Corneal Confocal Microscopy Detects Early Nerve Regeneration in Diabetic Neuropathy After Simultaneous Pancreas and Kidney Transplantation

Diabetic neuropathy is associated with increased morbidity and mortality. To date, limited data in subjects with impaired glucose tolerance and diabetes demonstrate nerve fiber repair after intervention. This may reflect a lack of efficacy of the interventions but may also reflect difficulty of the tests currently deployed to adequately assess nerve fiber repair, particularly in short-term studies. Corneal confocal microscopy (CCM) represents a novel noninvasive means to quantify nerve fiber damage and repair. Fifteen type 1 diabetic patients undergoing simultaneous pancreas–kidney transplantation (SPK) underwent detailed assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal sensitivity, and CCM at baseline and at 6 and 12 months after successful SPK. At baseline, diabetic patients had a significant neuropathy compared with control subjects. After successful SPK there was no significant change in neurologic impairment, neurophysiology, QST, corneal sensitivity, and intraepidermal nerve fiber density (IENFD). However, CCM demonstrated significant improvements in corneal nerve fiber density, branch density, and length at 12 months. Normalization of glycemia after SPK shows no significant improvement in neuropathy assessed by the neurologic deficits, QST, electrophysiology, and IENFD. However, CCM shows a significant improvement in nerve morphology, providing a novel noninvasive means to establish early nerve repair that is missed by currently advocated assessment techniques.

[1]  J. Najarian,et al.  Effects of pancreatic transplantation on diabetic neuropathy. , 1990, The New England journal of medicine.

[2]  R. Loewenson,et al.  Influence of Pancreas Transplantation on Cardiorespiratory Reflexes, Nerve Conduction, and Mortality in Diabetes Mellitus , 1990, Diabetes.

[3]  L. Janousek,et al.  Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation. , 2003, Transplantation proceedings.

[4]  X. Navarro,et al.  Long‐term effects of pancreatic transplantation on diabetic neuropathy , 1997, Annals of neurology.

[5]  D. Sutherland,et al.  Neuropathy profile of diabetic patients in a pancreas transplantation program , 1995, Neurology.

[6]  R. Bilous,et al.  Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys , 1993, The Lancet.

[7]  J. Chapman,et al.  Diabetic neuropathy after pancreas transplantation: determinants of recovery. , 1997, Transplantation.

[8]  P. K. Thomas,et al.  Sural nerve pathology in diabetic patients with minimal but progressive neuropathy , 2005, Diabetologia.

[9]  W. Litchy,et al.  Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort , 1997, Neurology.

[10]  Mitra Tavakoli,et al.  Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. , 2011, Journal of visualized experiments : JoVE.

[11]  C. Sumner,et al.  The spectrum of neuropathy in diabetes and impaired glucose tolerance , 2003, Neurology.

[12]  U. Boggi,et al.  Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients , 2006, Diabetologia.

[13]  I. Immonen,et al.  Corneal structure and sensitivity in type 1 diabetes mellitus. , 2000, Investigative ophthalmology & visual science.

[14]  F. Kruse,et al.  Corneal nerves: structure, contents and function. , 2003, Experimental eye research.

[15]  Rayaz A. Malik,et al.  Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments , 2010, Diabetes Care.

[16]  Philip B. Morgan,et al.  A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy , 2010 .

[17]  M. Baran Pancreas transplantation. , 1982, The Diabetes educator.

[18]  L. Melton,et al.  Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. , 1999, Diabetes care.

[19]  A. Boulton,et al.  Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy , 2011, Diabetic medicine : a journal of the British Diabetic Association.

[20]  T. Harrison Faculty Opinions recommendation of Lifestyle intervention for pre-diabetic neuropathy. , 2006 .

[21]  O. Pedersen,et al.  Effect of a multifactorial intervention on mortality in type 2 diabetes. , 2008, The New England journal of medicine.

[22]  N. Demartines,et al.  An Evidence‐Based Analysis of Simultaneous Pancreas‐Kidney and Pancreas Transplantation Alone , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  A. Secchi,et al.  Altered Kidney Graft High-Energy Phosphate Metabolism in Kidney-Transplanted End-Stage Renal Disease Type 1 Diabetic Patients , 2007, Diabetes Care.

[24]  R. Klein,et al.  The influence of combined kidney-pancreas transplantation on the progression of diabetic retinopathy. A case series. , 1994, Ophthalmology.

[25]  Nathan Efron,et al.  Corneal confocal microscopy: A novel means to detect nerve fibre damage in idiopathic small fibre neuropathy , 2009, Experimental Neurology.

[26]  Nathan Efron,et al.  Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy , 2007, Diabetes.

[27]  M. Horowitz,et al.  Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments(Diabetes Care (2010) 33, (2285-2293)) , 2010 .

[28]  Jiucheng He,et al.  Mapping the nerve architecture of diabetic human corneas. , 2012, Ophthalmology.

[29]  Steven Orlov,et al.  Detection of Diabetic Sensorimotor Polyneuropathy by Corneal Confocal Microscopy in Type 1 Diabetes , 2012, Diabetes Care.

[30]  A. Boulton,et al.  Corneal Sensitivity Is Reduced and Relates to the Severity of Neuropathy in Patients With Diabetes , 2007, Diabetes Care.

[31]  U. Boggi,et al.  Effects of pancreas–kidney transplantation on diabetic retinopathy , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[32]  W. Litchy,et al.  Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial , 2010, Muscle & nerve.

[33]  C. Schmitz,et al.  Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study , 2010, Journal of the peripheral nervous system : JPNS.

[34]  W. Schady,et al.  Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology , 2001, Acta Neuropathologica.

[35]  N. Pritchard,et al.  Corneal markers of diabetic neuropathy. , 2011, The ocular surface.

[36]  Y. Iwamoto,et al.  A long‐term prevention of diabetic nephropathy in a patient with type 1 diabetes after simultaneous pancreas and kidney transplantation , 2009, Clinical transplantation.

[37]  P. Hossain,et al.  Early detection of diabetic peripheral neuropathy with corneal confocal microscopy , 2005, The Lancet.

[38]  H. Sone,et al.  Vascular risk factors and diabetic neuropathy. , 2005, The New England journal of medicine.

[39]  A. Gaber,et al.  Improvement in quality of life reported by diabetic recipients of kidney-only and pancreas-kidney allografts. , 1994, Transplantation proceedings.

[40]  G. Smith,et al.  Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy , 2011, Diabetes/metabolism research and reviews.

[41]  D. Erkelens,et al.  Thermal Threshold Testing for the Assessment of Small Fibre Dysfunction: Normal Values and Reproducibility , 1992, Diabetic medicine : a journal of the British Diabetic Association.

[42]  A. Boulton,et al.  Prevalence and Characteristics of Painful Diabetic Neuropathy in a Large Community-Based Diabetic Population in the U.K. , 2011, Diabetes Care.

[43]  R. Freeman,et al.  Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy , 2011, Diabetes Care.

[44]  D. Aeppli,et al.  Neuropathy and mortality in diabetes: Influence of pancreas transplantation , 1996, Muscle & nerve.

[45]  C. Sommer,et al.  Severe depletion of intraepidermal nerve fibers in skin biopsies of pancreas transplant recipients. , 2005, Transplantation proceedings.

[46]  G F Vrensen,et al.  Architecture of human corneal nerves. , 1997, Investigative ophthalmology & visual science.

[47]  J. Albers,et al.  Effect of Prior Intensive Insulin Treatment During the Diabetes Control and Complications Trial (DCCT) on Peripheral Neuropathy in Type 1 Diabetes During the Epidemiology of Diabetes Interventions and Complications (EDIC) Study , 2010, Diabetes Care.

[48]  C. Sommer,et al.  Epidermal Innervation in Type 1 Diabetic Patients , 2008, Diabetes Care.

[49]  A. Boulton,et al.  The global burden of diabetic foot disease , 2005, The Lancet.

[50]  A. Orszag,et al.  Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy , 2011, Diabetic medicine : a journal of the British Diabetic Association.

[51]  Nathan Efron,et al.  Corneal confocal microscopy: A novel noninvasive means to diagnose neuropathy in patients with fabry disease , 2009, Muscle & nerve.

[52]  Asami Kawasaki,et al.  Corneal nerve fiber pathology in Japanese type 1 diabetic patients and its correlation with antecedent glycemic control and blood pressure , 2011, Journal of diabetes investigation.