Res Rev . 2006; 22: 411–419. [CrossRef] [PubMed]
Richard JL Reilhes L Buvry S Goletto M Faillie JL. Screening patients at risk for diabetic foot ulceration. A comparison between measurement of vibration perception threshold and 10-g monofilament test [published online ahead of print August 14, 2012]. Int Wound J . doi:10.1111/j.1742-481X.2012.01051.x .
Pritchard N Edwards K Shahidi AM Corneal markers of diabetic neuropathy. Ocul Surf . 2011; 9: 17–28. [CrossRef] [PubMed]
Figure 1
 
(a) A representative laser scanning in vivo confocal image of the central cornea showing SBNs in a healthy eye. (b) Visibly reduced SBN density in a subject with DM without a history of PRP. (c) SBNs in a subject with DR treated with PRP. Scale bar: 100 μm.
Figure 1
 
(a) A representative laser scanning in vivo confocal image of the central cornea showing SBNs in a healthy eye. (b) Visibly reduced SBN density in a subject with DM without a history of PRP. (c) SBNs in a subject with DR treated with PRP. Scale bar: 100 μm.
Figure 2. 
 
Scatter plot graph showing a modest positive correlation between corneal sensitivity and biothesiometry of medial malleolus.
Figure 2. 
 
Scatter plot graph showing a modest positive correlation between corneal sensitivity and biothesiometry of medial malleolus.
Table 1. 
 
Demographics Including Male:Female Ratio, Age, BMI, Smoking History, Alcohol Score, Ethnicity, Duration of DM (Years), and Type of DR (Subject Percentage Included) in Subjects With Retinopathy Treated by PRP and Untreated Retinopathy (Non-PRP) Group
Table 1. 
 
Demographics Including Male:Female Ratio, Age, BMI, Smoking History, Alcohol Score, Ethnicity, Duration of DM (Years), and Type of DR (Subject Percentage Included) in Subjects With Retinopathy Treated by PRP and Untreated Retinopathy (Non-PRP) Group
Groups t-test, P Values
PRP Non-PRP
Subjects, n 19 19
Male:female ratio 13:06 14:05
Age, y 57.0 ± 7.9 59.5 ± 14.2 0.50
BMI, kg/m2 29.6 ± 4.0 29.2 ± 5.1 0.78
Smoking history,
pack y
5.8 ± 12.1 4.4 ± 9.75 0.70
Alcohol score 2.20 ± 2.3 2.0 ± 2.6 0.75
Type 1:type 2 1:18 1:18
Mean DM duration, y 18.0 ± 10.4 13.6 ± 7.2
<10 2 4
10–20 11 13
>20 6 2
No active DR 0 (0%) 1 (5.3%)
Mild NPDR 0 (0%) 10 (52.6%)
Moderate NPDR 3 (15.8%) 2 (10.5%)
Severe NPDR 4 (21.1%) 5 (26.3%)
PDR 12 (63.2%) 1 (5.3%) -
Table 2. 
 
Comparison of SBN Density, HbA1c, Corneal Sensitivity, Michigan Neuropathy Symptomatic Score, and Beiothesiometry for Medial Malleolus (MM), Great Toe Plantar (GTP), and Great Toe Dorsal (GTD) of Patients With (n = 19) and Without (n = 19) a History of PRP
Table 2. 
 
Comparison of SBN Density, HbA1c, Corneal Sensitivity, Michigan Neuropathy Symptomatic Score, and Beiothesiometry for Medial Malleolus (MM), Great Toe Plantar (GTP), and Great Toe Dorsal (GTD) of Patients With (n = 19) and Without (n = 19) a History of PRP
PRP, Mean ± SD Non-PRP, Mean ± SD ANOVA, P Values
SBN density, mm/mm2 12.27 ± 4.28 12.75 ± 3.59 0.71
HbA1c, % 9.12 ± 1.89 8.56 ± 1.64 0.33
Corneal sensitivity, mBar 2.32 ± 2.23 2.46 ± 1.76 0.84
MNSI score 3.00 ± 2.60 2.10 ± 1.37 0.19
Biothesiometry - MM, V 27.15 ± 10.04 26.670 ± 8.89 0.77
Biothesiometry - GTP, V 20.21 ± 10.50 20.94 ± 8.62 0.81
Biothesiometry - GTD, V 19.630 ± 10.11 20.63 ± 8.59 0.71
Table 3. 
 
Correlations Between SBN Density (mm/mm2), HbA1c (%), Corneal Sensitivity (mBAR), Michigan Neuropathy Symptomatic Score, and Biothesiometry (V) for MM, GTP, and GTD of All Subjects With DM (N = 38)
Table 3. 
 
Correlations Between SBN Density (mm/mm2), HbA1c (%), Corneal Sensitivity (mBAR), Michigan Neuropathy Symptomatic Score, and Biothesiometry (V) for MM, GTP, and GTD of All Subjects With DM (N = 38)
SBN Density, μm/mm2 HbA1c, % CST, mBar VPT - MM, V VPT - GTP, V VPT - GTD, V MNSI Score
SBN density, μm/mm2
 Pearson correlation 1 0.098 0.302* 0.028 0.015 −0.051 0.000
 Significance, two-tailed 0.557 0.065 0.907 0.929 0.763 0.998
HbA1c, %
 Pearson correlation 1 0.084 −0.154 −0.094 −0.041 −0.043
 Significance, two-tailed 0.617 0.356 0.574 0.807 0.797
CST, mBar
 Pearson correlation 1 0.263 0.155 0.285 0.148
 Significance, two-tailed 0.110 0.353 0.082 0.374
VPT - MM, V
 Pearson correlation 1 0.811† 0.753† 0.240
 Significance, two-tailed 0.000 0.000 0.147
VPT - GTP, V
 Pearson correlation 1 0.836† 0.528†
 Significance, two-tailed 0.000 0.001
VPT - GTD, V
 Pearson correlation 1 0.586†
 Significance, two-tailed 0.000
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×