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Diabetic autonomic neuropathy

Author
Christopher H Gibbons, MD, MMSc, FAAN
Section Editors
David M Nathan, MD
Jeremy M Shefner, MD, PhD
Deputy Editor
John F Dashe, MD, PhD

INTRODUCTION

Diabetic autonomic neuropathy (DAN) is a common and debilitating form of neuropathy. DAN may be detected in the majority of patients with diabetes with neurophysiologic testing, but is classified as subclinical or clinical depending upon the presence or absence of symptoms [1]. A wide spectrum of symptoms affecting many different organ systems can occur, including the cardiovascular, gastrointestinal, genitourinary, pupillary, sudomotor, and neuroendocrine systems (table 1).

GLYCEMIC CONTROL AND RISK FACTOR REDUCTION

The therapy of diabetic autonomic neuropathy (DAN) can be difficult. It is therefore desirable to prevent this complication or, once established, to slow disease progression.

Poor glucose control and vascular risk factors appear to be associated with the development of diabetic neuropathy [2]. This observation is supported by the results of the EURODIAB study, which found that the incidence of neuropathy was associated with poor glucose control, elevated triglyceride levels, elevated body mass index, smoking, and hypertension [3]. (See "Pathogenesis and prevention of diabetic polyneuropathy", section on 'Risk factors'.)

However, results from a large prospective observational study suggest that the incidence of DAN is declining in type 1 diabetes, potentially reflecting improvements in the management of risk factors [4]. Furthermore, results from randomized trials suggest that intensive therapy reduces the onset and progression of autonomic neuropathy:

In the Diabetes Control and Complications Trial (DCCT), intensive therapy with insulin in subjects with type 1 diabetes was found to reduce cardiovascular autonomic neuropathy incidence by 53 percent [5], and the benefit of prior intensive therapy was found to persist for up to 14 years in these subjects [6].

                     

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Literature review current through: Jul 2017. | This topic last updated: May 24, 2017.
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References
Top
  1. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26:1553.
  2. Ko SH, Park SA, Cho JH, et al. Progression of cardiovascular autonomic dysfunction in patients with type 2 diabetes: a 7-year follow-up study. Diabetes Care 2008; 31:1832.
  3. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341.
  4. Pambianco G, Costacou T, Ellis D, et al. The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes 2006; 55:1463.
  5. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998; 41:416.
  6. Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 2009; 119:2886.
  7. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383.
  8. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580.
  9. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain 2015; 138:43.
  10. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998; 116:874.
  11. Chantelau E, Meyer-Schwickerath R. Reversion of 'early worsening' of diabetic retinopathy by deliberate restoration of poor metabolic control. Ophthalmologica 2003; 217:373.
  12. Davis MD, Beck RW, Home PD, et al. Early retinopathy progression in four randomized trials comparing insulin glargine and NPH [corrected] insulin. Exp Clin Endocrinol Diabetes 2007; 115:240.
  13. Chantelau E, Meyer-Schwickerath R, Klabe K. Downregulation of serum IGF-1 for treatment of early worsening of diabetic retinopathy: a long-term follow-up of two cases. Ophthalmologica 2010; 224:243.
  14. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33:2285.
  15. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol 2013; 117:279.
  16. Freeman R. Diabetic autonomic neuropathy. Handb Clin Neurol 2014; 126:63.
  17. Veglio M, Borra M, Stevens LK, et al. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia 1999; 42:68.
  18. Zander E, Schulz B, Heinke P, et al. Importance of cardiovascular autonomic dysfunction in IDDM subjects with diabetic nephropathy. Diabetes Care 1989; 12:259.
  19. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci 2011; 161:46.
  20. Gaspar L, Kruzliak P, Komornikova A, et al. Orthostatic hypotension in diabetic patients-10-year follow-up study. J Diabetes Complications 2016; 30:67.
  21. Fleg JL, Evans GW, Margolis KL, et al. Orthostatic Hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Blood Pressure Trial: Prevalence, Incidence, and Prognostic Significance. Hypertension 2016; 68:888.
  22. Gibbons CH, Freeman R. Clinical implications of delayed orthostatic hypotension: A 10-year follow-up study. Neurology 2015; 85:1362.
  23. Hornung RS, Mahler RF, Raftery EB. Ambulatory blood pressure and heart rate in diabetic patients: an assessment of autonomic function. Diabet Med 1989; 6:579.
  24. Istenes I, Keresztes K, Hermányi Z, et al. Relationship between autonomic neuropathy and hypertension--are we underestimating the problem? Diabet Med 2008; 25:863.
  25. Page MM, Watkins PJ. Provocation of postural hypotension by insulin in diabetic autonomic neuropathy. Diabetes 1976; 25:90.
  26. Mathias CJ, da Costa DF, Fosbraey P, et al. Hypotensive and sedative effects of insulin in autonomic failure. Br Med J (Clin Res Ed) 1987; 295:161.
  27. Stevens MJ, Edmonds ME, Mathias CJ, Watkins PJ. Disabling postural hypotension complicating diabetic autonomic neuropathy. Diabet Med 1991; 8:870.
  28. Jansen RW, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology, and clinical management. Ann Intern Med 1995; 122:286.
  29. Mathias CJ. Effect of food intake on cardiovascular control in patients with impaired autonomic function. J Neurosci Methods 1990; 34:193.
  30. Winkler AS, Landau S, Watkins PJ. Erythropoietin treatment of postural hypotension in anemic type 1 diabetic patients with autonomic neuropathy: a case study of four patients. Diabetes Care 2001; 24:1121.
  31. Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Reviews 1999; 7:342.
  32. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003; 26:1895.
  33. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010; 33:1578.
  34. O'Brien IA, McFadden JP, Corrall RJ. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med 1991; 79:495.
  35. Navarro X, Kennedy WR, Sutherland DE. Autonomic neuropathy and survival in diabetes mellitus: effects of pancreas transplantation. Diabetologia 1991; 34 Suppl 1:S108.
  36. Rathmann W, Ziegler D, Jahnke M, et al. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med 1993; 10:820.
  37. Sampson MJ, Wilson S, Karagiannis P, et al. Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics. Q J Med 1990; 75:635.
  38. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49:95.
  39. Watkins PJ, Mackay JD. Cardiac denervation in diabetic neuropathy. Ann Intern Med 1980; 92:304.
  40. Soedamah-Muthu SS, Chaturvedi N, Witte DR, et al. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care 2008; 31:1360.
  41. Nesto RW, Phillips RT, Kett KG, et al. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy. Ann Intern Med 1988; 108:170.
  42. Ambepityia G, Kopelman PG, Ingram D, et al. Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function. J Am Coll Cardiol 1990; 15:72.
  43. Langer A, Freeman MR, Josse RG, et al. Detection of silent myocardial ischemia in diabetes mellitus. Am J Cardiol 1991; 67:1073.
  44. Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet 1976; 1:601.
  45. Burgos LG, Ebert TJ, Asiddao C, et al. Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy. Anesthesiology 1989; 70:591.
  46. Veglio M, Sivieri R, Chinaglia A, et al. QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care 2000; 23:1381.
  47. Lown B, Verrier RL, Rabinowitz SH. Neural and psychologic mechanisms and the problem of sudden cardiac death. Am J Cardiol 1977; 39:890.
  48. Stevens MJ, Raffel DM, Allman KC, et al. Cardiac sympathetic dysinnervation in diabetes: implications for enhanced cardiovascular risk. Circulation 1998; 98:961.
  49. Suarez GA, Clark VM, Norell JE, et al. Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J Neurol Neurosurg Psychiatry 2005; 76:240.
  50. Astrup AS, Tarnow L, Rossing P, et al. Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2006; 29:334.
  51. Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004; 27:1954.
  52. Valensi P, Sachs RN, Harfouche B, et al. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001; 24:339.
  53. Forsén A, Kangro M, Sterner G, et al. A 14-year prospective study of autonomic nerve function in Type 1 diabetic patients: association with nephropathy. Diabet Med 2004; 21:852.
  54. Cohen JA, Estacio RO, Lundgren RA, et al. Diabetic autonomic neuropathy is associated with an increased incidence of strokes. Auton Neurosci 2003; 108:73.
  55. Brotman DJ, Bash LD, Qayyum R, et al. Heart rate variability predicts ESRD and CKD-related hospitalization. J Am Soc Nephrol 2010; 21:1560.
  56. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; 1:14.
  57. Rees PJ, Prior JG, Cochrane GM, Clark TJ. Sleep apnoea in diabetic patients with autonomic neuropathy. J R Soc Med 1981; 74:192.
  58. Ficker JH, Dertinger SH, Siegfried W, et al. Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular autonomic neuropathy. Eur Respir J 1998; 11:14.
  59. Neumann C, Martinez D, Schmid H. Nocturnal oxygen desaturation in diabetic patients with severe autonomic neuropathy. Diabetes Res Clin Pract 1995; 28:97.
  60. Bottini P, Dottorini ML, Cristina Cordoni M, et al. Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy. Eur Respir J 2003; 22:654.
  61. Bottini P, Redolfi S, Dottorini ML, Tantucci C. Autonomic neuropathy increases the risk of obstructive sleep apnea in obese diabetics. Respiration 2008; 75:265.
  62. Wieling W, Borst C, van Dongen Torman MA, et al. Relationship between impaired parasympathetic and sympathetic cardiovascular control in diabetes mellitus. Diabetologia 1983; 24:422.
  63. Policy Department, American Association of Neuromuscular & Electrodiagnostic Medicine, Rochester, Minnesota, USA. Proper performance of autonomic function testing. Muscle Nerve 2017; 55:3.
  64. Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011; 27:639.
  65. Bernardi L, Spallone V, Stevens M, et al. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev 2011; 27:654.
  66. Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 2004; 27:2942.
  67. Valensi P, Pariès J, Attali JR, French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications--the French multicenter study. Metabolism 2003; 52:815.
  68. Witte DR, Tesfaye S, Chaturvedi N, et al. Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia 2005; 48:164.
  69. Allman KC, Stevens MJ, Wieland DM, et al. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol 1993; 22:1425.
  70. Mäntysaari M, Kuikka J, Mustonen J, et al. Noninvasive detection of cardiac sympathetic nervous dysfunction in diabetic patients using [123I]metaiodobenzylguanidine. Diabetes 1992; 41:1069.
  71. Kreiner G, Wolzt M, Fasching P, et al. Myocardial m-[123I]iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM. Comparison with cardiovascular reflex tests and relationship to left ventricular function. Diabetes 1995; 44:543.
  72. Langer A, Freeman MR, Josse RG, Armstrong PW. Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. J Am Coll Cardiol 1995; 25:610.
  73. Wieland DM, Hutchins GD, Rosenspire K, et al. C-11 hydroxyephedrine (HED): a high specific activity alternative to F-18 fluorometaraminol (FMR) for heart neuronal imaging. J Nucl Med 1989; 30:A767.
  74. Melon PG, Nguyen N, DeGrado TR, et al. Imaging of cardiac neuronal function after cocaine exposure using carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol 1994; 23:1693.
  75. Nakajo M, Shimabukuro K, Yoshimura H, et al. Iodine-131 metaiodobenzylguanidine intra- and extravesicular accumulation in the rat heart. J Nucl Med 1986; 27:84.
  76. Schwaiger M, Kalff V, Rosenspire K, et al. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circulation 1990; 82:457.
  77. Pop-Busui R, Kirkwood I, Schmid H, et al. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 2004; 44:2368.
  78. Gæde P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016; 59:2298.
  79. Gibbons CH, Freeman R, Tecilazich F, et al. The evolving natural history of neurophysiologic function in patients with well-controlled diabetes. J Peripher Nerv Syst 2013; 18:153.
  80. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545.
  81. Howorka K, Pumprla J, Haber P, et al. Effects of physical training on heart rate variability in diabetic patients with various degrees of cardiovascular autonomic neuropathy. Cardiovasc Res 1997; 34:206.
  82. Pagkalos M, Koutlianos N, Kouidi E, et al. Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy. Br J Sports Med 2008; 42:47.
  83. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017.
  84. Kaufmann H, Brannan T, Krakoff L, et al. Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 1988; 38:951.
  85. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995; 99:604.
  86. Isaacson S, Shill HA, Vernino S, et al. Safety and Durability of Effect with Long-Term, Open-Label Droxidopa Treatment in Patients with Symptomatic Neurogenic Orthostatic Hypotension (NOH303). J Parkinsons Dis 2016; 6:751.
  87. Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 1993; 329:611.
  88. Bannister R, Mathias CJ. Management of postural hypotension. In: Autonomic Failure. A Textbook of Clinical Disorders of the Autonomic Nervous System, 2nd ed, Bannister R (Ed), Oxford University Press, Oxford 1988. p.569.
  89. Ten Harkel AD, van Lieshout JJ, Wieling W. Effects of leg muscle pumping and tensing on orthostatic arterial pressure: a study in normal subjects and patients with autonomic failure. Clin Sci (Lond) 1994; 87:553.
  90. Fealey RD, Low PA, Thomas JE. Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc 1989; 64:617.
  91. Wilkins RW, Kolb LC. Vasomotor disturbance in peripheral neuritis. Am J Med Sci 1941; 202:216.
  92. Bannister R, Mathias CJ. Management of postural hypotension. In: Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 2nd ed, Bannister R (Ed), Oxford University Press, Oxford 1988. p.569.
  93. Ryder RE, Kennedy RL, Newrick PG, et al. Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration. Diabet Med 1990; 7:726.
  94. Tentolouris N, Marinou K, Kokotis P, et al. Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med 2009; 26:302.
  95. Freeman R, Chapleau MW. Testing the autonomic nervous system. Handb Clin Neurol 2013; 115:115.
  96. Shahani BT, Halperin JJ, Boulu P, Cohen J. Sympathetic skin response--a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J Neurol Neurosurg Psychiatry 1984; 47:536.
  97. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 2010; 15:79.
  98. Luo KR, Chao CC, Chen YT, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol 2011; 70:930.
  99. Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology 2009; 72:1479.
  100. Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 2007; 56:2148.
  101. Stevens MJ, Edmonds ME, Douglas SL, Watkins PJ. Influence of neuropathy on the microvascular response to local heating in the human diabetic foot. Clin Sci (Lond) 1991; 80:249.
  102. Kempler P, Amarenco G, Freeman R, et al. Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes. Diabetes Metab Res Rev 2011; 27:665.
  103. Ioanid CP, Noica N, Pop T. Incidence and diagnostic aspects of the bladder disorders in diabetics. Eur Urol 1981; 7:211.
  104. Inman BA, Sauver JL, Jacobson DJ, et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009; 84:108.
  105. Brown JS, Wessells H, Chancellor MB, et al. Urologic complications of diabetes. Diabetes Care 2005; 28:177.
  106. Van Den Eeden SK, Sarma AV, Rutledge BN, et al. Effect of intensive glycemic control and diabetes complications on lower urinary tract symptoms in men with type 1 diabetes: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes Care 2009; 32:664.
  107. Sarma AV, Kanaya A, Nyberg LM, et al. Risk factors for urinary incontinence among women with type 1 diabetes: findings from the epidemiology of diabetes interventions and complications study. Urology 2009; 73:1203.
  108. Maiorino MI, Bellastella G, Esposito K. Diabetes and sexual dysfunction: current perspectives. Diabetes Metab Syndr Obes 2014; 7:95.
  109. Pontiroli AE, Cortelazzi D, Morabito A. Female sexual dysfunction and diabetes: a systematic review and meta-analysis. J Sex Med 2013; 10:1044.
  110. Giraldi A, Kristensen E. Sexual dysfunction in women with diabetes mellitus. J Sex Res 2010; 47:199.
  111. Amiel S. Glucose counter-regulation in health and disease: current concepts in hypoglycaemia recognition and response. Q J Med 1991; 80:707.
  112. Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest 1993; 91:819.
  113. Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle. Diabetes 1992; 41:255.
  114. Meyer C, Grossmann R, Mitrakou A, et al. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care 1998; 21:1960.
  115. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28:956.