Klinik und Diagnose der diabetischen autonomen Neuropathie

Zusammenfassung:

Die diabetische autonome Neuropathie (DAN) ist die häufigste autonome Neuropathie der westlichen Welt. Ihre Symptome sind vielfältig und betreffen nahezu alle Organsysteme. Im Vordergrund stehen dabei kardiovaskuläre Störungen wie eingeschränkte Herzfrequenzvariabilität und pathologische Orthostasereaktion. Ihre Diagnostik erfolgt im Wesentlichen durch die Analyse kardiovaskulärer Stimulationsmanöver. Nachfolgend soll ein Einblick in Epidemiologie, Klinik, Diagnostik, Pathogenese, Therapiemöglichkeiten und Prognose der diabetischen autonomen Neuropathie vermittelt werden.

Diabetic Autonomic Neuropathy:

Diabetic autonomic neuropathy is the most frequent autonomic neuropathy in western countries. Diabetic autonomic neuropathy affects almost every organ. Among the most common symptoms are cardiovascular disturbances such as reduced heart rate variability and pathologic orthostatic reaction. The diagnosis of diabetic autonomic neuropathy is mainly based on the analysis of cardiovascular challenge maneuvers. The following article describes epidemiology, clinical findings, diagnosis, pathogenesis, therapeutic options and prognosis in diabetic autonomic neuropathy.

Literatur

• 1 Flynn M D, O'Brien I A, Corrall R J. The prevalence of autonomic and peripheral neuropathy in insulin-treated diabetic subjects.  Diabet Med. 1995;  12 310-313
• 2 Fagerberg S E. A clinical and histological study on the significance of vascular affections.  Acta Med Scand. 1959;  164 (Suppl) 345
• 3 Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973.  Diabet Meta. 1977;  3 173-182
• 4 Rundles R W. Diabetic neuropathy. General review with report of 125 cases.  Medicine. 1945;  24 111-160
• 5 Sangiorgio L, Iemmolo R, Le Moli R. et al . Diabetic neuropathy: prevalence, concordance between clinical and electrophysiological testing and impact of risk factors.  Panminerva Med. 1997;  39 1-5
• 6 Ziegler D, Dannehl K, Muhlen H. et al . Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses at various stages of diabetic neuropathy.  Diabet Med. 1992;  9 806-814
• 7 Ziegler D, Gries F A, Spuler M. et al . The epidemiology of diabetic neuropathy. DiaCAN Multicenter Study Group.  Diabet Med. 1993;  10 (Suppl 2) 82-86
• 8 Ziegler D, Gries F A, Muhlen H. et al . Prevalence and clinical correlates of cardiovascular autonomic and peripheral diabetic neuropathy in patients attending diabetes centers. The Diacan Multicenter Study Group.  Diabetes Metab. 1993;  19 143-151
• 9 Ratzmann K P, Raschke M, Gander I. et al . Prevalence of peripheral and autonomic neuropathy in newly diagnosed type II (noninsulin-dependent) diabetes.  J Diabet Complications. 1991;  5 1-5
• 10 Dyck P J, Karnes J, O'Brien P C. Diagnosis, staging and classification of diabetic neuropathy and association with other complications. In: Dyck PJ, Thomas PK, Asbury AK (Eds). Diabetic neuropathy Philadelphia: WB Saunders 1987: 36-44
• 11 Low P A. Diabetic autonomic neuropathy.  Semin Neurol. 1996;  16 143-151
• 12 DCCT Research Group . Factors in development of diabetic neuropathy. Baseline analysis of neuropathy in feasibility phase of Diabetes Control and Complications Trial (DCCT).  Diabetes. 1988;  37 476-481
• 13 Hilsted J, Low P A. Diabetic autonomic neuropathy. In: Low PA (Ed). Clinical autonomic disorders Philadelphia: Lippincott-Raven Publishers 1997: 487-507
• 14 Neil H AW. The epidemiology of diabetic autonomic neuropathy. In: Bannister R, Matthias CJ (Eds). Autonomic failure. A textbook of Clinical Disorders of the Autonomic Nervous System Oxford: Oxford University Press 1992: 682-697
• 15 Watkins P J, Edmonds M E. Diabetic autonomic failure. In: Bannister R, Matthias CJ (Eds). Autonomic failure. A textbook of Clinical Disorders of the Autonomic Nervous System Oxford: Oxford University Press 1999: 378-386
• 16 Tomlinson D R. Report on the conjoint meetings of the Diabetic Neuropathy Study Group of the EASD (NEURODIAB) VII and the 4th Diabetic Neuropathy IDF satellite meeting held in Noordwijkerhout, The Netherlands.  Diabetologia. July 15 - 19, 1997;  40 suppl 46-48
• 17 Thomas P K, Tomlinson D R. Diabetic and hypoglycemic neuropathy. In: Dyck PJ, et al. (Eds). Peripheral Neuropathy Philadelphia: WB Saunders 1993: 1219-1250
• 18 Canal N, Comi G, Saibene V. The relationship between peripheral and autonomic neuropathy in insulin-dependent diabetes. A clinical and instrumental evaluation. In: Canal N, Pozza G (Eds). Peripheral neuropathies Amsterdam: Ellsiever 1978: 247
• 19 Fernandez-Castaner M, Mendola G, Levy I. et al . Prevalence and clinical aspects of cardiovascular vegetative neuropathy in a diabetic population.  Med Clin (Barc). 1985;  84 215-218
• 20 Chaudhuri K R. The neurology of diabetes.  Br J Hosp Med. 1997;  58 343-347
• 21 Neundörfer B. Die autonome Neuropathie aus neurologischer Sicht.  Der Kassenarzt. 1995;  31/32 31-34
• 22 Dyck P J. Detection, characterization, and staging of polyneuropathy: assessed in diabetics.  Muscle Nerve. 1988;  11 21-32
• 23 Dyck P J, Karnes J L, Daube J. et al . Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy.  Brain. 1985;  108 861-880
• 24 O'Brien I A, Corrall R J. Epidemiology of diabetes and its complications.  N Engl J Med. 1988;  318 1619-1620
• 25 Ziegler D, Gries F A, Spuler M. et al . The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group.  J Diabetes Complications. 1992;  6 49-57
• 26 Valensi P, Huard J P, Giroux C. et al . Factors involved in cardiac autonomic neuropathy in diabetic patients.  J Diabetes Complications. 1997;  11 180-187
• 27 Lanting P, Strijers R L, Bos J E. et al . The cause of increased pupillary light reflex latencies in diabetic patients: the relationship between pupillary light reflex and visual evoked potential latencies.  Electroencephalogr Clin Neurophysiol. 1991;  78 111-115
• 28 Smith S E, Smith S A, Brown P M. et al . Pupillary signs in diabetic autonomic neuropathy.  Br Med J. 1978;  2 924-927
• 29 Straub R H, Zietz B, Palitzsch K D. et al . Impact of disease duration on cardiovascular and pupillary autonomic nervous function in IDDM and NIDDM patients.  Diabetes Care. 1996;  19 960-967
• 30 Smith S A, Smith S E. Reduced pupillary light reflexes in diabetic autonomic neuropathy.  Diabetologia. 1983;  24 330-332
• 31 Smith S A, Smith S E. Pupil function: test and disorders. In: Bannister R, Matthias CJ (Eds). Autonomic failure. A textbook of Clinical Disorders of the Autonomic Nervous System Oxford: Oxford University Press 1999: 245-253
• 32 Pfeifer M A, Weinberg C R, Cook D L. et al . Autonomic neural dysfunction in recently diagnosed diabetic subjects.  Diabetes Care. 1984;  7 447-453
• 33 Jones D, Harris S J, Scicinski S R. Pupillometer for clinical applications using dual 256-element linear CCD arrays.  Med & Biol Eng & Comp. 1992;  30 487-490
• 34 Haslbeck M. Diabetes therapy in advanced age. Managing specific problems.  MMW Fortschr Med. 1999;  141 42-45
• 35 Sundkvist G, Almer L, Lilja B. Respiratory influence on heart rate in diabetes mellitus.  Br Med J. 1979;  1 924-925
• 36 Ziegler D. Diabetische Neuropathie. München, Wien, Baltimore: Urban & Schwarzenberg 1993
• 37 Wieling W, Smith A AJ, Karemaker J M. Diabetic autonomic neuropathy: conventional cardiovascular laboratory testing and new developments.  Neuroscience Research Communications. 1997;  21 67-74
• 38 Wheeler T, Watkins P J. Cardiac denervation in diabetes.  Br Med J. 1993;  4 584-586
• 39 Watkins P J. Natural history of the diabetic neuropathies.  Q J Med. 1990;  77 1209-1218
• 40 Freeman R. Diabetic autonomic neuropathy. In: Korczyn AD (Ed). Handbook of autonomic nervous system dysfunction New York: Marcel Dekker Inc 1995: 219-234
• 41 Ewing D J. Analysis of heart rate variability and other non-invasive tests with special reference to diabetes mellitus. In: Bannister R, Matthias CJ (Eds). Autonomic failure. A textbook of Clinical Disorders of the Autonomic Nervous System Oxford: Oxford University Press 1992: 312-333
• 42 Ewing D J. Diabetic autonomic neuropathy and the heart.  Diabetes Res Clin Pract. 1996;  30 Suppl 31-36
• 43 Kahn J K, Sisson J C, Vinik A I. QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy.  J Clin Endocrinol Metab. 1987;  64 751-754
• 44 Jermendy G, Toth L, Voros P. et al . Cardiac autonomic neuropathy and QT interval length. A follow-up study in diabetic patients.  Acta Cardiol. 1991;  46 189-200
• 45 Kumhar M R, Agarwal T D, Singh V B. et al . Cardiac autonomic neuropathy and its correlation with QTc dispersion in type 2 diabetes.  Indian Heart J. 2000;  52 421-426
• 46 Langen K J, Ziegler D, Weise F. et al . Evaluation of QT interval length, QT dispersion and myocardial m-iodobenzylguanidine uptake in insulin-dependent diabetic patients with and without autonomic neuropathy.  Clin Sci (Colch). 1997;  93 325-333
• 47 Meier M, Muhr D, Weiss M. et al . QTc interval and scintigraphically assessed myocardial perfusion in newly diagnosed and long-term type 1 diabetes mellitus.  J Diabetes Complications. 2000;  14 90-95
• 48 Shimabukuro M, Chibana T, Yoshida H. et al . Increased QT dispersion and cardiac adrenergic dysinnervation in diabetic patients with autonomic neuropathy.  Am J Cardiol. 1996;  78 1057-1059
• 49 Tentolouris N, Katsilambros N, Papazachos G. et al . Corrected QT interval in relation to the severity of diabetic autonomic neuropathy.  Eur J Clin Invest. 1997;  27 1049-1054
• 50 Veglio M, Borra M, Stevens L K. et al . The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group.  Diabetologia. 1999;  42 68-75
• 51 Veglio M, Sivieri R, Chinaglia A. et al . QT interval prolongation and mortality in type I 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 1381-1383
• 52 Whitsel E A, Boyko E J, Siscovick D S. Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis.  Diabetes Care. 2000;  23 241-247
• 53 Claus D, Feistel H, Brunholzl C. et al . Investigation of parasympathetic and sympathetic cardiac innervation in diabetic neuropathy: heart rate variation versus meta-iodo-benzylguanidine measured by single photon emission computed tomography.  Clin Auton Res. 1994;  4 117-123
• 54 Ziegler D, Weise F, Langen K J. et al . Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I] metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients.  Diabetologia. 1998;  41 443-451
• 55 Tamura K, Utsunomiya K, Nakatani Y. et al . Use of iodine-123 metaiodobenzylguanidine scintigraphy to assess cardiac sympathetic denervation and the impact of hypertension in patients with non-insulin-dependent diabetes mellitus.   Eur J Nucl Med. 1999;  26 1310-1316
• 56 Spallone V, Menzinger G. Diagnosis of cardiovascular autonomic neuropathy in diabetes.  Diabetes. 1997;  46 Suppl 2 S67-76
• 57 Schnell O, Muhr D, Dresel S. et al . Partial restoration of scintigraphically assessed cardiac sympathetic denervation in newly diagnosed patients with insulin-dependent (type I) diabetes mellitus at one-year follow-up.  Diabet Med. 1997;  14 57-62
• 58 Schnell O, Muhr D, Weiss M. et al . Three-year follow-up on scintigraphically assessed cardiac sympathetic denervation in patients with long-term insulin-dependent (type I) diabetes mellitus.  J Diabetes Complications. 1997;  11 307-313
• 59 Schnell O, Muhr D, Weiss M. et al . Reduced myocardial 123I-metaiodobenzylguanidine uptake in newly diagnosed IDDM patients.  Diabetes. 1996;  45 801-805
• 60 Schnell O, Kirsch C M, Stemplinger J. et al . Scintigraphic evidence for cardiac sympathetic dysinnervation in long-term IDDM patients with and without ECG-based autonomic neuropathy.  Diabetologia. 1995;  38 1345-1352
• 61 Ohno T, Toyama T, Hoshizaki H. et al . Evaluation of cardiac sympathetic nervous function by 123I-metaiodobenzylguanidine scintigraphy in insulin-treated non-insulin dependent diabetics with hypoglycemia unawareness (see comments).  Intern Med. 1996;  35 94-99
• 62 Nagamachi S, Jinnouchi S, Nakahara H. et al . 123I-MIBG myocardial scintigraphy in diabetic patients: relationship to autonomic neuropathy.  Nucl Med Commun. 1996;  17 621-632
• 63 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;  44 543-549
• 64 Ewing D J, Martyn C N, Young R J. et al . The value of cardiovascular autonomic function tests: 10 years experience in diabetes.  Diabetes Care. 1985;  8 491-498
• 65 Hilsted J, Parving H H, Christensen N J. et al . Hemodynamics in diabetic orthostatic hypotension.  J Clin Invest. 1981;  68 1427-1434
• 66 Hilz M J, Hecht M J, Berghoff M. et al . Abnormal vasoreaction to arousal stimuli - an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry.  J Clin Neurophysiol. 2000;  17 419-425
• 67 Low P A, Walsh J C, Huang C Y. et al . The sympathetic nervous system in diabetic neuropathy. A clinical and pathological study.  Brain. 1975;  98 341-356
• 68 Paolisso G, Cennamo G, Marfella R. et al . Exaggerated orthostatic hypotension as first sign of diabetic autonomic neuropathy in the elderly.  Arch Gerontol Geriatr. 1989;  9 107-113
• 69 Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology.  Neurology. 1996;  46 1470
• 70 Kooner J S, Raimbach S, Watson L. et al . Relationship between splanchnic vasodilation and postprandial hypotension in patients with primary autonomic failure.  J Hypertens Suppl. 1989;  7 S40-41
• 71 Hoeldtke R D, Cilmi K M. Norepinephrine secretion and production in diabetic autonomic neuropathy.  J Clin Endocrinol Metab. 1984;  59 246-252
• 72 Hoeldtke R D, Boden G. Epinephrine secretion, hypoglycemia unawareness, and diabetic autonomic neuropathy.  Ann Intern Med. 1994;  120 512-517
• 73 Lien E A, Graue M, Iversen T H. et al . Prognosis of diabetes mellitus type 1. A follow-up study.  Tidsskr Nor Laegeforen. 1989;  109 1145-1149
• 74 Weston P J, Gill G V. Is undetected autonomic dysfunction responsible for sudden death in Type 1 diabetes mellitus? The ‘dead in bed’ syndrome revisited (see comments).  Diabet Med. 1999;  16 626-631
• 75 Saitta A, Bonaiuto M, Mileto A. et al . Changes in the QT interval caused by autonomic cardiovascular involvement in diabetes mellitus.  Minerva Med. 1991;  82 545-551
• 76 Ziegler D. Clinical aspects, diagnosis and therapy of diabetic neuropathy.  Ther Umsch. 1996;  53 948-957
• 77 Ewing D J, Campbell I W, Clarke B F. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications.  Ann Intern Med. 1980;  92 308-311
• 78 Donaghue K C. Autonomic neuropathy: diagnosis and impact on health in adolescents with diabetes.  Horm Res. 1998;  50 (Suppl 1) 33-37
• 79 Soler N G, Eagleton L E. Autonomic neuropathy and the ventilatory responses of diabetics to progressive hypoxemia and hypercarbia.  Diabetes. 1982;  31 609-614
• 80 Inoguchi T, Yamashita T, Umeda F. et al . High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 2000;  47 37-44
• 81 MiSAD . Prevalence of unrecognized silent myocardial ischemia and its association with atheroslerotic risk factors in noninsulin-dependent diabetes mellitus. Milan Study on Atherosclerosis and Diabetes (MiSAD) Group.  Am J Cardiol. 1997;  79 134-139
• 82 Ziegler D, Gries F A. Diagnostik und Therapie der kardiovaskulären autonomen, diabetischen Neuropathie.  Diabetes und Stoffwechsel. 1994;  3 22-31
• 83 Haslbeck M. Autonomic neuropathies in diabetes mellitus: diagnosis - therapy - risks.  Z Gesamte Inn Med. 1993;  48 162-176
• 84 Mancini M, Filippelli M, Seghieri G. et al . Respiratory muscle function and hypoxic ventilatory control in patients with type I diabetes.  Chest. 1999;  115 1553-1562
• 85 Santos e Fonseca C M, Manco J C. et al . Cholinergic bronchomotor tone and airway caliber in insulin-dependent diabetes mellitus.  Chest. 1992;  101 1038-1043
• 86 Scano G, Filippelli M, Romagnoli I. et al . Hypoxic and hypercapnic breathlessness in patients with type I diabetes mellitus.  Chest. 2000;  117 960-967
• 87 Williams J G, Morris A I, Hayter R C. et al . Respiratory responses of diabetics to hypoxia, hypercapnia, and exercise.  Thorax. 1984;  39 529-534
• 88 Edmonds M E, Watkins B J. Clinical presentations of diabetic autonomic failure. In: Bannister R, Matthias CJ (Eds). Autonomic failure. A textbook of Clinical Disorders of the Autonomic Nervous System Oxford: Oxford University Press 1992: 698-720
• 89 Annese V, Bassotti G, Caruso N. et al . Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus.  J Clin Gastroenterol. 1999;  29 171-177
• 90 Bittinger M, Barnert J, Wienbeck M. Autonomic dysfunction and the gastrointestinal tract.  Clin Auton Res. 1999;  9 75-81
• 91 Clarke B F, Ewing D J, Campbell I W. Diabetic autonomic neuropathy.  Diabetologia. 1979;  17 195-212
• 92 Cotroneo P, Grattagliano A, Rapaccini G L. et al . Gastric emptying rate and hormonal response in type II diabetics.  Diabetes Res. 1991;  17 99-104
• 93 Feldman M, Schiller L R. Disorders of gastrointestinal motility associated with diabetes mellitus.  Ann Intern Med. 1983;  98 378-384
• 94 Folwaczny C, Riepl R, Tschop M. et al . Gastrointestinal involvement in patients with diabetes mellitus: Part I (first of two parts). Epidemiology, pathophysiology, clinical findings.  Z Gastroenterol. 1999;  37 803-815
• 95 Maleki D, Locke G R 3rd, Camilleri M. et al . Gastrointestinal tract symptoms among persons with diabetes mellitus in the community.  Arch Intern Med. 2000;  160 2808-2816
• 96 Samsom M, Akkermans L M, Jebbink R J. et al . Gastrointestinal motor mechanisms in hyperglycaemia induced delayed gastric emptying in type I diabetes mellitus.  Gut. 1997;  40 641-646
• 97 Spallone V, Menzinger G. Autonomic neuropathy: clinical and instrumental findings.  Clin Neurosci. 1997;  4 346-358
• 98 Nakamura T, Takebe K, Imamura K. et al . Decreased gastric secretory functions in diabetic patients with autonomic neuropathy.  Tohoku J Exp Med. 1994;  173 199-208
• 99 Scarpello J H, Greaves M, Sladen G E. Small intestinal transit in diabetics.  Br Med J. 1976;  2 1225-1226
• 100 Enck P, Rathmann W, Spiekermann M. et al . Prevalence of gastrointestinal symptoms in diabetic patients and non-diabetic subjects.  Z Gastroenterol. 1994;  32 637-641
• 101 Jermendy G, Fornet B, Koltai M Z. et al . Correlation between oesophageal dysmotility and cardiovascular autonomic dysfunction in diabetic patients without gastrointestinal symptoms of autonomic neuropathy.  Diabetes Res. 1991;  16 193-197
• 102 Maddern G J, Horowitz M, Jamieson G G. The effect of domperidone on oesophageal emptying in diabetic autonomic neuropathy.  Br J Clin Pharmacol. 1995;  19 441-444
• 103 Pozzi M, Rivolta M, Gelosa M. et al . Upper gastrointestinal involvement in diabetes mellitus: study of esophagogastric function.  Acta Diabetol Lat. 1988;  25 333-341
• 104 Vannini P, Ciavarella A, Corbelli C. et al . Oesophageal transit time and cardiovascular autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus.  Diabetes Res. 1989;  11 21-25
• 105 Samsom M, Smout A J. Abnormal gastric and small intestinal motor function in diabetes mellitus.  Dig Dis. 1997;  15 263-274
• 106 Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum).  Ann Int Med. 1958;  48 797-812
• 107 Weck M, Ott P, Matthies K. Reduced gastric emptying and mesenteric blood flow in IDDM with cardiac autonomic neuropathy.  Acta Med Austriaca. 1997;  24 180-184
• 108 Kong M F, Horowitz M. Gastric emptying in diabetes mellitus: relationship to blood-glucose control.  Clin Geriatr Med. 1999;  15 321-338
• 109 Merio R, Festa A, Bergmann H. et al . Slow gastric emptying in type I diabetes: relation to autonomic and peripheral neuropathy, blood glucose, and glycemic control.  Diabetes Care. 1997;  20 419-423
• 110 Horowitz M, Harding P E, Maddox A F. et al . Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus.  Diabetologia. 1989;  32 151-159
• 111 Braden B, Adams S, Duan L P. et al . The [13C]acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals.  Gastroenterology. 1995;  108 1048-1055
• 112 Pfaffenbach B, Schaffstein J, Adamek R J. et al . The 13C-acetate breath test for the noninvasive assessment of the gastric emptying of a liquid/solid test meal in diabetics.  Dtsch Med Wochenschr. 1996;  31 713-718
• 113 Ghoos Y F, Maes B D, Geypens B J. et al . Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test.  Gastroenterology. 1993;  104 1640-1647
• 114 Ziegler D, Schadewaldt P, Pour Mirza A. et al . [13C]octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function.  Diabetologia. 1996;  39 823-830
• 115 Guy R J, Dawson J L, Garrett J R. et al . Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology.  J Neurol Neurosurg Psychiatry. 1984;  47 686-691
• 116 Vaisman N, Weintrob N, Blumental A. et al . Gastric emptying in patients with type I diabetes mellitus.  Ann N Y Acad Sci. 1999;  873 506-511
• 117 Jones K L, Horowitz M, Berry M. et al . Blood glucose concentration influences postprandial fullness in IDDM.  Diabetes Care. 1997;  20 1141-1146
• 118 Jones K L, Horowitz M, Wishart M J. et al . Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus.  J Nucl Med. 1995;  36 2220-2228
• 119 Silvers D, Kipnes M, Broadstone V. et al . Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group.  Clin Ther. 1998;  20 438-453
• 120 Tanis A A, Baggen M G, Wiggers R H. et al . Side-effects of oral erythromycin for treatment of diabetic gastroparesis.  Lancet. 1993;  342 1431
• 121 Borovicka J, Lehmann R, Kunz P. et al . Evaluation of gastric emptying and motility in diabetic gastroparesis with magnetic resonance imaging: effects of cisapride.  Am J Gastroenterol. 1999;  94 2866-2873
• 122 Katz L A, Spiro H M. Gastrointestinal manifestations of diabetes.  N Engl J Med. 1966;  275 1350-1361
• 123 Battle W M, Snape Jr W J, Alavi A. et al . Colonic dysfunction in diabetes mellitus.  Gastroenterology. 1980;  79 1217-1221
• 124 Barnett J L, Vinik A I. Gastrointestinal disturbances. In: Lebovitz AE (Ed). Therapy for Diabetes Mellitus and Related Disorders Alexandria, VA: American Diabetes Association 1991: 279-287
• 125 Schiller L R, Santa Ana C A, Morawski S G. et al . Studies of the antidiarrheal action of clonidine. Effects on motility and intestinal absorption.  Gastroenterology. 1985;  89 982-988
• 126 Fedorak R N, Field M, Chang E B. Treatment of diabetic diarrhea with clonidine.  Ann Intern Med. 1985;  102 197-199
• 127 Tsai S T, Vinik A I, Brunner J F. Diabetic diarrhea and somatostatin.  Ann Intern Med. 1986;  104 894
• 128 Cozzolino D, Salvatore T, Giugliano D. et al . Sensorimotor evaluation of ano-rectal complex in diabetes mellitus.  Diabete Metab. 1991;  17 520-524
• 129 Ludwig E B, Gross J L, Pecis M. et al . Abnormalities in gallbladder dynamics of type 1 (insulin-dependent) diabetic patients with autonomic neuropathy.  Braz J Med Biol Res. 1995;  28 531-536
• 130 Itoh H, Matsumoto T, Tanimoto N. et al . Cholecystoparesis with diabetic autonomic neuropathy.  Intern Med. 1997;  36 624-627
• 131 Varkonyi T, Lengyel C, Madacsy L. et al . Gallbladder hypomotility in diabetic polyneuropathy.  Orv Hetil. 1997;  138 1177-1182
• 132 Bucceri A M, Brogna A, Ferrara R. Sonographic study of postprandial gallbladder emptying and common bile duct changes in patients with diabetes or cholelithiasis.  Abdom Imaging. 1994;  19 427-429
• 133 Stone B G, Gavaler J S, Belle S H. et al . Impairment of gallbladder emptying in diabetes mellitus.  Gastroenterology. 1988;  95 170-176
• 134 Ruhl C E, Everhart J E. Association of diabetes, serum insulin, and C-peptide with gallbladder disease.  Hepatology. 2000;  31 299-303
• 135 Appell R A, Whiteside H V. Diabetes and other peripheral neuropathies affecting lower urinary tract function. In: Krane RJ, Siroky MB (Eds). Clinical Neuro-Urology Boston: Little, Brown & Co 1992: 365-373
• 136 Bradley W E. Diagnosis of urinary bladder dysfunction in diabetes mellitus.  Ann Intern Med. 1980;  92 323-326
• 137 Buck A C, Reed P I, Siddiq Y K. et al . Bladder dysfunction and neuropathy in diabetes.  Diabetologia. 1976;  12 251-258
• 138 Ellenberg M. Development of urinary bladder dysfunction in diabetes mellitus.  Ann Intern Med. 1980;  92 321-323
• 139 Fowler C J. Investigation and treatment of bladder and sexual dysfunction in diseases affecting the autonomic nervous system. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system Oxford: Oxford University Press 1999: 296-306
• 140 Ueda T, Yoshimura N, Yoshida O. Diabetic cystopathy: relationship to autonomic neuropathy detected by sympathetic skin response.  J Urol. 1997;  157 580-584
• 141 Clarke B F, Ewing D J, Campbell I W. Clinical features of diabetic autonomic neuropathy.  Horm Metab Res Suppl. 1980;  9 50-60
• 142 Ellenberg M, Weber H. Bladder decompensation correlates with diabetic neuropathy.  JAMA. 1966;  197 39
• 143 Strian F, Haslbeck M. Neurologische Erkrankungen. In: Mehnert H, Standl E, Usadel KH (Eds). Diabetologie in Klinik und Praxis Stuttgart: Thieme Verlag 1999: 456-480
• 144 Stief C, Thon W, Truss M. et al . Blasenfunktionsstörungen und erektile Dysfunktion bei Diabetes mellitus.  Deutsches Ärzteblatt. 1996;  33 A2082-A2086
• 145 Klein R, Klein B E, Lee K E. et al . Prevalence of self-reported erectile dysfunction in people with long-term IDDM.  Diabetes Care. 1996;  19 135-141
• 146 McCulloch D K, Young R J, Prescott R J. et al . The natural history of impotence in diabetic men.  Diabetologia. 1984;  26 437-440
• 147 Quadri R, Veglio M, Flecchia D. et al . Autonomic neuropathy and sexual impotence in diabetic patients: analysis of cardiovascular reflexes.  Andrologia. 1989;  21 346-352
• 148 Wellmer A, Sharief M K, Knowles C H. et al . Quantitative sensory and autonomic testing in male diabetic patients with erectile dysfunction.  BJU Int. 1999;  83 66-70
• 149 Saenz de Tejada I, Kim N, Lagan I. et al . Regulation of adrenergic activity in penile corpus cavernosum.  J Urol. 1989;  142 1117-1121
• 150 Saenz de Tejada I, Goldstein I, Azadzoi K. et al . Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence.  N Engl J Med. 1989;  320 1025-1030
• 151 Stewart J D. Autonomic regulation of sexual function. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 129-134
• 152 Ellenberg M, Weber H. Retrograde ejaculation in diabetic neuropathy.  Ann Intern Med. 1966;  65 1237-1247
• 153 Barany F R, Cooper E H. Pilomotor and sudomotor innervation in diabetes.  Clin Sci. 1956;  15 533-540
• 154 Fealey R D. Thermoregulatory sweat test. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 245-257
• 155 Fealey R D, Low P A, Thomas J E. Thermoregulatory sweating abnormalities in diabetes mellitus.  Mayo Clin Proc. 1989;  64 617-628
• 156 Kennedy W R, Sakuta M, Sutherland D. et al . The sweating deficiency in diabetes mellitus: methods of quantitation and clinical correlation.  Neurology. 1984;  34 758-763
• 157 Low P A, Fealey R D. Evaluation of sudomotor function. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system Oxford: Oxford University Press 1999: 263-270
• 158 Goodman J I. Diabetic anhidrosis.  Am J Med. 1966;  41 831-835
• 159 Stewart J D, Low P A, Fealey R D. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes.  Muscle Nerve. 1992;  15 661-665
• 160 Shaw J E, Parker R, Hollis S. et al . Gustatory sweating in diabetes mellitus.  Diabet Med. 1996;  13 1033-1037
• 161 van der Linden J, Sinnige H A, van den Dorpel M A. Gustatory sweating and diabetes.  Neth J Med. 2000;  56 159-162
• 162 Watkins P J. Facial sweating after food: a new sign of diabetic autonomic neuropathy.  Br Med J. 1973;  1 583-587
• 163 Spitzer A, Lang E, Birklein F. et al . Cardiac autonomic involvement and peripheral nerve function in patients with diabetic neuropathy.  Funct Neurol. 1997;  12 115-122
• 164 Spitzer A, Claus D. Untersuchungsmethoden des peripheren autonomen Nerven.  Nervenheilkunde. 1996;  15 391-398
• 165 Low P A, Caskey P A, Tuck R R. et al . Quantitative sudomotor axon reflex test in normal and neuropathic subjects.  Ann Neurol. 1983;  14 573-580
• 166 Lang E, Foerster A, Pfannmuller D. et al . Quantitative assessment of sudomotor activity by capacitance hygrometry.  Clin Auton Res. 1993;  3 107-115
• 167 Stevens M J, Edmonds M E, Douglas S L. et al . Influence of neuropathy on the microvascular response to local heating in the human diabetic foot.  Clin Sci. 1991;  80 249-256
• 168 Pitei D L, Watkins P J, Edmonds M E. NO-dependent smooth muscle vasodilatation is reduced in NIDDM patients with peripheral sensory neuropathy.  Diabet Med. 1997;  14 284-290
• 169 Edmonds M E, Morrison N, Laws J W. et al . Medial arterial calcification and diabetic neuropathy.  Br Med J. 1982;  284 928-930
• 170 Ewing D J, Bellavere F, Espi F. et al . Correlation of cardiovascular and neuroendocrine tests of autonomic function in diabetes.  Metabolism. 1986;  35 349-353
• 171 Ewing D J, Clarke B F. Autonomic neuropathy: its diagnosis and prognosis.  Clin Endocrinol Metab. 1986;  15 855-888
• 172 Cryer P E. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness.  Endocrinol Metab Clin North Am. 1999;  28 495-500
• 173 Davis S N, Fowler S, Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes.  Diabetes. 2000;  49 65-72
• 174 Hepburn D A, Patrick A W, Brash H M. et al . Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation.  Diabet Med. 1991;  8 934-945
• 175 Jorneskog G, Lins P E, Adamson U. et al . Patients with type 1 diabetes lack vasoconstrictor response in skin microcirculation during insulin-induced hypoglycemia.  Int J Microcirc Clin Exp. 1994;  14 262-268
• 176 Sussman K E, Crout J R, Marble A. Failure of warning in insulin-induced hypoglycemic reactions.  Diabetes. 1963;  12 38
• 177 Stephenson J M, Kempler P, Perin P C. et al . Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study.  Diabetologia. 1996;  39 1372-1376
• 178 Gerich J E, Langlois M, Noacco C. et al . Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect.  Science. 1973;  182 171-173
• 179 Association A D, Consensus Statement . Report and recommendation of the San Antonio Consensus Conference on Diabetic Neuropathy.  Diabetes Care. 1988;  11 592-597
• 180 Braune H-J. Early detection of diabetic neuropathy: a neurophysiological study on 100 patients.  Electromyogr Clin Neurophysiol. 1997;  37 399-407
• 181 Low P A, Denq J C, Opfer-Gehrking T L. et al . Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects.  Muscle Nerve. 1997;  20 1561-1568
• 182 Low P A. The effect of aging on the autonomic nervous system. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 161-175
• 183 Low P A, Opfer-Gehrking T L, Proper C J. et al . The effect of aging on cardiac autonomic and postganglionic sudomotor function.  Muscle Nerve. 1990;  13 152-157
• 184 Mathias C J, Bannister R. Investigation of autonomic disorders. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system Oxford: Oxford University Press 1999: 169-195
• 185 Ziegler D, Laux G, Dannehl K. et al . Assessment of cardiovascular autonomic function: age-related normal ranges and reproducibility of spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses.  Diabet Med. 1992;  9 166-175
• 186 Ewing D J. Noninvasive evaluation of heart rate: the time domain. In: Low PA (Ed). Clinical Autonomic Disorders Boston: Little, Brown & Co 1993: 297-314
• 187 Freeman M R, Newman D, Dorian P. et al . Relation of direct assessment of cardiac autonomic function with metaiodobenzylguanidine imaging to heart rate variability in diabetes mellitus.  Am J Cardiol. 1997;  80 247-250
• 188 Low P A. Laboratory evaluation of autonomic function. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 179-208
• 189 Ziegler D, Rathmann W. Neue Aspekte zur kardiovaskulären autonomen diabetischen Neuropathie.  Diabetes und Stoffwechsel. 1994;  3 410-416
• 190 Wieling W, Karemaker J M. Measurement of heart rate and blood pressure to evaluate disturbances in neurocardiovascular control. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system. Oxford: Oxford University Press 1999: 196-210
• 191 Wieling W, Lieshout v J J. Maintenance of postural normotension in humans. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 73-82
• 192 Wieling W. Non-invasive continuous recording of heart rate and blood pressure in the evaluation of neurovascular control. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system Oxford: Oxford University Press 1992: 291-311
• 193 Smith S A, Smith S E. Reduced sinus arrhythmia in diabetic autonomic neuropathy.  Br Med J (Clin Res Ed). 1983;  286 723
• 194 Smith S E, Smith S A. Heart rate variability in healthy subjects measured with a bedside computer-based technique.  Clin Sci. 1981;  61 379-383
• 195 Ziegler D, Dannehl K, Volksw D. et al . Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis and standard tests of heart-rate variation in newly diagnosed IDDM patients.  Diabetes Care. 1992;  15 908-911
• 196 Karemaker J M. Analysis of blood pressure and heart rate variability: theoretical considerations. In: Low PA (Ed). Clinical Autonomic Disorders Philadelphia: Lippincott-Raven Publishers 1997: 309-322
• 197 Parati G, Di Rienzo M, Omboni S. et al .Computer analysis of blood pressure and heart rate variability in subjects with normal and abnormal autonomic cardiovascular control. In: Bannister R, Mathias CJ (Eds). Autonomic failure. A textbook of clinical disorders of the autonomic nervous system Oxford: Oxford University Press 1999: 211-223
• 198 Pomeranz B, Macaulay R J, Caudill M A. et al . Assessment of autonomic function in humans by heart rate spectral analysis.  Am J Physiol. 1985;  248 H151-H153
• 199 Pagani M, Lombardi F, Guzzetti S. et al . Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.  Circ Res. 1986;  59 178-193
• 200 Mestivier D, Chau N P, Chanudet X. et al . Relationship between diabetic autonomic dysfunction and heart rate variability assessed by recurrence plot.  Am J Physiol. 1997;  272 H1094-H1099
• 201 Greene D A, Lattimer S A, Sima A A. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications.  N Engl J Med. 1987;  316 599-606
• 202 Low P A. Recent advances in the pathogenesis of diabetic neuropathy.  Muscle Nerve. 1987;  10 121-128
• 203 Sima A A, Sugimoto K. Experimental diabetic neuropathy: an update.  Diabetologia. 1999;  42 773-788
• 204 Dyck P J. Hypoxic neuropathy: does hypoxia play a role in diabetic neuropathy? The 1988 Robert Wartenberg lecture.  Neurology. 1989;  39 111-118
• 205 Dyck P J, Giannini C. Pathologic alterations in the diabetic neuropathies of humans: a review.  J Neuropathol Exp Neurol. 1996;  55 1181-1193
• 206 Low P A, Nickander K K, Tritschler H J. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy.  Diabetes. 1997;  46 Suppl 2 38-42
• 207 Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.  N Engl J Med. 1988;  318 1315-1321
• 208 Bucala R, Tracey K J, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.  J Clin Invest. 1991;  87 432-438
• 209 Zochodne D W. Is early diabetic neuropathy a disorder of the dorsal root ganglion? A hypothesis and critique of some current ideas on the etiology of diabetic neuropathy.  J Peripher Nerv Syst. 1996;  1 119-130
• 210 Ejskjaer N, Arif S, Dodds W. et al . Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus.  Diabet Med. 1999;  16 544-549
• 211 Hoeldtke R D, Bryner K D, Hobbs G R. et al . Antibodies to glutamic acid decarboxylase and peripheral nerve function in type 1 diabetes.  J Clin Endocrinol Metab. 2000;  85 3297-3308
• 212 Husebye E S, Winqvist O, Sundkvist G. et al . Autoantibodies against adrenal medulla in type 1 and type 2 diabetes mellitus: no evidence for an association with autonomic neuropathy.  J Intern Med. 1996;  239 139-146
• 213 Muhr D, Mollenhauer U, Ziegler A G. et al . Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.  Diabetes Care. 1997;  20 1009-1012
• 214 Muhr-Becker D, Ziegler A G, Druschky A. et al . Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction.  Diabet Med. 1998;  15 467-472
• 215 Rabinowe S L, Brown F M, Watts M. et al . Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Autonomic brake index and heart-rate variation.  Diabetes Care. 1990;  13 1084-1088
• 216 Schnell O, Muhr D, Dresel S. et al . Autoantibodies against sympathetic ganglia and evidence of cardiac sympathetic dysinnervation in newly diagnosed and long-term IDDM patients.  Diabetologica. 1996;  39 970-975
• 217 Zochodne D W. Neurotrophins and other growth factors in diabetic neuropathy.  Semin Neurol. 1996;  16 153-161
• 218 Brewster W J, Fernyhough P, Diemel L T. et al . Diabetic neuropathy, nerve growth factor and other neurotrophic factors.  Trends Neurosci. 1994;  17 321-325
• 219 Diemel L T, Brewster W J, Fernyhough P. et al . Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brain-derived neurotrophic factor.  Brain Res Mol Brain Res. 1994;  21 171-175
• 220 Maeda K, Fernyhough P, Tomlinson D R. Regenerating sensory neurones of diabetic rats express reduced levels of mRNA for GAP-43, gamma-preprotachykinin and the nerve growth factor receptors, trkA and p75NGFR.  Brain Res Mol Brain Res. 1996;  37 166-174
• 221 Faradji V, Sotelo J. Low serum levels of nerve growth factor in diabetic neuropathy.  Acta Neurol Scand. 1990;  81 402-406
• 222 Tomlinson D R, Fernyhough P, Diemel L T. Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors.  Diabetes. 1997;  46 Suppl 2 43-49
• 223 Zanone M M, Banga J P, Peakman M. et al . An investigation of antibodies to nerve growth factor in diabetic autonomic neuropathy.  Diabet Med. 1994;  11 378-383
• 224 Didangelos T P, Karamitsos D T, Athyros V G. et al . Effect of aldose reductase inhibition on cardiovascular reflex tests in patients with definite diabetic autonomic neuropathy over a period of 2 years.  J Diabetes Complications. 1998;  12 201-207
• 225 Giugliano D, Marfella R, Quatraro A. et al . Tolrestat for mild diabetic neuropathy. A 52-week, randomized, placebo-controlled trial.  Ann Intern Med. 1993;  118 7-11
• 226 Ziegler D. Therapie der peripheren diabetischen Neuropathie.  Diab Stoffw. 1998;  7 103-113
• 227 Levi-Montalcini R. The nerve growth factor 35 years later.  Science. 1987;  237 1154-1162
• 228 DCCT Research Group . The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT).  Diabetologia. 1998;  41 416-423
• 229 Thomas P K. Mechanisms and Treatment of Pain. In: Dyck PJ, Thomas PK (Eds). Diabetic Neuropathy Philadelphia: WB Saunders 1998: 387-397
• 230 Clarke B F, Campbell I W, Ewing D J. Prognosis in diabetic autonomic neuropathy.  Horm Metab Res Suppl. 1980;  9 101-104
• 231 Sampson M J, Wilson S, Karagiannis P. et al . Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics.  Q J Med. 1990;  75 635-646
• 232 Schnell O, Stenner T, Standl E. et al . The diagnostic value of the rate-corrected QT interval in long-term type-1 diabetes mellitus.  Dtsch Med Wochenschr. 1996;  121 819-822
• 233 Orchard T J, Ce L L, Maser R E. et al . Why does diabetic autonomic neuropathy predict IDDM mortality? An analysis from the Pittsburgh Epidemiology of Diabetes Complications Study.  Diabetes Res Clin Pract. 1996;  34 Suppl 165-171
• 234 O'Brien I A, McFadden J P, Corrall R J. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes.  Q J Med. 1991;  79 495-502
• 235 Ewing D J, Campbell I W, Clarke B F. The natural history of diabetic autonomic neuropathy.  Q J Med. 1980;  49 95-108