university of groningen the diabetic foot syndrome ...92 - the diabetic foot syndrome abstract...

University of Groningen

The diabetic foot syndrome, diagnosis and consequencesMeijer, Johannes Wilhelmus Gerardus

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Chapter 8

Dissociation in polyneuropathy and cardiovascular autonomic neuropathy

in diabetes mellitus

J.W.G. Meijer, J.D. Lefrandt, T.P. Links, W.H. Eisma, J. Trip, A.J. Smit

Submitted.

92 - The diabetic foot syndrome

Abstract Introduction Cardiac autonomic neuropathy (CAN) tests,

recommended as one of the diagnostic categories for diabetic polyneuropathy (PNP), may be more a reflection of cardiovascular abnormalities than of PNP in diabetes.

Aim To test the agreement between several CAN tests and other neuropathy, and vascular categories over a broad range of diabetic patients.

Methods In a random sample of 45 diabetic patients (18 type 1, 27 type 2; diabetes duration 11.8 years), the Ewing battery, short-term heart rate variability and baroreflex sensitivity as CAN tests were compared with PNP examination (DNE) and symptom (DNS) scores and with monofilaments (MF) and vibration perception threshold (VPT). CAN tests were also related to ankle- and toe-brachial index (A/TBI) and to laser Dopplerflow (LDF) measures (Tmax) at the foot.

Results A weak relation of the Ewing test score to the MF scores and VPT (r= .33 with MF hallux, and .32 with VPT hallux) was not significant after age correction, while no association was evident with DNE- and DNS-scores. For HFnu the relation remained significant after age correction with the DNE-score (r= .41), monofilament scores and VPT (r= .37 and .32, respectively). BRS was not associated to peripheral neuropathy scores. CAN tests were not related to A/TBI. HFnu was associated to LDF-Tmax (r=.47), the DNE-score was related to Vmax (r= -.42). No other relation was found with microcirculation.

Conclusion CAN tests are weakly related to MF, VPT and DNE-score, and even less to DNS-score for diabetic PNP. Some CAN tests might both reflect microvascular angiopathy and diabetic PNP.

8.1 Introduction Because no ‘gold standard’ exists for diagnosing diabetic polyneuropathy (PNP) in clinical practice, a consensus panel from the San Antonio Conference on Diabetic Neuropathy recommended that 1 measurement should be performed of 5 diagnostic categories 1. One of these categories is Autonomic Function Testing, to diagnose autonomic neuropathy (ANP). The consensus recommended the Ewing Battery for this category 1,2. Disadvantages of this battery are its limited reproducibility and sensitivity, and the requirement of active co-operation of the patient 3. Recently, newer techniques like measurement of heart rate variability (HRV), QT interval prolongation and dispersion, and baroreflex sensitivity (BRS) have been reported to detect ANP, or more specifically Cardiovascular Autonomic Neuropathy (CAN), in an early stage 4-6. The diagnostic use of Ewing tests, and even more so HRV and BRS measurements, assumes that these hemodynamic tests assess primarily the presence and degree of CAN, or at least dysfunction, as a component of diabetic neuropathy. However, considerable evidence suggests that CAN testing is influenced by other factors than neuropathy alone. CAN, as measured by one of the techniques above, is dissociated from other manifestations of ANP like gastrointestinal motor dysfunction 7. We recently reported on the important independent contribution of microalbuminuria to HRV and BRS abnormalities in diabetes, as confirmed by others 8-11. Di Carli elegantly demonstrated the close link between cardiac sympathetic innervation and impaired vasodilator response of coronary resistance vessels, both measured using PET scanning, in diabetics 12. Long-term effects of converting enzyme inhibition on autonomic modulation, tested with HRV, were found in diabetes patients with autonomic neuropathy 13, 14. Vascular structure, defined as aortic stiffness measured by pulse wave velocity is strongly related to the E/I ratio during the Ewing deep breathing test in type 1 diabetes mellitus 15. We also found carotid intimal-medial thickness to be strongly related to BRS in hypertension 16. HRV and BRS have been found to be strong independent predictors of cardiovascular mortality in conditions like congestive heart failure and after myocardial infarction 17. Thus, evidence exists that functional or structural vascular abnormalities have an important effect on several autonomic neuropathy tests. Although overt cardiac abnormalities were already longer known to affect Ewing test results, more subtle cardiovascular abnormalities, very prevalent in diabetes mellitus, might thus also affect one of the test categories for diabetic polyneuropathy.

Chapter 8: Dissociation in PNP and CAN - 93

The aim of our study was to test the relation between several cardiac autonomic neuropathy tests, other diagnostic categories for diabetic neuropathy, and vascular functioning, over a broad range of patients with diabetes mellitus, prone to or suffering from diabetic foot disease. 8.2 Patients and Methods Patients Our study group consisted of 45 patients with diabetes mellitus, both type 1 and 2. Exclusion criteria were factors that may interfere with the neurological condition of the subjects other than PNP, a history or clinically apparent cardiac disease, electrocardiographic abnormalities or the use of betablokkers or calcium antagonists. The patients were randomly selected from the diabetes outpatient clinic of the University Hospital (Groningen, the Netherlands). The characteristics of the patients are shown in Table 1. The participants all gave informed consent and the study was conducted according to recommendations of the Declaration of Helsinki. Table 1: Patient Characteristics n = 45 Sex: Male : Female

32 : 13

Mean age (yrs)(SD) Min-max (yrs)

52.3 (13.8) 18-78

Mean duration DM (yrs)(SD) Min – max (yrs)

11.8 (8.8) 1 – 36

Type of DM 1 : 2

18 : 27

Mean HbA1c (%)(SD) Min – max

8.7 (1.5) 6.8 – 13.5

Methods The following tests were performed in all patients: (1) cardiovascular autonomic neuropathy (CAN) tests, (2) a diabetic PNP symptom and physical examination score, (3) Quantitative Sensory Tests (QST), and (4) a vascular examination. Tests (2) and (3) were performed by the same researcher (J.-W.G.M.), (1) and (4) in a separate session by technicians, unaware of the results of the PNP scores and QST.


(1) Cardiovascular Autonomic Neuropathy (CAN) tests To assess CAN, the Ewing test battery, Heart Rate Variability and Baroreflex Sensitivity were tested. The tests were performed in a quiet room with a temperature of 22 0C. The patients rested in the supine position. Blood pressure was monitored by a Finapres (Ohmeda 2300, Inglewood, Col., USA) and heart rate by an ECG monitor (Hewlett-Packard 78351T, Palo Alto, Ca., USA) during all tests. The Finapres-cuff was put on the right middle finger. Ewing test battery The Ewing test battery consists of 5 tests: deep breathing, Valsalva manoeuvre, isometric handgrip and standing up (influence on heart rate and blood pressure, respectively) 2. The execution and interpretation of the test manoeuvres has been described in detail elsewhere3, 18,19. Autonomic neuropathy was classified categorically as follows: 1 = all tests within normal range, 2 = 1 abnormal and 1 or 2 in the borderline range, 3 = 2 or more tests abnormal. Heart rate variability HRV analysis was performed in accordance with the guidelines of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology 20. The Finapres and ECG signal were sampled at 100 Hz and stored on a personal computer during 15 min. Offline, 300 seconds of each recording was analysed by the CARSPAN programme (IEC ProGamma, Groningen, the Netherlands), as described previously 21. After artefact correction and stationarity check, discrete Fourier transformation of systolic blood pressure and RR interval length was performed. Time domain and frequency domain HRV parameters can be analysed, we only addressed frequency domain parameters in the present study. Because absolute values of low and high frequency are related to total frequency power and heart rate, we also used normalised low and high frequency units, LFnu and HFnu, calculated as low frequency * 100 %/ total frequency and high frequency * 100 %/ total frequency, respectively. Baroreflex sensitivity measurement To assess baroreflex sensitivity (BRS) blood pressure and heart rate were measured beat-to-beat by Finapres. BRS was determined by the ‘transfer function’ method 21 using the CARSPAN programme, as previously described in more detail8.


(2) PNP symptom and physical examination score The Diabetic Neuropathy Symptom (DNS) score and the Diabetic Neuropathy Examination (DNE) score were performed. The DNS-score Both the DNS-score and DNE-score have been described in detail elsewhere 22,23. In short, the DNS score is a 4 item validated symptom score, with high predictive value to screen for PNP in DM 23. Symptoms of unsteadiness in walking, neuropathic pain, paraesthesia and numbness are elicited. The presence of a symptom is scored as 1 point; the maximum score is 4 points. A score of one or higher is defined as positive for PNP. The DNE-score The DNE-score is a sensitive and validated hierarchical scoring system for diabetic PNP 23. The score contains 2 items concerning muscle strength, 1 concerning reflexes and 5 concerning sensation, with a total of 8 items. Each item is scored from 0 to 2 (0 is normal and 2 severely disturbed). The maximum score is 16 points. A score of more than 3 points is defined as positive for PNP. (3) Quantitative Sensory Tests (QST) Semmes-Weinstein monofilaments (SWMFs) and Vibration Perception Threshold (VPT) testing were used to assess QST. SWMFs were tested on the plantar surface of the hallux and centrally at the heel (when necessary after removal of excessive calluses). This method was standardised according to generally accepted guidelines 24, 25. The "yes/no" method was used, which means that the patient says "yes" each time that he or she senses the application of a monofilament. Six trials were administered. The 10-g monofilament was used. We present the results in 2 categories: category 1: 10-g monofilament felt (=normal) and category 2: 10-g monofilament not felt (= abnormal). VPTs were determined using a hand-held biothesiometer (Biomedical Instruments, Newbury, OH). VPT was tested at the dorsum of the hallux on the interphalangeal joint. It was performed in a standardised way as described elsewhere 26-28. The voltage of vibration was increased until the patient could perceive a vibration. This was done 3 times. The mean of these 3 trials was used to determine the VPT. Age-adjusted reference values were used 27, 28.


(4) Vascular examination: Toe and ankle pressures Ankle and toe pressures were measured using standard procedures as described in detail previously29. The ratio of the ankle and toe pressure and the simultaneously recorded brachial systolic blood pressure was the ankle-brachial (ABI), and toe-brachial index (TBI), respectively. Laser Doppler flow measurements A post-occlusive reactive hyperaemia (PORH) procedure with laser Doppler skin blood flow was performed and analysed according to previously described methods, with a Diodopp LDF meter at the pulpar side of the extremity of one of the toes30. We used in PORH after occlusion the maximal blood flow (Vmax) and the time to reach this maximum (Tmax) for analysis. We also tried to establish the half time of the period after reaching this maximum till flow values had reached baseline skin blood flow again, but often this was not possible because flow did not reach baseline levels again and showed considerable variability after the occlusion period. Therefore, we did not further take this parameter into account in our analysis. Statistical analyses The statistical package SPSS-PC 10.0.07 (Chicago) was used to compute the descriptive statistics, factor analysis, Pearson's and Spearman’s correlation coefficient r, and Student-t test. Mean, standard deviation, minimum and maximum are given. For BRS a logarithmic transformation was used (lnBRS) to obtain a normal distribution for further analysis. In cases with normal distribution of variables Pearson’s correlation was assessed, in case of non-normal distribution or of categorical values Spearman’s correlation was used. The number of 45 patients is sufficient to detect an r of 0.3 with a power of 80 % and P < 0.05. No further subgroup analysis was performed.


8.3 Results The group scores for CAN, PNP and vascular tests are shown in Table 2. Table 2: Group scores for CAN, PNP and vascular tests. Means and SD

Range

CAN tests: Ewing score 23 / 12 / 8 HRV lnHFnu .53 .22 .14-.88 HRV lnLFnu .47 .22 .12-.86 HRV LFHF -.66 1.02 -3.4-1.9 lnBRS 1.8 .72 .11- 3.3 PNP scores: DNS 1.0 1.2 0 - 4 DNE 4.4 3.1 0-11 QST: SW-MF Hallux 29n/16a SW-MF Heel 27/n18a VPT Hallux 22.2 15.2 2-50 VPT Malleolus med 23.4 13.9 4-50 Vascular tests: ABI 117 21 10-174 TBI 82.6 20 10-131 LDF-tMax ( n = 19) 22.9 15.2 1.3-52.8 The group scores are expressed as numbers in categories, or as mean, SD and range for CAN tests (Ewing score, categories 1, 2 and 3, resp.); HRV expressed as lnHFnu, lnLFnu and lnLFHF; and lnBRS), PNP scores (DNS-, DNE-score), QST (SW-MF, VPT) and vascular measurements (ABI, TBI, LDF=tMax and t1/2). Interrelationships between CAN tests The score of the Ewing autonomic neuropathy tests was not related to the HRV measure HFnu or any other HRV measure, but was strongly related to lnBRS (Spearman’s r = -0.57, p < 0.0001). lnBRS was modestly related to HFnu, but more strongly related to other HRV measures (ln total power Pearson’s r = 0.89; with lnHF 0.83, respectively). CAN tests compared to PNP symptom and physical examination scores The sum scores of the Ewing autonomic neuropathy tests were not related to any of the PNP scores, without or with correction for age.


Using several HRV measures, a relation was found between Hfnu and the DNE- score (r=0.41 after age correction). Other HRV measures were not related to any of the PNP scores. For lnBRS, without or with correction for age, no significant relations were found with any of the PNP scores. CAN tests compared to QST The sum scores of the Ewing autonomic neuropathy tests were not related to the results of the tests with monofilaments at the hallux, a weak relation (Spearman’s r = 0.33, p = 0.02) was found with monofilaments at the heel, which became non-significant after correction for age. With VPT at the hallux comparable results were found (r = 0.32, p = 0.02 in bivariate analysis, loss of significance after correction for age). Of several HRV measures HFnu was modestly related to monofilament and VPT scores (after correction for age, monofilaments hallux and heel 0.37 and 0.36, respectively; VPT hallux 0.32; all P < 0.05). For lnBRS, after correction for age, no significant relations were found with monofilament or VPT scores. CAN tests compared to toe and ankle pressures The sum scores of the Ewing autonomic neuropathy tests and lnBRS were not related to toe or ankle pressures. HFnu was related to the toe-arm-index, but this relation was not present any more after correction for age (without correction for age r = 0.39, p = 0.01; after age correction r = -0.23, n.s.). No relation of HFnu was found with ankle pressures. CAN tests, PNP symptom and physical examination, and QST scores compared to LDF measurements Because of technical problems with the laser Doppler equipment during a substantial period of the study LDF measurements could be obtained in only 19 persons. This group was otherwise comparable to the other participants. Within this group a significant relation was found between total power and high frequency power (Hfnu) in the heart rate variability measurement and the Tmax LDF value (r = 0.44, and 0.47, respectively, both p < 0.05). This relation remained present after correction for age. No relation was found with baseline flow or maximal flow during PORH. As for the PNP scores and QST, the DNE score was related to V max (r = -0.42). No relations were found with the baseline LDF signal.


8.4 Discussion This study shows that several so-called cardiac autonomic neuropathy (CAN) tests are not, or only very weakly, related to the QST (SWMF and VPT) and the PNP physical examination score (DNE-score), and even less to the PNP symptom score. The assumption that CAN tests may also be a reflection of diabetic microangiopathy was confirmed in the relations of some of the CAN scores with laser Doppler flow measures. No relation existed between CAN scores and toe or ankle pressures. However, toe or ankle pressures are a marker for macrovascular disease, and not of other forms of vasculopathy in diabetes, especially microangiopathy. A complex interrelationship between neuropathy and angiopathy exists in diabetes mellitus. Ample evidence supports a role for functional and structural vascular abnormalities in the pathogenesis of diabetic polyneuropathy: Veves demonstrated endothelial dysfunction in patients with diabetic neuropathy and diabetic foot disease 31. Conversely, their analysis shows neuropathy as the most important contributing factor in explaining endothelial dysfunction. Jude showed increased levels of cell adhesion molecules, partly of endothelial origin, in diabetic polyneuropathy 32. Histologically, Dyck et al showed microscopic vasculitis in patients with diabetic lumbosacral radiculo/plexus neuropathy 33. On the other hand neuropathy is considered to be an essential factor in the pathogenesis of microangiopathy in diabetes. This is also supported by our results, which showed that LDF measures were not only related to CAN scores but also to other neuropathy symptom scores. Loss of shunt control by mainly sympathetic denervation is held responsible for increased baseline skin flow and decreased flow reserve in skin blood flow in diabetes. Unfortunately, the small number of LDF measurements in our group did allow only limited assessment of the relations. Hilz et al 34 recently described the use of laser Doppler flowmetry with assessment of abnormal reaction to arousal stimuli as a complement to sympathetic skin response testing for the diagnosis of autonomic neuropathy. In our study several measures of CAN were assessed concomitantly. Several authors consider the Ewing tests to be moderately sensitive for CAN, and propose that sensitivity may be improved with HRV measures or BRS. In the comparison of different CAN tests the interrelations were modest, further illustrating the limitations of the Ewing tests in assessing CAN. Recently, Tank et al also found marked discrepancies between BRS and conventional CAN test results 35.


In our analysis of relations between CAN tests and other neuropathy tests, we corrected for age, because Gerritsen et al found that this is one of the strongest determinants of autonomic function 36. The observation that CAN reflects both neuropathy as well as microcirculatory abnormalities increases the value of CAN tests for risk assessment for diabetic foot disease. Toyry described that the development of autonomic and peripheral neuropathies is divergent in type 2 diabetes and suggests different pathophysiological mechanisms 37. Boyko et al confirmed autonomic neuropathy, tested as orthostatic blood pressure fall, as an independent predictor of diabetic foot disease in a large population of diabetes patients 38. Aso et al showed that HRV parameters were more disturbed in patients with neuropathic foot disease compared to an otherwise matched group of patients with neuropathy but without neuropathic foot complications 39. It is at this moment difficult to draw conclusions on the value of CAN tests in the follow up of interventions intended to lower the risk of diabetic foot disease. Reversibility of CAN abnormalities, measured as HRV, was shown by Burger 40, but is not known whether this is also associated with a decrease in risk for diabetic foot problems. Another merit of CAN testing is its prognostic value for all-cause and cardiovascular mortality in diabetes36, which has also been found for other conditions like post-infarction17. Our results are for the most part in line with those of Ducher who also found the Ewing tests to be related to HRV and BRS41. Discrepancies like those for the BRS may be due to differences in the methods used, for example Ducher used the sequential technique for BRS assessment instead of our results obtained with transfer function analysis. In conclusion, our study shows that CAN tests are very weakly related to the clinical standards for diabetic distal neuropathy (SW-MF and VPT, DNE-score), and even less to the DNS-score. Some of the CAN scores, especially HRV measures, were related to microcirculatory parameters. This supports the assumption that CAN scores are equally associated with diabetic microvascular angiopathy as with diabetic polyneuropathy. It should be kept in mind that a close interrelationship exists between neuropathy and microcirculatory abnormalities in diabetes mellitus.


8.5 References 1 Consensus Statement: Report and recommendation of the San Antonio

conference on diabetic neuropathy. Diabetes Care 1988; 11:592-597. 2 Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular

effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med. 1980; 92:308-311.

3 Reyners AK, Hazenberg BP, Haagsma EB, Tio RA, Reitsma WD, Smit AJ.The assessment of autonomic function in patients with systemic amyloidosis: methodological considerations. Amyloid 1998; 5:193-199.

4 Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. 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; 23:1381-1383.

5 Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia 1999; 42:68-75.

6 Frattola A, Parati G, Gamba P, Paleari F, Mauri G, Di Rienzo M, Castiglioni P, Mancia G. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia 1997; 40: 1470-1475.

7 Annese V, Bassotti G, Caruso N, De Cosmo S, Gabbrielli A, Modoni S, Frusciante V, Andriulli A. Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus. J Clin Gastroenterol 1999; 29: 171-177.

8 Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RP, Gans ROB, Smit AJ. Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres. Diabetologia 1999; 42: 1345-1349.

9 Rutter MK, McComb JM, Brady S, Marshall SM. Autonomic neuropathy in asymptomatic subjects with non-insulin-dependent diabetes mellitus and microalbuminuria. Clin Auton Res 1998; 8: 251-257.

10 Wirta OR, Pasternack AI, Mustonen JT, Laippala PJ, Reinikainen PM. Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus. J Intern Med 1999; 245: 329-335.


11 Clarke CF, Eason M, Reilly A, Boyce D, Werther GA. Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria. Diabet Med 1999; 16: 550-554.

12 Di Carli MF, Bianco-Batlles D, Landa ME, Kazmers A, Groehn H, Muzik O, Grunberger G. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999; 100: 813-819.

13 Athyros VG, Didangelos TP, Karamitsos DT, Papageorgiou AA, Boudoulas H, Kontopoulos AG. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 1998; 53: 201-209.

14 Lluch I, Hernandez A, Real JT, Morillas C, Tenes S, Sanchez C, Ascaso JF. Cardiovascular autonomic neuropathy in type 1 diabetic patients with and without peripheral neuropathy. Diabetes Res Clin Pract 1998;42:35-40.

15 Ahlgren AR, Sundkvist G, Wollmer P, Sonesson B, Lanne T. Increased aortic stiffness in women with type 1 diabetes mellitus is associated with diabetes duration and autonomic nerve function. Diabetic Med 1999; 16: 291-297.

16 de Vries R, Lefrandt JD, Terpstra WF, Smit AJ, May J. Increased intima media thickness of the carotid artery negatively affects baroreflex function in mild to moderate hypertensive subjects. Presented at the ‘Tenth European Meeting on Hypertension’ of the European Society of Hypertension, Goteborg, May 2000.

17 La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351: 478-84.

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19 Imholz BP, van Montfrans GA, Settels JJ, van der Hoeven GM, Karemaker JM, Wieling W. Continuous non-invasive blood pressure monitoring: reliability of Finapres device during the Valsalva manoeuvre. Cardiovasc res 1988; 22: 390-397.

20 Task Force of the European Society of Cardiology and the Northern American Society of Pacing and Electrophysiology. Heart Rate Variability: Standards of measurement, physiological interpretation and clinical use. Circulation 1996; 93: 1043-65.


21 Robbe HW, Mulder LJ, Ruddel H, Langewitz WA, Veldman JB, Mulder G: Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987; 10: 538-543.

22 Meijer JWG, Smit AJ, van Sonderen E, Groothoff JW, Eisma WH, Links TP: Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score. Diabetic Medicine, in press.

23 Meijer JWG, van Sonderen E, Blaauwwiekel EE, Smit AJ, Groothoff JW, Eisma WH, Links TP: Diabetic Neuropathy Examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 23 (6): 750-53, 2000.

24 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inex-pensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: 63-68.

25 Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: 68-71.

26 Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J of Neur, Neurosurg and Psych 1979; 42: 793-803.

27 Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non-diabetic subjects. BMJ 1984; 288: 1793-95.

28 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.

29 Andriessen MP, Barendsen GJ, Wouda AA, de Pater L. The effect of six months intensive physical training on the circulation in the legs of patients with intermittent claudication. VASA 1989; 18: 56-62.

30 Van de Ven LLM, Van Leeuwen JTM, Smit AJ. The influence of chronic treatment with betablockade and angiotensin converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication. A comparative cross-over trial. VASA 1994; 23: 357-362.

31 Veves A, Akbari CM, Primavera J, Donaghue VM, Zacharoulis D, Chrzan JS, DeGirolami U, LoGerfo FW, Freeman R. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 1998; 47: 457-463


32 Jude EB, Abbott CA, Young MJ, Anderson SG, Douglas JT, Boulton AJ. The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy. Diabetologia 1998; 41(3): 330-336.

33 Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999; 53: 2113-2121.

34 Hilz MJ, Hecht MJ, Berghoff M, Singer W, Neundoerfer B. Abnormal vasoreaction to arousal stimuli--an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry. J Clin Neurophysiol 2000; 17: 419.

35 Tank J, Neuke A, Molle A, Jordan J, Weck M. Spontaneous baroreflex sensitivity and heart rate variability are not superior to classic autonomic testing in older patients with type 2 diabetes. Am J Med Sci 2001; 322: 24-30.

36 Gerritsen J, Dekker JM, TenVoorde BJ, Kostense PJ, Heine RJ, Bouter LM, Heethaar RM, Stehouwer CD. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care 2001; 24: 1793-1798.

37 Toyry JP, Partanen JV, Niskanen LK, Lansimies EA, Uusitupa MI. Divergent development of autonomic and peripheral somatic neuropathies in NIDDM. Diabetologia 1997; 40: 953-8.

38 Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG. A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care 1999; 22: 1036-1042.

39 Aso Y, Fujiwara Y, Inukai T, Takemura Y. Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration. Diabetes Care 1998; 21:1173-1177.

40 Burger AJ, Weinrauch LA, D'Elia JA, Aronson D. Effect of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 1999; 84: 687-691.

41 Ducher M, Cerutti C, Gustin MP, Abou-Amara S, Thivolet C, Laville M, Paultre CZ, Fauvel JP. Non-invasive exploration of cardiac autonomic neuropathy. Four reliable methods for diabetes? Diabetes Care 1999; 22: 1387-1388.


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