Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online March 19, 2007
Diabetes Care 30:1895-1897, 2007
DOI: 10.2337/dc07-0175
© 2007 by the American Diabetes Association
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0175v1
30/7/1895    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tavakoli, M.
Right arrow Articles by Malik, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tavakoli, M.
Right arrow Articles by Malik, R. A.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Pathophysiology/Complications
Brief Report

Corneal Sensitivity Is Reduced and Relates to the Severity of Neuropathy in Patients With Diabetes

Mitra Tavakoli, MSC1, Panagiotis A. Kallinikos, PHD1, Nathan Efron, PHD2, Andrew J.M. Boulton, MD, FRCP1 and Rayaz A. Malik, PHD, MRCP1

1 Division of Cardiovascular Medicine, University of Manchester and Manchester Royal Infirmary, Manchester, U.K.
2 Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia

Address correspondence and reprint requests to Dr. R.A. Malik, Division of Cardiovascular Medicine, University of Manchester, Manchester, M13 9NT, U.K. E-mail: rayaz.a.malik{at}man.ac.uk

Abbreviations: C-BA, Cochet-Bonnet aesthesiometer • NCCA, noncontact corneal aesthesiometer • NDA, neuropathy deficit score


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
The focus in relation to the consequences of nerve damage in diabetes has been the loss of sensation in the feet predisposing to the development of foot ulceration and lower extremity amputation (1). However, the cornea is 300–600 times more sensitive than skin (2). In addition to serving a protective function, corneal nerves regulate corneal epithelial integrity, proliferation, and wound healing (3). In diabetic patients, corneal sensitivity is reduced (4), due to a loss of corneal nerve fibers (5), which leads to corneal keratopathy (6,7) and a susceptibility to injury, with recurrent erosions and ulcers (8). Thus, these changes are analogous to the diabetic foot, but because the cornea is not exposed to high pressures, ulceration infrequently occurs. Corneal sensation is mediated via myelinated A-{delta} and C-nerve fibers (9,10), which can be evaluated using the Cochet-Bonnet aesthesiometer (C-BA) (2) or the noncontact corneal aesthesiometer (NCCA) (11), respectively. In diabetic patients, the C-BA has been used to show a reduction in corneal sensitivity in some (12) but not other (13) studies. Furthermore, loss of corneal sensation has been related to the severity of retinopathy (12) and neuropathy (14).

We have assessed corneal sensitivity in a large group of diabetic patients using both C-BA and NCCA to assess concordance between the two methods and also to define whether C-nerve fibers are the earliest to undergo damage (15). Using corneal confocal microscopy, we have previously shown that corneal nerve fiber damage is directly related to the severity of somatic neuropathy (16,17). Thus, detecting loss of corneal sensation may well be a logical screening tool for neuropathy, and hence we have assessed the relationship between loss of corneal sensitivity and the severity of diabetic neuropathy.


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
After local research ethics committee (Greater Manchester Health Authority) approval and written informed consent, 147 diabetic patients and 18 age-matched control subjects underwent assessment of the neuropathy deficit score (NDS) (18,19) and were stratified into the following groups: no neuropathy (NDS 0–2), mild neuropathy (NDS 3–5), moderate neuropathy (NDS 6–8), and severe neuropathy (NDS 9–10). A C-BA (model II; Luneau Ophthalmlogie, Chartres, France) was used to measure the corneal touch threshold 2 mm superior to the six o'clock limbal position to avoid a reflex blink (20). The filament length was decreased in steps of 0.5 cm until the subject felt the stimulus, which was repeated four to six times. The corneal sensation threshold corresponds to the filament length (mm), giving a positive response to 50% of the presentations (21). The NCCA (Caledonian University, Glasgow, U.K., 1996) uses a puff of air on the center of the cornea, lasting 0.9 s, to exert a force expressed in millibars, which quantifies corneal sensitivity using established methodology (4,11,21). Data are presented as means ± SD and analyzed using one-way ANOVA and Scheffe Post hoc test to study differences between groups and the Pearson test for correlation between variables.


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
147 diabetic patients with no, mild, moderate, and severe neuropathy were compared with 18 control subjects (Table 1). Age, type of diabetes, and A1C did not differ significantly between groups, and diabetes duration increased with neuropathic severity (r = 0.40, P < 0.0001). Corneal sensitivity assessed using the CB-A was significantly reduced in diabetic patients compared with control subjects (31.4 ± 19.4 mm vs. 52.3 ± 9.7 mm, respectively; P < 0.0001). It was not reduced in diabetic patients without neuropathy (P = 0.32) but demonstrated a significant reduction in mild (P = 0.01), moderate (P < 0.0001), and severe (P < 0.0001) neuropathy (Table 1). Corneal sensitivity assessed using NCCA was significantly reduced in diabetic patients compared with control subjects (1.4 ± 0.9 mbar vs. 0.7 ± 0.1 mbar; P < 0.0001). It was not significantly reduced in patients without (P = 0.31) or with mild (P = 0.13) neuropathy but was significantly reduced in those with moderate (P < 0.0001) and severe (P = 0.02) neuropathy (Table 1). C-BA correlated significantly with NCCA (r = –0.42, P < 0.0001). Age correlated with C-BA (r = –0.22, P = 0.018) but not NCCA (r = 0.13, P = 0.14). Duration of diabetes correlated with NCCA (r = 0.28, P = 0.002) and C-BA (r = –0.30, P = 0.001). There was a significant correlation between neuropathic severity assessed using NDS with NCCA (r = 0.35, P <0.0001) and C-BA (r = –0.62, P < 0.0001).


View this table:
[in this window]
[in a new window]

  		Table 1— Clinical details and corneal sensitivity using C-BA and NCCA in control subjects and diabetic patients with increasing neuropathic severity in accordance with NDS, with statistical difference compared with control subjects

 

   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Diabetic patients may develop epithelial defects and corneal erosions (4,5,15–17,22,23) secondary to loss of corneal sensitivity (4,5,23,24). Increasing age and duration of diabetes may lead to loss of corneal sensation (25). We have shown that increasing age is related to loss of corneal sensation, confirming some (4,25) but not other (26) studies. We also demonstrate a significant association between the duration of diabetes and loss of corneal sensitivity using both NCCA and C-BA, which is in contrast with a previous study using NCCA (4). C-BA demonstrated considerable variability in corneal sensitivity, consistent with quantitative sensory testing in general (27). We also demonstrate a correlation between C-BA and NCCA, which has not been reported in previous studies (4,21). Although the development and progression of retinopathy, nephropathy, and neuropathy are closely associated (28), loss of corneal sensitivity has been related to the severity of retinopathy in one (12) but not other (14,24) studies. In the present study, we did not quantify retinopathy or nephropathy and therefore could not assess for any association with loss of corneal sensitivity. However, one would expect loss of corneal sensation to be most strongly associated with neuropathy. Indeed, we (15–17) and others (5,14) have previously demonstrated that corneal nerve fiber abnormalities are related to the severity of neuropathy. Accordingly, we show that corneal sensation is reduced in diabetic patients and progresses with the severity of neuropathy, suggesting that corneal nerve fiber damage accompanies somatic nerve fiber damage. In conclusion, loss of corneal sensation is easily quantifiable, occurs in diabetic patients with mild to moderate somatic neuropathy, and progresses with the severity of neuropathy. These findings have important clinical implications regarding the development of corneal abnormalities in diabetic patients and also raise the possibility that corneal sensation could be used to screen for diabetic neuropathy.


   Acknowledgments
 
This work was supported by National Institutes of Health Grant R01 NS46259-01 and Juvenile Diabetes Research Foundation International (5-2002-185).


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc07-0175.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication January 29, 2007. Accepted for publication March 14, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458–1486, 2004[Free Full Text]
  2. Millodot M: A review of research on the sensitivity of the cornea. Ophthalmic Physiol Opt 4:305–318, 1984[Medline]
  3. Millodot M, Owens H The influence of age on the fragility of the cornea. Acta Ophthalmol (Copenh) 62:819–824, 1984[Medline]
  4. Murphy PJ, Patel S, Kong N, Ryder RE, Marshall J: Noninvasive assessment of corneal sensitivity in young and elderly diabetic and nondiabetic subjects. Invest Ophthalmol Vis Sci 45:1737–1742, 2004[Abstract/Free Full Text]
  5. Rosenberg ME, Tervo TM, Immonen IJ, Muller LJ, Gronhagen-Riska C, Vesaluoma MH: Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci 41:2915–2921, 2000[Abstract/Free Full Text]
  6. Didenko TN, Smoliakova GP, Sorokin EL, Egorov VV: Clinical and pathogenetic features of neurotrophic corneal disorders in diabetes. Vestn Oftalmol 115:7–11, 1999[Medline]
  7. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R: Diabetic retinopathy. Diabetes Care 21:143–156, 1998[Medline]
  8. Kabosova A, Kramerov AA, Aoki AM, Murphy G, Zieske JD, Ljubimov AV: Human diabetic corneas preserve wound healing, basement membrane, integrin and MMP-10 differences from normal corneas in organ culture. Exp Eye Res 77:211–217, 2003[Medline]
  9. Müller LJ, Pels L, Vrensen GFJM: Ultrastructural organization of human corneal nerves. Invest Ophthalmol Vis Sci 37:476–488, 1996[Abstract/Free Full Text]
  10. Müller LJ, Vrensen GFJM, Pels L, Nunes Cardozo B, Willekens B: Architecture of human corneal nerves. Invest Ophthalmol Vis Sci 38:985–994, 1997[Abstract/Free Full Text]
  11. Murphy PJ, Patel S, Marshall J: A new non-contact corneal aesthesiometer (NCCA). Ophthalmic Physiol Opt 16:101–117, 1996[Medline]
  12. Saini JS, Khandalavla B: Corneal epithelial fragility in diabetes mellitus. Can J Ophthalmol 30:142–146, 1995[Medline]
  13. O'Donnell C, Efron N, Boulton AJM: A prospective study of contact lens wear in diabetes mellitus. Ophthalmic Physiol Opt 21:127–138, 2001[Medline]
  14. Dogru M, Katakami C, Inoue M: Tear function and ocular surface changes in non-insulin-dependent diabetes mellitus. Ophthalmology 108:586–592, 2001[Medline]
  15. Hossain P, Sachdev A, Malik RA: Early detection of diabetic peripheral neuropathy using corneal confocal microscopy. Lancet 366:1340–1343, 2005[Medline]
  16. Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P, Efron N, Boulton AJM: Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46:683–688, 2003[Medline]
  17. Kallinikos P, Berhanu M, O'Donnell C, Boulton AJM, Efron N, Malik RA: Corneal nerve tortuosity in diabetic patients with neuropathy. Invest Ophthalmol Vis Sci 45:418–422, 2004[Abstract/Free Full Text]
  18. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH: A multicenter study of the prevalence of diabetic peripheral neuropathy in the United-Kingdom hospital clinic population. Diabetologia 36:150–154, 1993[Medline]
  19. Abbott CA, Carrington AL, Ashe H Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ER, Whalley AM, Widdows P, Williamson S, Boulton AJ; North-West Diabetes Foot Care Study: The North-West Diabetes Food Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19:377–384, 2002[Medline]
  20. Bonnet R, Millodot M: L'esthesie corneenne: sa mesure dams l'obscurite. Clin Ophthalmol 6:74–78, 1965 [in French]
  21. Murphy PJ, Lawrenson JG, Patel S, Marshall J: Reliability of the non-contact corneal aesthesiometer and its comparison with the Cochet-Bonnet aesthesiometer. Ophthalmic Physiol Opt 18:532–539, 1998[Medline]
  22. Ishida N, Rao GN, del Gerro M, Aquavella JV: Corneal nerve alterations in diabetes mellitus. Arch Ophthalmol 102:1380–1384, 1984[Abstract]
  23. McNamara NA, Brand RJ, Polse KA, Bourne WM: Corneal function during normal and high serum glucose levels in diabetes. Invest Ophthalmol Vis Sci 39:3–17, 1998[Abstract/Free Full Text]
  24. Alvarenga LS, Martins EN, Grottone GT, Morales PH, Paranhos A Jr, Freitas D, Scarpi MJ: Usefulness of corneal esthesiometry for screening diabetic retinopathy. Rev Saude Publica 37:609–615, 2003[Medline]
  25. Millodot M: The influence of age on the sensitivity of cornea. Invest Ophthalmol Vis Sci 16:240–242, 1997
  26. Draeger J: Corneal Sensitivity Measurement and Clinical Importance. New York, Springer-Verlag, 1984
  27. Gruener G, Dyck PJ: Quantitative sensory testing: methodology, applications, and future directions. J Clin Neurophysiol 11:568–583, 1994[Medline]
  28. Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ, O'Brien PC: Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 22:1479–1486, 1999[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Diabetes CareHome page
V. S. E. Jeganathan, J. J. Wang, and T. Y. Wong
Ocular Associations of Diabetes Other Than Diabetic Retinopathy
Diabetes Care, September 1, 2008; 31(9): 1905 - 1912.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
S. K. Dash
Corneal Sensitivity Is Reduced and Relates to the Severity of Neuropathy in Patients with Diabetes: Response to Tavakoli et al.
Diabetes Care, December 1, 2007; 30(12): e142 - e142.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
M. Tavakoli, P. A. Kallinikos, N. Efron, A. J.M. Boulton, and R. A. Malik
Corneal Sensitivity Is Reduced and Relates to the Severity of Neuropathy in Patients With Diabetes: Response to Dash
Diabetes Care, December 1, 2007; 30(12): e143 - e143.
[Full Text] [PDF]

Home page
 Diabetes CareHome page
S. Mehra, M. Tavakoli, P. A. Kallinikos, N. Efron, A. J.M. Boulton, T. Augustine, and R. A. Malik
Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes
Diabetes Care, October 1, 2007; 30(10): 2608 - 2612.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0175v1
30/7/1895    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tavakoli, M.
Right arrow Articles by Malik, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tavakoli, M.
Right arrow Articles by Malik, R. A.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum