Citation for published version (APA): Meijer, J. W. G. (2002). The diabetic foot syndrome, diagnosis and consequences Groningen: s.n.

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1 University of Groningen The diabetic foot syndrome, diagnosis and consequences Meijer, Johannes Wilhelmus Gerardus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2002 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Meijer, J. W. G. (2002). The diabetic foot syndrome, diagnosis and consequences Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 The Diabetic Foot Syndrome, diagnosis and consequences

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4 RIJKSUNIVERSITEIT GRONINGEN The Diabetic Foot Syndrome, diagnosis and consequences Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 6 november 2002 om uur door Johannes Wilhelmus Gerardus Meijer geboren 21 januari 1966 te Hulst

5 Promotores Co-promotores Prof. drs. W.H. Eisma Prof. dr. J.W. Groothoff Dr. T.P. Links Dr. A.J. Smit Beoordelingscommissie Prof. dr. J.H. Arendzen Prof. dr. R.O.B. Gans Prof. dr. J.A. Lutterman

6 voor Miriam paranimfen H.R. Schiphorst Preuper F. de Laat

7 Correspondence Rehabilitation Centre Tolbrug Tolbrugstraat 11 PO Box ME 's-hertogenbosch the Netherlands tel: /2128 fax: Printed by Cover drawings Ponsen & Looijen BV, Wageningen, the Netherlands Christiaan en Roeland Meijer The publication of this thesis is financially supported by: Novo Nordisk Farma BV, OIM Groep, Diabetes Fonds, Vereniging Beatrixoord Haren, Coloplast BV, LIVIT Orthopedie, Basko Health Care BV, Maatschap Revalidatiegeneeskunde Den Bosch Meijer, Jan-Willem G. The diabetic foot syndrome, diagnosis and consequences. Thesis University of Groningen, the Netherlands With ref. With summary in Dutch. ISBN-number : J.W.G. Meijer, Vlijmen, the Netherlands. All rights reserved. No parts of this publication may be printed or utilized in any form by any electronic, mechanical or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without written permission of the copyright holder.

8 Contents Chapter 1 Introduction and outline of the thesis 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Evaluation of a screening and prevention programme for diabetic foot complications 11 Quality of life in patients with diabetic foot ulcers 23 Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score 35 Diabetic Neuropathy Examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes 51 Clinical diagnosis of diabetic polyneuropathy with the DNS and DNE score 63 Early polyneuropathy in diabetes: concurrent sensory and motor disturbances 77 Dissociation in polyneuropathy and cardiovascular autonomic neuropathy in diabetes mellitus 91 Chapter 9 Discussion and conclusions 107 Summary 127 Samenvatting 133 Northern Centre for Healthcare Research (NCH) and previous dissertations 139 Dankwoord 145 Curriculum Vitae 151

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10 Chapter 1 Introduction and outline of the thesis

11 2 - The diabetic foot syndrome

12 1.1 Introduction A very disabling long-term complication of diabetes mellitus (DM) is the diabetic foot syndrome. The diabetic foot syndrome can be defined as an array of foot abnormalities, resulting from peripheral neuropathy, macroangiopathy and other consequences of metabolic disturbances 1. These different causal factors may be present alone, but mostly occur in combination in patients with DM. Neuropathy, particularly symmetric distal polyneuropathy, is the major etiological factor, and is present in 85% of the patients with a diabetic foot problem 2. A clinical important manifestation of the diabetic foot syndrome is the diabetic foot ulcer, sometimes followed by amputation. In 2000, worldwide 157 million people are suffering from DM, of which about 20 million in Europe 3. In 1994 the prevalence of DM in the Netherlands among men and women of 20 years and older was estimated to be 33.4/1000, and 42.5/1000, respectively, leading to people with DM 4. About 50% of these people are undiagnosed 4. Type 2 DM is most frequent, with a presence of 80-90%, type 1 DM is present in 10-20% of the population 4. As a sequence of demographic changes of the Dutch society, as there are growth of the population and changes in age and sex distribution, the prevalence of DM will increase with 35-45% during the period This increase will be even higher due to the development of more adequate case finding/screening techniques and the tendency of increasing incidence rates in certain population subgroups 5. An ulcer will affect 15-25% of all individuals with diabetes at least once in their lifetime, with an annual incidence of 2-3% 6,7. A cross-sectional study in 4 general practitioner practices in the Netherlands showed that the prevalence of an infected foot lesion or ulcer in patients with diabetes was 3% 8. An other study showed that 5% had an ulcer or had undergone an amputation 9. Thus, diabetic foot problems are common in our society. The relative risk of diabetes related lower extremity amputation has been reported to vary between 10 (United Kingdom) and 40 (USA) 10,11. The incidence of amputation in the Northern part of the Netherlands has been studied by van Houtum et al. and Rommers et al. Van Houtum found an ageadjusted incidence rate of 8/ in the non-diabetic population and 345/ in the diabetic population in the province of Groningen in , with a relative risk for patients with DM of The percentage of amputations due to diabetes was 62%. For the entire Dutch population, the age adjusted incidence in the non-diabetic population was 12/ , for the diabetic population 250/ , with a relative risk of The percentage of amputations due to diabetes was 47%. Rommers et al. found an incidence Chapter 1: Introduction and outline - 3

13 rate of amputations of 18-20/ in the northern region of the Netherlands 13. This rate was rather constant from and showed no sharp decrease in frequency despite new techniques such as used in intervention radiology and in vascular surgery. Unfortunately, the contribution of diabetes is not known in these data. Apelqvist et al. showed that the recurrence of foot ulcers after 1, 3 and 5 years of observation was 34%, 61% and 70% in diabetic patients with previous foot ulcers, respectively. The long-term survival after amputation was 80%, 59%, and 27% after 1, 3 and 5 years of observation. In patients with primary healed ulcers, without the need of amputation, this was 92%, 73% and 58%, respectively 14. Once amputated, 30-50% of the patients undergo amputation of the contralateral leg within 3 years 15. This leads to a major burden both on the patient and the health care system. The risk of amputation is a life long threat to the diabetic patient, and the costs due to diabetic ulcers and amputation are high. In 1989, 3790 patients were hospitalised due to diabetic foot ulcer in the Netherlands, costs of hospital stay only already were estimated 45 million euro 16. In 1992, 1810 amputations were performed in diabetic patients, the medical costs were estimated 20 million euro, costs of absenteeism and rehabilitation were not taken into account 17. Ragnarson-Tennvall and Apelqvist studied the costeffectiveness of the management of diabetic foot ulcers 18. Although methodological aspects caused difficulties in comparing results between countries and settings, they state that treatment alternatives in which the limb is saved are more effective according long-term economic and quality of life aspects. Frequent assessment of risk factors is necessary for early detection of patients at risk, followed by strict diabetes regulation, patient education about foot care and appropriate footwear 1. These measures can reduce or even prevent amputations for diabetic foot disease 19. Bakker et al. evaluated the effectiveness of a Dutch diabetic foot clinic 20. Co-ordinated screening, prevention and multidisciplinary treatment at this specialised clinic resulted in a decrease in number and duration of hospital admissions due to foot ulcers. Furthermore, a reduction was found in amputations of 43% 20. Edmonds et al. achieved healing in 86% of neuropathic ulcers and 72% of ischaemic ulcers, and a reduction of 50% of amputations, with a specialised foot clinic 21. This is also the goal of the St. Vincent declaration 1989: a reduction of 50% of amputation in diabetic patients. The high number of amputations in patients with DM in the Northern part of the Netherlands, more specific in the province of Groningen, illustrated that 4 - The diabetic foot syndrome

14 there was an urgent need to evaluate the care for the diabetic foot in that region. In the early nineties, no specific screening and prevention programmes existed, and foot complications were treated by various specialists, without multidisciplinary attunement. At the University Hospital Groningen, the care for diabetic foot disorders became more organised after starting a study in In this study, the Departments of Rehabilitation Medicine, Internal Medicine and Endocrinology were collaborating. This resulted in this thesis and in a multidisciplinary approach of the diabetic foot in the University Hospital. This present study focuses on the extent of the problem of the diabetic foot syndrome, the consequences of the diabetic foot syndrome on quality of life, the development of tests to diagnose diabetic neuropathy, and the relation between neuropathy and angiopathy in diabetes. Chapter 1: Introduction and outline - 5

15 6 - The diabetic foot syndrome

16 1.2 Aims of the study and outline of the thesis This study was performed at the diabetes outpatient clinic of the Department of Endocrinology of the University Hospital Groningen, and at the Department of Diabetes and Vascular Diseases of the Rehabilitation Centre Beatrixoord, to investigate the following questions: 1 How many patients from the diabetes outpatient clinic of a University Hospital, unknown with diabetic foot complications, are at risk to develop these complications and what is their actual state of prevention? In chapter 2 the current diabetic foot screening and prevention programme of the diabetes outpatient clinic of the University Hospital Groningen has been evaluated. Therefore, 50 patients with diabetes mellitus, unknown with foot complications, were selected at random to assess a risk-profile and the preventional status. The aim was to get insight in the extent of the local population at risk and to form a basis for further development and organisation of diabetic foot care at our hospital and rehabilitation centre. 2 What is the influence of having a present or former foot ulcer on the quality of life of patients with diabetes mellitus? In chapter 3 quality of life was measured in a group of diabetic patients with present or former foot ulcers and compared with diabetic patients unknown with foot complications. Quality of life was studied on the domains physical, social and psychological functioning. Special attention was paid to mobility and physical disabilities because of expected limitations on these items. 3 Is it possible to modify the Neuropathy Symptom Score (NSS) and the Neurological Disability Score (NDS) into valid, easily managed, graded and accurate scoring systems for diagnosing distal symmetric polyneuropathy in diabetes mellitus? Neuropathy, especially distal symmetric polyneuropathy, is a major etiological factor in diabetic foot complications; in 85% of the diabetic patients with ulcers neuropathy is present. Because of the lack of a gold standard to diagnose neuropathy, the San Antonio Consensus Statement of 1988 recommended to perform at least one measurement of 5 different diagnostic categories, including a symptom score and a physical examination Chapter 1: Introduction and outline - 7

17 score. Several scores are used, the Neuropathy Symptom Score (NSS) and the Neurological Disability Score (NDS) are the most accepted scores. Both are scores for neuropathy in general and not specific for distal symmetric polyneuropathy. The aim of this study was to adapt the NSS and NDS into valid, easily managed, graded and accurate scoring systems for diagnosing distal symmetric polyneuropathy. These studies are described in chapter 4, 5 and 6, respectively. 4 Is polyneuropathy present in patients with DM before any sign of micro- or macroangiopathy is detectable? Does sensory polyneuropathy occur prior to motor neuropathy or do they occur simultaneously? In the pathogenesis of diabetic neuropathy a vascular and a metabolic hypothesis exist. In this study, presence of sensory and motor polyneuropathy was evaluated in diabetic patients without micro- or macroangiopathy. In distal symmetric polyneuropathy, sensory dysfunction seems to run ahead of motor dysfunction, because of compensating mechanisms, such as collateral innervation and muscle fiber hypertrophy. Invasive muscle fiber conduction velocity (I-MFCV) offers sensitive information about muscle fiber volume and conduction velocity, and thus of early denervation. In chapter 7, I-MFCV was used as an indicator for early motor dysfunction in diabetic patients. 5 Do cardiovascular autonomic neuropathy tests reflect diabetic polyneuropathy or diabetic vasculopathy? The frequently used Ewing Battery is known to have a high predictive value in the development of diabetic foot complications. The San Antonio Consensus Statement recommends cardiovascular autonomic neuropathy (CAN) tests, as one of the five different categories for diagnosing diabetic neuropathy. However, evidence exists that the association with other diagnostic categories for neuropathy is weak, and that CAN is more strongly related to vasculopathy in diabetes mellitus. Recently, new methods have been developed to measure CAN, such as Heart Rate Variability (HRV) and Baroreflex Sensitivity (BRS). In chapter 8 these tests for cardiovascular dysfunction were studied, and compared with conventional tests for distal symmetric polyneuropathy and vascular examination. 8 - The diabetic foot syndrome

18 1.3 References 1 Syllabus Richtlijnen diabetische retinopathie, diabetische nefropathie, diabetische voet en hart en vaatziekten bij diabetes mellitus. Richtlijnen NDF/CBO september Banda Heerenveen BV, the Netherlands. 2 Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: Post D, Tuinstra J, Groothoff JW. Zorgconsumptie van patiënten met diabetes mellitus. Tijdschrift voor Gezondheidswetenschappen 2000; 78 (6): Volksgezondheid Toekomst Verkenning 1997, I De gezondheidstoestand: een actualisering. 5 Volksgezondheid Toekomst Verkenning 1997, De som der delen. 6 Palumbo PJ, Melton LJ. Peripheral vascular diseases and diabetes. In: Harris MI, Hamman RF, eds. Diabetes in America. NIH publication No Washington: US Government Printing Office, 1985: XV Most R, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care 1983; 6: Crebolder HFJM. De huisarts en de diabetische voet. In: Consensus bijeenkomst diabetische voet. Utrecht: CBO, 1985: Verhoeven S, Ballegooije E van, Casparie AT. Impact of late complications in type II diabetes in a dutch population. Diabet Med 1991; 8: Gujral JS, McNally PG, O'Malley BP, Burden AC. Ethnic differences in the incidence of lower extremity amputation secondary to diabetes mellitus. Diabet Med 1993; 10: Connel FA, Shaw C, Will J. Lower extremity amputations among persons with diabetes mellitus. Washington, MMWR 1991; 40: Houtum van WH, Lavery LA. Regional variation in the incidence of diabetes-related amputations in the Netherlands. Diabetes Res and Clin Practice 1996; 31: Rommers GM, Vos LDW, Groothoff JW, Eisma WH. Epidemiology of lower limb amputees in the north of the Netherlands: Aetiology, discharge destination and prosthetic use. Prosthetics and Orthotics International 1997; 21: Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. J of Internal Medicine 1993; 233: Chapter 1: Introduction and outline - 9

19 15 Bild DE, Selby JV, Sinnock P, Browner WS, Braveman P, Showstack JA. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care 1989; 12: Bouter KP, Storm AJ, Groot RR de, Uitslager R, Erkelens DW, Diepersloot RJA. The diabetic foot in Dutch hospitals: epidiological features and clinical outcome. Eur J Med 1993; 2(4): Houtum van WH, Lavery LA, Harkless LB. The cost of diabetesrelated lower extremity amputations in the Netherlands. Diabet Med 1995; 12: Ragnarson-Tennvall G, Apelqvist J. Cost-effective management of diabetic foot ulcers, a review. Pharmaco-economics 1997; 12 (1): Assal JP, Muhlhauser I, Pernat A, Gfeller R, Jorgens V, Berger M. Patient education as the basis for diabetic care in clinical practice. Diabetologia 1985; 28: Bakker K, Dooren J. Een gespecialiseerde voetenpolikliniek voor diabetespatienten vermindert het aantal amputaties en is kostenbesparend. NTvG 1994; 138(11): Edmonds ME, Blundell MP, Morris ME, Thomas EM, Cotton LT. Improved survival of the diabetic foot: the role of a specialized clinic. Q J Med 1986; 60 (232): The diabetic foot syndrome

20 Chapter 2 Evaluation of a screening and prevention programme for diabetic foot complications J.W.G. Meijer, T.P. Links, A.J. Smit, J.W. Groothoff, W.H. Eisma Prosthetics and Orthotics International 2001; 25: by ISPO; reprinted with their kind permission

21 Abstract Introduction Methods Results Discussion Foot complications in diabetes can be decreased by preventive measures. The current diabetic foot screening and prevention programme of the diabetes outpatient clinic of a university hospital was evaluated, by assessing the presence of risk factors for the development of foot disorders and the preventive measures taken. 50 diabetic patients not known to have foot complications were selected at random. Risk factors and preventive measures were inventarised with the Coleman riskcategorisation system and the Preventive Measures Scale, respectively. 60% of the patients were at risk of developing diabetic foot complications. The preventive measures were low in these patients. Patient knowledge was insufficient and behaviour even worse. Basal preventive shoe adaptations were absent in most patients at risk. No relation between risk category and the preventional status was found. Cross-sectional examination at a university outpatient clinic showed serious risk profiles for foot complications, which were not balanced by the application of generally accepted preventive measures. At the outpatient clinic, screening should be optimised The diabetic foot syndrome

22 2.1 Introduction Foot complications have an enormous impact on the quality of life of patients with diabetes mellitus and the financial cost is considerable 1,2. Frequent assessment of risk factors (neuropathy, foot deformity, history of ulceration and angiopathy) is necessary for the early detection of patients at risk for developing foot disease and for preventing amputation. Better patient education about foot care and appropriate footwear are expected to prevent at least half of the amputations for diabetic foot disease 3-7. At the time of this study, standardised diabetes patient education with the usual attention to diabetic foot care was being given at the university outpatient clinic. This individual education is repeated every two years and the feet are examined once a year or more frequently on indication. The aim of this study was to evaluate the clinic's current screening and prevention programme by assessing the risk profile and the actual state of prevention in a sample of patients, not known to have diabetic foot complications, at the outpatient clinic. The information was intended to form a basis for further development and organisation of diabetic foot care at the hospital and rehabilitation centre. 2.2 Patients and Methods Patients At the diabetes outpatient clinic of the University Hospital Groningen, 55 patients who had been suffering from diabetes mellitus for at least one year, but did not have any documented foot complications, were selected at random. Exclusion criteria were: causes of neuropathy other than diabetes mellitus, other neurological diseases or peripheral nerve disorders, high dose benzodiazepine or analgesic use, cognitive or psychological problems as far as they might interfere with the test results, the presence or a history of foot ulceration and foot amputation. Five patients refused to take part in this research project. Methods The same specialist (JWGM) examined all 50 patients. In the same session, risk factors and preventive measures were assessed using a riskcategorisation system and the Preventive Measure Scale, respectively. Patients were not informed about the results of the tests. Chapter 2: Evaluation of screening and prevention - 13

23 1 Coleman's risk categorisation No generally accepted risk profile is available to determine a patient's risk of developing foot problems. The American Diabetes Association (ADA) recommends assessment of the four major risk factors: neuropathy, foot deformity, ulceration and angiopathy 8. As risk profile, Coleman's risk-categorisation system was chosen 9, which covers these major risk factors. Four different risk categories are used (see Table 1). In risk category 0 the only risk factor present is foot deformity. In category 1 neuropathy is present. In category 2 the presence of neuropathy is combined with foot deformity, while in category 3 angiopathy or an ulcer are present. Table 1: Risk profile according to Coleman 9 risk category Neuropathy Foot deformity -/ Ulceration and/or vascular laboratory findings implying angiopathy Number of patients (%) 20 (40%) (20%) 4 (8%) 16 (32%) 1a Neuropathy According to the recommendations of the ADA, the presence of neuropathy was determined with Semmes Weinstein Monofilaments (SWMF) and the Vibration Perception Threshold (VPT) 10. These are semi-quantitative, reliable instruments, complementary to each other, with proven predictive value for the development of clinical problems, such as foot ulcers and the need for amputation Both were applied 6 times to two locations on both feet. Insensitivity to the 10 gram SWMF was scored as absence of protective sensibility. The VPT was determined with a hand-held biothesiometer (Biomedical Instruments Inc., Ohio, USA) and compared to the reference values published by Young et al. 17. Neuropathy was defined as a disturbed VPT and/or insensitivity to the 10-gram SWMF at one location or more. 1b Foot deformity Foot deformity was defined as comprising at least one of the following obvious deformities: claw toes, overlying toes, prominent bony parts and hallux rigidus or valgus The diabetic foot syndrome

24 1c Ulceration Patients with ulceration or a history of ulceration were excluded from this study. 1d Angiopathy In Coleman's system, angiopathy is defined as vascular laboratory findings indicating significant angiopathy. Ankle/brachial indexes at the arteria dorsalis pedis and arteria tibialis posterior and toe/brachial indexes at the hallux on both sides using laser-doppler flowmetry, were measured. Ankle/brachial indexes of below 0.90 and toe/brachial indexes of below 0.75 were considered abnormal 19. Angiopathy was diagnosed if one or more abnormal value was observed. 2 The Preventive Measures Scale According to recommendations of the American Diabetes Association, diabetic patients should be educated regarding their risk factors and appropriate management 10. Assessment of a person's current knowledge and care practices should be obtained. Patients should understand the implications of the loss of protective sensation, the importance of foot monitoring on a daily basis, the proper care of the foot, including nail and skin care, and the selection of appropriate footwear. It is known that the type of evidence for the effectiveness of these specific interventions varies, ranging from evidence based (randomised controlled trials) for prescription of adequate footwear to expert or consensus opinions of the other interventions. In literature there is no valid score available to quantify the preventive status of these patients. Therefore, a panel of medical specialists of the University Hospital, all members of the Diabetic Foot working group, developed the PMS on expert and consensus opinion regarding the recommendations of the ADA, several education programmes, guidelines for shoes, and the literature 9,10, The PMS has four sub-scales: (1) patient knowledge (7 items), (2) care practice (9 items), (3) condition of feet and shoes (10 items) and (4) prevention by health care workers (5 items). Sub-scales 1, 2 and 4 are based on self-reporting, 3 is based on observation. The PMS is standardised, selfreporting questions could be answered yes or no. Observation criteria for subscale 3 were described in detail before starting the study. Adequate measures received 0 points, inadequate measures received 1 point, thus the maximum score was 31 points. The PMS is shown in Appendix 1. Chapter 2: Evaluation of screening and prevention - 15

25 Statistics The statistical package SPSS-PC was used for all the analyses, including computation of the descriptive statistics, Spearman's Correlation Coefficient and Oneway Multiple Range Test. 2.3 Results Characteristics of the 50 participants are shown in Table 2. The mean age was 51.4 years (min 18, max 89 yrs), while the mean duration of DM was 14.1 years (min 1, max 36 yrs). The group consisted of 32 men and 18 women; 22 had type 1 DM and 28 had type 2 DM. Table 2: Patient characteristics N 50 mean age (years) (SD) min max (years) mean duration diabetes (years) (SD) min max (years) 51.4 (16.2) (9.1) 1 36 sex male : female 32:18 type of diabetes type 1 : type 2 22 : 28 mean HbA1c (%) (SD) min max 8.6 (1.4) Coleman's risk categorisation 60% of the patients had scores that placed them in risk categories 1-3. These patients were at risk. 40% scored in category 0, which means the lowest risk, because there were no risk factors (or only the presence of foot deformity without any other risk factors) (Table 1). 2 Preventive measures Table 3 presents the mean scores on the sub-scales of the Preventive Measures Scale for each risk category. A large percentage of the patients were not taking any preventive measures in any of the four sub-scales. Foot The diabetic foot syndrome

26 care behaviour and foot-care knowledge were inadequate. The scores for foot-care behaviour were even worse than those for foot-care knowledge. Basal preventive demands of shoes, such as fitting, presence of seamless insides and pressure distributing inlays, were absent in most patients at risk, in 53% (16/30), 67% (20/30) and 70% (21/30), respectively. No relation was found between the risk category and the preventive measures scale (Spearman's correlation coefficient 0.24). There were no significant differences in the scores on the preventive measures scale between the four risk categories. Table 3: Preventive Measures Scale The mean percentage of patients in each category who were not performing the preventive measure risk category number of patients Patient Knowledge: Patient Care Practice: Condition of Feet and Shoes: Preventive Measures by Health Workers: Discussion Using Coleman's risk-categorisation system, 60 per cent of the study group were found to be at serious risk of developing diabetic foot complications, despite the availability of a screening and education programme. The sample was recruited at a university hospital outpatient clinic and did not have any documented foot disorders. Foot-care knowledge and foot-care behaviour were inadequate. The scores for preventive foot-care behaviour were worse than those for foot-care knowledge; there was no relation between the subscale prevention and risk category. Protective measures by shoe adaptations were insufficient. This means that the screening and prevention programme, even though it follows generally prescribed procedures, is inadequate and that patients do not comply sufficiently with preventive self-care. This might be Chapter 2: Evaluation of screening and prevention - 17

27 exacerbated by the fact that doctors and patients are inclined to underestimate foot care. In both doctors and patients thresholds need to be overcome in examining the feet. In doctors, time is scarce and foot inspection takes time. Many patients have visual problems, which complicate inspection, and some have cosmetic objections towards wearing orthopaedic footwear. The study group was not fully representative of the entire population at the outpatient clinic, because of the exclusion criteria used. The study group was younger, did not have any documented foot problems, had a shorter duration of diabetes mellitus and there were relatively more male patients. The objection might be raised that the study sample was small and, because it was university-hospital-based, it was not representative. However, the percentage at risk was so high that valid conclusions can be drawn about the need for preventive care, even in this small sample. Similar risk estimates for the general population will underestimate the situation, because patients with (a history of) foot ulcers were excluded and because everyone had received standardised diabetes patient education. Several validated tests to diagnose and evaluate neuropathy are available in different diagnostic categories, such as symptom scoring, physical examination, quantitative sensory testing, electrodiagnostic studies and autonomic function testing. According to a consensus statement one test from each of these five diagnostic categories has to be used to diagnose and evaluate neuropathy 23. In clinical practice, certainly at an outpatient clinic, this is not feasible for screening purposes. The ADA recently recommended the use of psychophysical somatosensory threshold tests (especially VPT by Biothesiometry and SWMF testing) because these tests provide the best discrimination in the clinical setting to identify the loss of sensation 10. Both recommended tests have been used in this study. However, there is still no combination of tests available with the optimal predictive value to diabetic foot ulcer. By using only these two methods still cases will be missed during screening, so the percentage at risk will even be higher than 60%. It is questionable whether the highest risk category should be defined by the presence of angiopathy. Several studies have shown that neuropathy played a larger role in the development of ulceration and the need for amputation than angiopathy 7,20, This means that for the entire 60% (categories 1-3: neuropathy present) the risk is high and preventive foot care is of great importance. Because there was no score available in literature, the Preventive Measures Scale was developed to standardise the quantification of the preventive measures being taken by patients. Validation of the PMS was beyond the 18 - The diabetic foot syndrome

28 scope of this study. The PMS is not broad enough to evaluate education programmes, because information about the social system, coping, behaviour and health locus of control are lacking. However, the PMS does provide a simple, standardised instrument to assess the preventive measures being taken by patients. Three sub-scales are based on self-report. Patients might respond socially desirable, which means that the real situation of prevention is even worse than reported. In view of the findings of this evaluation, the screening and prevention programme has to be revised. Because our programme closely follows generally accepted programmes, this need for revision will hold for many institutions. In our opinion, the screening programme needs to be adapted to follow the advice of the 1998 Dutch consensus on diabetic foot disease 27, which means more intense examination of the presence of risk factors. Naturally, to be of any benefit, early diagnosis of patients at risk will have to be followed by preventive measures and regular check-ups. For this purpose, a multidisciplinary diabetic foot team and intensive education programmes have been started at the University Hospital and rehabilitation centre. The education programme offers information and individual or group training given by a multidisciplinary rehabilitation team. The major goal of this programme is to increase the level of preventive self-care. Physicians, podiatrists and shoe-technicians need to be aware that they will have to provide adequate footwear to an enormous number of patients at risk. Furthermore they should underpin their work, specifically the indications and effects of adaptations and their preventive value. Using a simple risk-categorisation system combined with improved prevention strategies for patients at risk of developing diabetic foot problems, we are attempting to balance the presence of risk factors and the application of preventive measures. It is clear that patients, health care workers and health insurance companies will have to invest a great deal of time and money in foot care to reach the goal of the St. Vincent Declaration, i.e. a 50% reduction in major amputations. Chapter 2: Evaluation of screening and prevention - 19

29 2.5 References 1 Bakker K, Dooren J. Een gespecialiseerde voetenpolikliniek voor diabetespatiënten vermindert het aantal amputaties en is kostenbesparend. NTvG 1994; 11: Ollendorf DA, Kotsanos JG, Wishner WJ. Potential economic benefits of lower-extremity amputation prevention strategies in diabetes. Diabetes Care 1998; 21: Assal JP, Muhlhouser I, Pernet A, Gfeller R, Jorgens V, Berger M. Patient education as the basis for diabetic foot care in clinical practice. Diabetologia 1985; 28: Edmonds ME, Blundell MP, Morris ME, Maelor TE, Thomas E, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of the specialised foot clinic. Quart J of Med 1986; 232: Schaff PS, Cavanagh PR. Shoes for the insensitive foot: the effect of a "rocker bottom" shoe modification of plantar pressure distribution. Foot Ankle 1990; 11: Barth R, Campbell LV, Allen S, Jupp JJ, Chisholm DJ. Intensive education improves knowledge, compliance and foot problems in type 2 diabetes. Diabet Med 1991; 8: Thomson FJ, Veves A, Ashe H, Knowles EA, Gem J, Walker MG. A team approach to diabetic foot care: the Manchester experience. The Foot 1991; 2: American Diabetes Association. Preventive foot care in people with diabetes. Diabetes Care 2000; 23: s Coleman WC. Footwear in a management program for injury prevention. In: Levin ME, O'Neal LW, Bowker JH (eds). The Diabetic Foot, 5th edition. St. Louis: Mosby-Year Book, 1993, P Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21: 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: Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 nondiabetic subjects. BMJ 1984; 288: Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Lepr Rev 1986; 57: Sosenko JM, Kato M, Soto R, BiId DE. Comparison of quantitative sensory-threshold measures for their association with foot ulceration in diabetic patients. Diabetes Care 1990; 13: The diabetic foot syndrome

30 15 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: Veves A, Uccioli L, Manes C, van Acker K, Komninou H, Philippides P, Katsilambros N, de Leeuw I, Menzinger G, Boulton AJM. Comparison of risk factors for foot problems in diabetic patients attending hospital outpatient clinics in four different European States. Diabet Med 1994; 11: Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: Valk GD, De Sonnaville JJJ, van Houtum WH. The assessment of diabetic polyneuropathy in daily clinical practice. Muscle and Nerve 1997; 20: Conier SA. Role of pressure measurements. In: Bernstein EF (ed). Vascular Diagnosis, 4th edition. St. Louis: Mosby, 1993, p Boulton AJM. Peripheral neuropathy and the diabetic foot. The Foot 1992; 2: Edmonds ME, Foster AVM. Diabetic Foot Clinic. In: Levin ME, O'Neal LW, Bowker JH (eds). The Diabetic Foot, 5th edition. St. Louis: Mosby-Year Book, 1993, p Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994; 331: American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on Diabetic neuropathy (Consensus Statement). Diabetes Care 1988; 11: Boulton AJM, Kubrusly DB, Bowker JH, Gadia MT, Quintero L, Becker DM, Skyler JS, Sosenko JM. Impaired vibratory perception and diabetic foot ulceration. Diabet Med 1986; 3: Pecaro RE, Reiber GE, Burgess EM. Causal pathways to amputation: basis for prevention. Diabetes Care 1990; 13: Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: CBO/NDF. Diabetische retinopathie, diabetische nefropathie, diabetische voet, hart en vaatziekten bij diabetes mellitus. Heerenveen, the Netherlands: Banda, Chapter 2: Evaluation of screening and prevention - 21

31 Appendix 1: Preventive Measures Scale 1: Patient Foot-care Knowledge: 7 items Do you know about the necessity of: taking special foot care due to diabetes? daily inspection of the feet to control for presence of ulcers? daily washing of the feet? not walking barefoot? adequate fitting of the shoes? visit the doctor for wound care? special shoe demands? 2: Patient Foot-care Practice: 9 items Do you pay special attention to: care of the feet? daily washing of the feet? the use of oil for the skin? examine the feet for wounds daily? the use of a mirror for inspection? foot inspection by others? not to walk barefoot? inspection of the shoes? wearing seamless stockings? 3: Condition of feet and shoes: 10 items Observation criteria: scored as: condition of nails inadequate: fungal infections, inadequate trimming, ingrown nails condition of skin inadequate: dry crackled skin, maceration, callus, tinea pedis stockings adequate: seamless fitting of stockings inadequate: pinch off effects inside of shoes adequate: seamless fitting of shoes adequate: widest part at MTP-I, length longest toe to shoe cm, sufficient room at toes shoe counter adequate: fixation of heel and foot, no slipping sole adequate: rigid protecting against penetration trauma distributing inlay adequate: distribution of pressure over entire plantar surface rocker bottom adequate: right place, decreasing pressure plantar forefoot 4: Preventive Measures by Health Care Workers: 5 items Do your health care workers offer: foot care (by general practitioner)? foot care (by endocrinologist)? prescription for special shoes? urgent visit for wounds? annual foot inspection? 22 - The diabetic foot syndrome

32 Chapter 3 Quality of life in patients with diabetic foot ulcers J.W.G. Meijer, J. Trip, S.M.H.J. Jaegers, T.P. Links, A.J. Smit, J.W. Groothoff, W.H. Eisma Disability and Rehabilitation 2001; 23 (8): by Taylor and Francis; reprinted with their kind permission

33 Abstract Aim Methods Results Discussion To compare Quality of Life (QoL) between diabetic patients with (former or present) and without foot ulcers. Two patient groups of comparable age, sex distribution, type distribution and duration of diabetes were studied. Fourteen patients with former or present, but clinically stable diabetic foot ulcers (DFUs) were examined. The control group were 24 patients not known to have DFUs. None of the participants had other diabetic complications or conditions that would potentially affect QoL. A diabetic foot risk score and QoL were assessed. QoL was scored with the RAND-36, the Barthel Score (ADL) and the Walking and Walking Stairs Questionnaire (WSQ). Marked and significant differences were found in physical functioning (p<.001), social functioning (p<.05), physical role (p<.001) and health experience (p<.05) between the two groups with the RAND-36 and the four sub-scales of the WSQ (all p<.001). On all these scales, QoL was significantly poorer in the study group. A correlation was found between the risk score and QoL (physical functioning and physical role Spearman's r: -.66, -.56 and WSQ -.63, -.64, -.67 and -.71, respectively). Presence or history of DFUs has a large impact on physical role, physical functioning and mobility. Physical impairments especially influenced QoL. Probably, QoL can be increased by providing attention that will enhance mobility and by giving advice about adaptations and special equipment The diabetic foot syndrome

34 3.1 Introduction A disabling long-term complication of diabetes mellitus (DM) is the diabetic foot ulcer (DFU), caused by the presence of neuropathy, angiopathy and/or foot deformity 1. DFUs are common and it is estimated that they affect 15% of all individuals with DM during their lifetime 2. Recently, three studies have been published on Quality of Life (QoL) in patients with DFUs. Rijken et al. 3 studied the association of foot pain with several other parameters in the field of impairments, disabilities and quality of life in 29 patients, without controls. There were no patients with ulcers included. Several clinical variables and four unvalidated functional variables were assessed on fatigue, functional ability, walking distance and quality of life. In this study foot pain was related to fatigue, disability in walking and a lower level of quality of life. Carrington et al. 4 examined 13 diabetic patients with ulcers, 13 diabetic patients with a unilateral amputation and 26 controls. They assessed psychological adjustment to illness (PAIS), anxiety and depression (HAD) and life satisfaction (QoL ladder) and concluded that the psychological status of mobile amputees is better than that of the diabetic foot ulcer patients, but not as good as diabetic controls. They did not assess mobility. Brod 5 studied quality of life in diabetic patients with foot ulcers and their caregivers, by semi-structured discussions on the domains of social, psychological, physical and economic impact. Two groups participated, consisting of 14 patients and 11 caregivers without a control group. A negative impact on all domains of QoL was experienced because of the limitations in mobility caused by the ulcer. The conclusions were group findings and not based on individual assessments. In conclusion, QoL in diabetic patients with foot ulcers is greatly influenced by physical (especially mobility), social and psychological impairments and disabilities. However, it is not clear which specific domains of QoL are most affected by DFUs. The aim of this study was to evaluate the QoL of individual patients with present or former DFUs by comparing them to DM patients not known to have DFUs. QoL was defined as "the physical, social and psychological functioning of the patients as being influenced by disease or therapy", and was investigated using the sub-items mobility, activities of daily living and general QoL 6-8. Chapter 3: Quality of life - 25

35 3.2 Patients and Methods Patients A cross-sectional patient-control study was performed on patients who were admitted to the Diabetes Department of the Rehabilitation Centre Beatrixoord between 1993 and Two groups were composed, a study group with patients with DM who had been hospitalised because of DFUs and a control group with patients without any foot problems, who had a diabetes duration of at least 1 year and had been admitted because of diabetic dysregulation. Patients were included if they were ambulatory at the time of the study. Exclusion criteria were: not diabetes related diseases ( neurological or orthopaedic problems, cardiac or pulmonary problems), diabetes related problems (severe retinopathy, nephropathy, amputation above the level of the toes, unstable ulcers on the feet and symptomatic diabetic polyneuropathy) and cognitive or psychological problems. During the period studied, 410 patients had been admitted to the department for various reasons (dysregulation, amputation, instruction and prevention, ulcers etc). To select patients and controls, the records were read by JT and checked by JWGM. Referring to the in- and exclusion criteria mentioned, 31 patients were initially selected for the study group and 53 for the control group. To get informed about the actual state of the patients, their general practitioners were contacted to check in- and exclusion criteria just before starting the study. This led to the exclusion of 12 patients of the study group and 20 of the control group, the reasons are described in Table 1. Unfortunately 5 patients of the study group and 9 of the controls refused to take part in the study, resulting in 14 participants of the study group and 24 of the control group, as shown in Table 1. Table 1: Patient selection Study group Control group initially selected died 3 died check general comorbidity comorbidity practitioner 2 moved house 2 moved house selected refused -9 refused participated The diabetic foot syndrome

36 Methods Risk profiles for diabetic foot complications were determined and QoL was assessed. The same observer examined all the patients (JT). 1 Risk Profile The risk profile test from the Dutch consensus report on the diabetic foot was used to assess the risk of developing foot complications 1. This profile employs the known risk factors neuropathy, angiopathy, foot deformity and ulceration. Risk is graded from 0 (no risk) to 3 (highest risk). In grade 0, none of the 4 risk factors are present. In grade 1 the only risk factor present is neuropathy; in grade 2 neuropathy is present combined with angiopathy or foot deformity, while in grade 3 there is an existing or previous ulcer 1. Neuropathy was diagnosed with Semmes Weinstein Monofilaments. Inability to feel the 10-gram filament at 4 plantar locations on the foot was defined as the presence of neuropathy Angiopathy was defined as symptomatic arterial disease (Fontaine class 2 or higher) and/or absence of arterial foot pulsations. Foot deformity was defined as the presence of hallux valgus/rigidus, prominent bony parts or pressure areas. Ulceration was present when there were Wagner stage 1 to 5 abnormalities Quality of Life QoL was assessed with the RAND-36, the Barthel Index and the Walking and Walking Stairs Questionnaire (WSQ). 2.1 RAND-36 The RAND-36 is a general questionnaire for measuring the influence of health on QoL (physical, psychological and social aspects) 13. It has proven to be valid and reliable 13. There are 8 domains: physical and social functioning, emotional and physical impairment of role, mental health, vitality, pain and experienced health. For each domain there is a minimum score of 0 and a maximum score of 100. The higher the score, the better the quality of life. 2.2 Barthel Index The Barthel index is a questionnaire on skills/disabilities of activities of daily living (ADL), which consists of 10 questions ranging from bowel and bladder control items to mobility and personal care items 14,15. The maximum score is 20 points (normal); less than 10 points means severely impaired ADL. 2.3 Walking and Walking Stairs Questionnaire A reliable and valid preliminary version of the Walking and Walking Stairs Questionnaire (WSQ) was used to evaluate mobility 16,17. This questionnaire consists of 62 items, divided into 4 hierarchical scales: using stairs (16 items), Chapter 3: Quality of life - 27

37 walking indoors (18 items), walking outdoors (20 items) and walking velocity (8 items). Each scale has a maximum of 100 points; the higher the score, the better the mobility. Statistics The statistical package SPSS-PC was used to compute descriptive statistics, Spearman's correlation coefficient and the Mann Whitney test. Significance level: p <.05. Differences on item level were computed by calculating the Effect Size (EF) ( t-tests for means), defined as 18 : Mean A MeanB, where Sp Sp = SSA + SSB ( N 1) + ( N 1) A B Mean A = mean of group A, Mean B = mean of group B, Sp = Pooled standard deviation, SS A = sum of squares of group A, SS B = sum of squares of group B, N A = total of group A, N B = total of group B Interpretation of the ES: no or trivial effect < 0.20; small effect = ; medium effect = ; large effect = > Results Patient characteristics are shown in Table 2. The two groups were found to be comparable regarding age, sex distribution, known duration and type of DM (no significant differences). The patients selected initially for the study (n=31) and control (n=53) groups were compared to the patients who actually participated in the two groups on the items sex distribution, age, known duration and type of diabetes. In the participating control group, the mean duration of diabetes was significantly longer than that in the excluded group. In the study group with foot ulcers there were significantly more men than in the group of excluded patients. No other significant differences were found between the subjects selected initially and those who actually participated The diabetic foot syndrome

38 Table 2: Patient characteristics study group control group n Sex (male : female) 10 : 4 13 : 11 Age (years) (mean (SD)) 62.8 (13.8) 58.7 (13.8) Duration DM (years) (mean (SD)) 11.3 (10.8) 12.8 (12.0) Type of DM (1 : 2) 3 : : 14 1 Risk Profile A significant difference was found in the risk profile between the two groups (p-value <.0001). The study group had a higher risk of developing foot complications (mean score of 3.00; SD 0.0) than the control group (mean score 0.58; SD 1.10). 2 Quality of Life 2.1 RAND-36 Patients in the study group scored both relevantly and significantly lower (experienced a lower QoL) than the controls on the domains physical functioning, social functioning, physical role and health experience, as shown in Table 3. On an item level, the most relevant and significant differences (Effect Size) were present for producing moderate (1.4) and heavy physical effort (1.8), walking distances of more than 500 metres (1.2) and using stairs (1.4). The patients also experienced problems with working, especially a lower productivity (1.1). There were no differences in complaints about pain. Chapter 3: Quality of life - 29

39 Table 3: RAND-36 study group mean ± SD control group mean ± SD Physical functioning 52.1 ± 31.7 ** 90.0 ± 15.9 Social functioning 80.4 ± 27.6 * 96.4 ± 7.8 Physical role 42.9 ± 34.6 ** 83.3 ± 29.2 Emotional role 92.3 ± 14.6 ns 84.7 ± 31.1 Mental health 75.7 ± 19.5 ns 77.2 ± 15.6 Vitality 71.2 ± 16.0 ns 72.3 ± 15.9 Pain 68.7 ± 28.4 ns 76.2 ± 14.3 Health experience 51.1 ± 23.1 * 66.4 ± 14.9 * p <.05, ** p <.001, ns not significant 2.2 Barthel Index The study group scored 19.2 points (SD 1.5), and the control group scored 19.8 points (SD 0.5) (not significant). 2.3 WSQ In all four categories, the study group had significantly lower scores than the control group, which means that the patients with foot ulceration experienced more disabilities on mobility than the controls. The study group scored 80.0 points for using stairs versus 96.7 points in the controls (p<.001); for walking indoors the scores were 54.8 and 90.3 (p<.001), respectively. For walking outdoors, the study group scored 54.5 points versus 87.0 in the controls (p<.001), while for walking velocity, these scores were 51.8 and 89.1 points (p<.001) respectively. On the level of individual items, the most relevant and significant differences (Effect Size) between the two groups were observed for using stairs both up and down (more effort (1.4), more time (1.1)) and for walking small distances in (1.1) and outdoors (1.5) The diabetic foot syndrome

40 3 Relation between Risk Profile and Quality of Life In Table 4 the significant correlations between risk profile and QoL are shown for the entire study population. The severity of the risk profile was significantly related to QoL on all the scales of the WSQ and on the physical functioning and impairment of physical role domains of the RAND-36. There was no significant correlation between risk profile and social functioning, self-perceived health and the other domains of the RAND-36 or the Barthel Index. Table 4: Relation between Risk Profile and Quality of Life (Spearman's r) RAND-36 Physical functioning -.66* Physical role -.56* WSQ Using stairs -.64* Walking indoors -.67* Walking outdoors -.71* Walking velocity -.63* Only the significant correlations are shown, * p < Discussion This study addressed the interrelations between physical, social and psychological dimensions of QoL in DM patients. The obvious physical limitations of patients with DFUs, reflected by the WSQ and by the physical functioning domain of the RAND-36, greatly affected QoL, and were probably causing limitations in social functioning. On an individual level, there were highly relevant and significant differences for producing moderate and heavy physical effort, walking in and outdoors, using the stairs both up and down (more effort, more time) and working (lower production). In contrast with the results reported by Rijken 3, we did not find a relation between having a DFU and complaints of pain. Whereas other studies found more psychological complaints in patients with foot Chapter 3: Quality of life - 31

41 disease 4, this was not found in our study for the item psychological functioning. Very few of our patients had an acute phase of foot disease. Perhaps they had learnt to accept their disabilities and had found a new psychological balance. In conclusion, an existing or previous ulcer has an obvious negative influence on the physical and social aspects of quality of life in patients with diabetes mellitus. This is in line with the findings of earlier studies 3,5. In a general population of patients with diabetes, psychological and social aspects contributed to the overall QoL, while physical complaints had less influence 20. This suggests that having a diabetic foot changes the spectrum of factors that influence QoL, with an increase in the impact of limitations related to physical functioning and mobility. The population studied is not very large and selected at a specific institution. Therefore generalisation might be limited. However, the influence of physical disabilities on quality of life, by decreasing mobility of patients, is very significant and relevant for workers in the field of rehabilitation. Despite the fact that the clinical situation was stable in all the patients with DFUs at the time of the study, their mobility and physical functioning were limited. The significant correlation between risk profile and QoL suggests that the decrease in physical functioning and mobility in the patients with foot disease was caused by physical restrictions due to the DFU itself, or due to signs and symptoms of risk factors, such as neuropathy or angiopathy. This decrease might have been further strengthened by restrictions imposed by preventive patient education (for example patients are advised to walk only short distances). Our data emphasize the necessity to pay attention to mobility in patients with clinical stable foot ulcers. In conclusion, diabetic foot ulcers have a large impact on quality of life, especially on physical functioning, social functioning and mobility. Physical disabilities, due to the presence of risk factors or ulcers, are responsible for this decrease in quality of life. In our opinion, combining diabetic foot prevention programmes with a rehabilitation programme for patients with DFUs can increase quality of life. Such a programme might provide physical training for these patients (to enhance their condition and decrease disabilities), increase awareness about adaptations and equipment to enhance mobility (prescription of special footwear, walking aids or electric trikes and stair-lifts) and offer vocational therapy. This study was sponsored by a grant from the Vereniging Beatrixoord, Haren, the Netherlands 32 - The diabetic foot syndrome

42 3.5 References 1 Centraal Begeleidingsorgaan voor de Intercollegiale Toetsing, Nederlandse Diabetes Federatie. Richtlijnen NDF/CBO de Diabetische Voet. Heerenveen:Banda, Palumbo PJ, Melton LJ. Peripheral vascular disease and diabetes. In: Harris MI, Hamman RF eds. Diabetes in America. NIH publ. No Washington: US Government Printing Office, 1985; XV: Rijken PM, Dekker J, Dekker E et al. Clinical and functional correlates of foot pain in diabetic patients. Disability and Rehabilitation 1998; 20(9): Carrington AL, Mawdsley SKV, Morley M, Kincey J, Boulton AJM. Psychological status of diabetic people with or without lower limb disability. Diabetes Research and Clinical Practice 1996; 32: Brod M. Quality of life issues in patients with diabetes and lower extremity ulcers: patients and care givers. Quality of Life Research 1998; 7 (4): Fitzpatrick R, Fletcher A, Gore S, Jones D, Spiegelhalter D, Cox D. Quality of life measures in health care: applications and issues in assessment. British Medical Journal 1992; 305: Revicki DA. Quality of life and non-insulin-dependent diabetes mellitus. Diabetes spectrum 1990; 3: World Health Organisation. The first ten years of the World Health Organisation. Geneva: WHO, 1959: Caputo JW, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes mellitus. New England Journal of Medicine 1994; 331: Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: Uccioli L, Boulton AJM. Comparison of risk factors for foot problems in diabetic patients attending hospital outpatient clinics in four different European states. Diabet Med 1994; 11: Wagner FW. The dysvascular foot: a system for diagnosis and treatment. Foot and Ankle 1981; 2: Zee K van der, Sanderman R. Het meten van de algemene gezondheidstoestand met de RAND-36. Noordelijk Centrum voor Gezondheidsvraagstukken, Rijksuniversiteit Groningen, 1993: Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965; 14: Wade DT, Collin C. The Barthel ADL Index: A standard measure of physical disability? International Disability Studies 1988; 10: Chapter 3: Quality of life - 33

43 16 Roorda LD, Roebroeck ME, Lankhorst GJ, Tilburg TG van. De vragenlijst loopvaardigheid: hierarchische schalen om beperkingen in het opstaan en lopen te meten. Revalidata 1996; 18: Roorda LD, Roebroeck ME, Lankhorst GJ, Tilburg TG van. Measuring functional limitations in rising and sitting down: development of a questionnaire. Archives of Physical Medicine and Rehabilitation 1996; 77: J.H.Zar, Biostatistical Analyses, 1999, New Jersey. 19 J.Cohen, Statistical Power Analysis for the Behavioral Scienes, New York, Rose M, Burkert U, Scholler G, Schirop T, Danzer G, Klapp BF. Determinants of quality of life of patients with diabetes under intensified insulin therapy. Diabetes Care 1998; 21(11): The diabetic foot syndrome

44 Chapter 4 Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score J.W.G. Meijer, A.J. Smit, E. van Sonderen, J.W. Groothoff, W.H. Eisma, T.P. Links Diabetic Medicine, short version, in press by Blackwell Ltd and Diabetes UK; reprinted with their kind permission

45 Abstract Aims Methods Results Conclusions Distal polyneuropathy (PNP) is the major risk factor for diabetic foot disease. One of its diagnostic categories is symptom scoring. Several scoring systems are available. The generally accepted Neuropathy Symptom Score (NSS) (17 items) is valid but extensive. We developed, on expert opinion, the 4 item Diabetic Neuropathy Symptom (DNS) score, very manageable but not yet validated. The aim of this study was to validate the DNS-score for diagnosing distal PNP in diabetes. In 73 patients, the score characteristics of the NSS and the DNS-score were compared, and construct validity, predictive value and reproducibility were assessed with the Diabetic Neuropathy Examination score, Semmes Weinstein Monofilaments and Vibration Perception Threshold (clinical standards). 43 men and 30 women were studied (mean duration of diabetes 15 years (1-43), mean age 57 years (19-90)). Twenty-four patients had type 1 diabetes, and 49 type 2. Correlation between NSS and DNS-score was high (Spearman r = 0.88). Patients scored more differentiated on the DNS-score. The relation of the NSS and DNSscore, respectively, with the clinical standards was good (Spearman r = ). Both scores had a comparable predictive value. Reproducibility of the DNS-score was good (Cohen weighted Kappa ). The DNS-score was easier to perform and therefore preferred above the NSS. The DNS-score is a validated symptom score, fast and easy to perform in clinical practice, with high predictive value to screen for PNP in diabetes The diabetic foot syndrome

46 4.1 Introduction Distal symmetric polyneuropathy (PNP) is a very common complication of diabetes and is considered to be a major causal factor in the majority of foot ulcers in diabetic patients 1,2. To diagnose PNP, the San Antonio consensus report advises that at least one measurement should be performed in 5 different diagnostic categories 3. One of these categories is symptom scoring. In our opinion, the value of systematic assessment of symptoms is often misunderstood in clinical practice, and is not based on standardised scoring of a specific set of questions. Diagnosis is usually based on Quantitative Sensory Testing or Physical Examination. However, symptoms are important to evaluate, because they reflect the complaints of the patient, they may be of additional diagnostic or prognostic value and treatment might be possible 4. As diagnostic tests, symptom scores should fulfil the criteria as described by Jaeschke et al. 5. The scores have to be validated (presence of an independent reference standard, adequate spectrum and number of patients, standardisation, soundly based item selection), they should be of predictive value and manageable in clinical practice (reproducibility, performance in clinical practice) 5. Several scores have been developed to assess symptoms of diabetic neuropathy. The Neuropathy Symptom Score (NSS) 4, 6-8 and the Neuropathy Symptom Profile (NSP) 9 both assess diabetic neuropathy. The NSS is the most widely studied and accepted score, and known to be valid and sensitive 4, 6-8. The Neuropathy Symptom Profile contains 34 test categories. It is validated and can be read and scored by computer 9. Because both scores assess neuropathy in general, they are rather extensive in clinical practice. The Michigan Neuropathy Screening Instrument (MNSI) 10 and the modified NSS scores of Veves and Young 11,12 have been developed specifically for distal diabetic polyneuropathy. The MNSI is a combination of a symptom score (15 items) and a physical examination score 10. The combination is valid and has a high predictive value. However, there is no separate symptom score, as advised by consensus reports 3. No information is available to review the modifications of the NSS scores of Veves and Young 11,12. The Diabetes Symptom Checklist type 2 (DSC-type 2) 13 and the McGill Pain Questionnaire 14 are scores for diabetes in general and pain, respectively. The DSC-type 2 has been validated both as an entire score and for neuropathy symptoms alone 13. Of the items concerning neuropathy, only numbness and tingling sensations at both hand and feet were associated with other diagnostic standards for diabetic neuropathy 15. The McGill Pain Questionnaire scores for painful diabetic leg problems 14, but no data is available about validity and predictive value. The Diabetic Neuropathy Symptom score (DNS-score), developed at Chapter 4: the DNS-score - 37

47 our hospital, consists of 4 items chosen on clinical relevance and experience, as the most typical and clinically relevant for distal symmetric PNP in diabetes. This score has not been validated or published before. Because none of these scoring systems fulfil Jaeschke's criteria for diagnostic tests 5, the aim of this study was to validate the DNS-score for diagnosing distal symmetric PNP in diabetes, and to compare its score-characteristics with the NSS. 4.2 Patients and Methods Patients: Our study group consisted of 73 patients with diabetes, covering the entire spectrum of secondary complications. Informed consent was obtained from all participating patients. Exclusion criteria were factors that may interfere with the neurological condition of the subjects other than PNP. Fifty of these 73 patients were randomly selected from the diabetes outpatient clinic of the University Hospital Groningen. The other 23 patients, all known with obvious diabetic foot complications or clinical neuropathy, were selected from the Department of Diabetes at the Rehabilitation Centre Beatrixoord. The characteristics of the 73 patients are shown in Table 1. Table 1: Patient Characteristics N 73 Mean age (years)(sd) 56.9 (16.1) Min max (years) Mean duration DM (years) (SD) 14.9 (9.9) Min max (years) 1 43 Sex Male female Type DM Mean HbA1c (%) (SD) 8.7 (1.4) Min max Retinopathy 40% Nephropathy 42% Peripheral vascular disease 38% Present or former ulcer 20% 38 - The diabetic foot syndrome

48 Methods: The same researcher (J.-W.G.M.) examined all 73 patients. First, the symptom scores were performed followed by clinical standards; a physical examination score ( the Diabetic Neuropathy Examination (DNE) score) and quantitative sensory tests (Semmes Weinstein Monofilaments and vibration perception thresholds), respectively. 1 Symptom Scores 1.1 NSS The NSS consists of 17 items, 8 focusing on muscle weakness, 5 on sensory disturbances and 4 on autonomic symptoms 4,6. Items that are answered negative/absent are scored 0, presence scored as 1 point. Maximum score of the NSS is 17 points 4, DNS-score An expert panel of the University Hospital (Groningen, the Netherlands) developed a 4 item symptom score for diabetic PNP. The panel consisted of a diabetologist/endocrinologist, a specialist for internal vascular diseases, a neurologist and a physician for rehabilitation medicine; all experienced in diagnosing diabetic neuropathy. The DNS-score consists of the following items: (1) unsteadiness in walking, (2) pain, burning or aching at legs or feet, (3) prickling sensations at legs or feet, and (4) numbness at legs or feet. Presence is scored as 1 point, absence as 0 points, maximum score 4 points. Guidelines to use with the score are shown in Appendix 1. 2 Clinical Standards The Diabetic Neuropathy Examination (DNE) score, Semmes-Weinstein Monofilaments (SWMF) and Vibration Perception Threshold (VPT) were chosen as clinical standards to study the construct validity of the symptom scoring systems for PNP. 2.1 DNE-score The DNE-score is a validated, hierarchical physical examination score to diagnose distal symmetric PNP in diabetes 16. It exists of 8 items; 2 items testing muscle strength, 1 item testing a tendon reflex and 5 items testing sensation. The maximum score is 16 points. A score of > 3 points is defined as disturbed/abnormal. 2.2 Semmes-Weinstein Monofilaments (SWMF) SWMF's were tested on the plantar surface of the hallux and central at the heel (when necessary after removal of excessive callus). This method was performed standardised according to generally accepted guidelines The Chapter 4: the DNS-score - 39

49 "yes-no" method was used. This means that the patient says yes each time that he or she senses the application of a monofilament. Six trials were taken, when the patient was unable to respond correct in more than 1 trial, a heavier monofilament was taken. The 1, 10 and 75 gram monofilaments have been used This resulted in four categories: category 1: 1 gram monofilament felt; category 2: 10 gram felt, 1 gram not felt; category 3: 75 gram felt, 10 gram not felt; category 4: 75 gram not felt. In categories 1 and 2 sensitivity is present, therefore they are scored as normal. Categories 3 and 4 are scored as abnormal. 2.3 Vibration Perception Threshold (VPT) VPTs were determined using a hand-held biothesiometer (Biomedical Instruments Inc., Ohio, USA). VPT was tested at the dorsum of the hallux on the interphalangeal joint and at the lateral malleolus. It was performed in a standardised way The voltage of vibration was increased until the patient could perceive a vibration. This was done three times. The mean of these three was used to determine the VPT. Age-adjusted reference values were used Values higher than the mean+2*sd (reference value) were considered as abnormal. Reproducibility In order to test reproducibility of the DNS-score, inter- and intrarater agreement were assessed in a separate study on 10 patients. The 6 women and 4 men, with a mean age of 50.0 years (SD15.9) had a wide range of neuropathy severity. The mean duration of DM was 11.5 years (SD 10.5); 3 participants had type 1 DM and 7 had type 2 DM. Two doctors, an endocrinologist and a physician for rehabilitation medicine, both experienced in diagnosing diabetic neuropathies, rated these patients twice with an interval of one week. Statistical Analyses Internal consistency of the symptom scores was assessed by calculating Cronbach's alpha, and reliability coefficient Rho, which is comparable to alpha. The statistical package SPSS-PC was used to compute the descriptive statistics, reliability coefficient Crohnbach s alpha, Spearman's correlation coefficient r, Student's t-test and ROC curves 24. Inter- and intrarater agreement was assessed using Cohen s weighted Kappa 25, The diabetic foot syndrome

50 4.3 Results In Table 2 general information about the NSS and the DNS-score is shown. The reliability of the DNS-score seems to be a little lower than of the NSS. This is, however, due to the considerable reduction of items, and not to a lower association between the items. Correlation (Spearman r) between these two symptom scores is, as expected, high:.88. Table 2: Characteristics of the symptom scores. NSS DNS-score Mean (SD) 1.9 (2.0) 1.1 (1.3) Reliability (alpha) Number of items 17 4 Maximum score 10 4 Non used items 4 0 Relationship of the NSS and DNS-score with the Clinical Standards Spearman's correlation coefficient r for the DNE-score with the NSS and DNS-score was similar with values of.56 and.60 (both p<.001), respectively. Spearman's correlation coefficient r for the SWMF with the NSS and DNS-score was.21 (not significant) and.25 (p<.05), respectively. For VPT, Spearman's correlation coefficient r with the NSS and DNS-score was.46 and.56 (both p<.001), respectively. The NSS and the DNS-score predicted the results of the clinical standards adequately, as shown in Table 3. Chapter 4: the DNS-score - 41

51 Table 3 Relation Clinical Standards - Symptom Scores group 0= normal on clinical standard, group 1= disturbed on clinical standard DNE-score: N mean NSS (SD) mean DNS (SD) (1.47).42 (.93) (2.07) 1.52 (1.24) p.002 p.000 Semmes Weinstein Monofilaments Hallux: N mean NSS (SD) mean DNS (SD) (1.42).84 (1.04) (2.63) 1.56 (1.41) p.014 p.019 Vibration Perception Threshold Hallux: N mean NSS (SD) mean DNS (SD) (1.47).67 (.98) (2.34) 1.69 (1.30) p.004 p.000 Sensitivity / Specificity Figure 1 shows the ROC-curves of, respectively, the NSS and DNS-score as compared with the DNE-score. For NSS and DNS-score the areas under the curve are.75 and.78, respectively. Using the SWMF at the hallux these values are.62 and.65, respectively; and using VPT.68 and.73, respectively. At a cut off point of 0 versus 1-4 for the DNS-score, sensitivity was 79% and specificity 78% regarding the DNE-score. Regarding SWMF sensitivity was 81% and specificity 56%, for VPT sensitivity was 81% and specificity 58% The diabetic foot syndrome

52 Figure 1: ROC-curves of NSS and DNS-score, respectively, in relation to the DNE-score. 1,00,75,50 sensitivity,25 Referenc e Li DNS-score 0,00 0,00,25,50,75 1,00 NSS 1-specificity Reproducibility of the DNS-score The intrarater agreement showed Cohen s weighted Kappa s for both raters of.89 and.78, the interrater agreement on two occasions was.95, and.83, respectively, indicating a good to very good level of agreement 25,26. Chapter 4: the DNS-score - 43

53 4.4 Discussion The NSS is a validated and widely accepted symptom score for diabetic neuropathy 4, 6-8. The most frequent form of neuropathy in diabetes and major risk factor for diabetic foot disease is distal symmetric PNP 1. Several items of the NSS are seldom scored, because the NSS has not been developed specifically for distal PNP. Large groups of diabetic patients need to be screened regularly to diagnose PNP early as part of prevention of diabetic foot ulcers. Consequently, several other scoring systems and modifications have been developed, but they do not sufficiently fulfil all the criteria necessary for adequate diagnostic tests. In this study, the DNS-score was validated with the aim of achieving a manageable symptom scoring system for diagnosing distal symmetric diabetic PNP in clinical practice and epidemiological studies. We compared the score-characteristics of the DNS-score with the original NSS. Furthermore, the construct validity of the NSS and DNS-score has been studied by comparing the scores with the clinical standards chosen: the DNEscore, SWMF and VPT. We conclude that both symptom scores adequately fulfil the criteria for diagnostic tests, as mentioned in the introduction. We prefer the DNS-score for further use as symptom score, because the differences between the scores on validity and predictive value are small and not clinically relevant, and the manageability of the DNS-score is excellent. Consisting of only 4 items, the DNS-score is fast and easy to perform in clinical practice with a high reproducibility. Diagnostic tests can be discriminative (diagnosis), predictive (prognosis) or evaluative (follow up). The DNS-score is validated with clinical standards on discriminative and predictive values. For evaluation of treatment or follow up, the score might be too short with only four items. However, in the NSS the number of items related to PNP is also very limited. Unfortunately the exact weight of the different categories, individual or in combination, in diagnosing diabetic PNP and predicting diabetic foot complications, is not yet known. Sensitivity and specificity of the DNS-score were high regarding the DNE score, SWMF and VPT. Because the DNS-score will be used for screening purposes, sensitivity is preferred above specificity. A score of 1 or more points on the DNS-score is very sensitive for presence of diabetic PNP. In combination with the results of the other diagnostic categories of the San Antonio Consensus, this gives an indication of type and severity of PNP The diabetic foot syndrome

54 Controversy exists about the use of symptom scoring in diagnosing PNP in diabetes. Because symptoms of neuropathy (pain, numbness and tingling) are present in 30-40% of all people with diabetes, Mayfield et al. concluded that the presence or absence of symptoms should not be used to assess the risk of ulcers or amputation 27. Valk et al. found that symptoms of neuropathic pain and paraesthesia were neither correlated with the results of physical examination nor with the results of neurophysiological examination 15. In another study they concluded that only symptoms of numbness and tingling sensations in hand and feet (items of the DSC-type 2), were associated with the clinical examination, but not with neurophysiological examination 28. Franse et al. studied whether a patient history could replace the Clinical Neurological Examination (CNE). The individual symptoms were insufficiently predictive for the presence of polyneuropathy. They concluded that individual symptoms could not replace the CNE 29. Dyck et al. found an association between complaints of diabetic neuropathy, abnormalities of the clinical examination and abnormalities of nerve conduction 7. In our report significant and clinically relevant correlations have been shown between the symptom scores and the DNE-score, SWMF and VPT, respectively; which are all accepted tests with known predictive value for diabetic foot complications. Therefore, as the consensus advises, we state that symptom scoring deserves to be a part of the diagnostic set, complementary to other diagnostic categories for diabetic PNP 3. It is known that the reliability of symptom scores may be poorer than the reliability of the other diagnostic categories 3,4,8. This might be caused by the subjectivity of the scores, leading to a poor reproducibility. The consensus advises to score dichotomous to enhance reliability 3. In the DNS-score, a short and dichotomous symptom score, the reproducibility is high. In conclusion, the DNS-score, a symptom score specific for distal symmetric PNP in diabetes, has now been validated, and is fast and easy to perform in clinical practice. As the consensus advises, this scale has to be used complementary to other diagnostic categories as for example standardised physical examination (for example the DNE-score) and quantitative sensory testing. Further prospective studies are necessary with the DNS-score, the DNE-score and other diagnostic tests, to assess the predictive value of the scales and items. Chapter 4: the DNS-score - 45

55 4.5 References 1 Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: s12-s16. 2 Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994; 331: Consensus Statement: Report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988; 11: Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: Jaeschke R, Guyatt G, Sacket DL. Users' guides to the medical literature: how to use an article about a diagnostic test. JAMA 1994; 271: Dyck PJ, Sherman WR, Hallcher LM Service FJ, O'Brien PC, Grina LA, Palumbo PJ, Swanson CJ. Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry. Annals of Neurology 1980; 6: Dyck PJ, Karnes JL, Daube J, O'Brien P, Service JF. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, Rizza RA, Zimmerman BR. The Rochester diabetic neuropathy study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 1991; 41: Dyck PJ, Karnes J, O'Brien PC, Swanson CJ. Neuropathy Symptom Profile in health, motor neuron disease, diabetic neuropathy, and amyloidosis. Neurology 1986; 36: Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. Practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17: Veves A, Manes C, Murray HJ, Young MJ, Boulton AJM. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993; 16: Young MJ, Boulton AJM, Macleod AF, Williams DRR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: The diabetic foot syndrome

56 13 Grootenhuis PA, Snoek FJ, Heine RJ, Bouter LM. Development of a type 2 diabetes symptom checklist: a measure of symptom severity. Diabet Med 1994; 11: Masson EA, Hunt L, Gem JM, Boulton AJM. A novel approach to the diagnosis and assessment of symptomatic diabetic neuropathy. Pain 1989; 38: Valk GD, Grootenhuis PA, Bouter LM, Bertelsmann FW. Complaints of neuropathy related to the clinical and neurophysiological assessment of nerve function in patients with diabetes mellitus. Diab Res and Clin Pract 1994; 26: 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 2000; 23: Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG. Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Archives of Internal Medicine 1998; 158: 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: Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 nondiabetic subjects. BMJ 1984; 288: Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: Hanley JA, McNeil BJ. A method of comparing the areas under the receiver operating characteristic curves derived from the same cases. Radiology 1983; 148: Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33: Chapter 4: the DNS-score - 47

57 26 Altman DG, ed. Practical statistics for medical research. London: Chapman and Hall, Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21: Valk GD, Nauta JJP, Strijers RLM, Bertelsman FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med 1992; 9: Franse LV, Valk GD, Dekker JH, Heine RJ, van Eijk JTM. Numbness of the feet is a poor indicator for polyneuropathy in type 2 diabetic patients. Diabet Med 2000; 17: The diabetic foot syndrome

58 Appendix 1: DNS-score DNS-score and guidelines 1 Are you suffering of unsteadiness in walking? need for visual control, increase in the dark, walk like a drunk man, lack of contact with floor remark: it is assumed that the patient has no limiting visual, hearing or central neurological deficits. 2 Do you have a burning, aching pain or tenderness at your legs or feet? remark: it is assumed that intermittent claudication has been made unlikely by excluding pain which develops during walking and disappears upon halting, and that ischaemic rest pain is made unlikely by lack of effect of dependency, in both cases further supported by the lack of absent foot-ankle pulsation and/or reduced ankle- and toe pressures. 3 Do you have prickling sensations at your legs and feet? occurring at rest or at night, distal>proximal, stocking glove distribution 4 Do you have places of numbness on your legs or feet? Distal>proximal, stocking glove distribution The questions should be answered "yes" (positive: 1 point) if a symptom occurred more times a week during the last 2 weeks or "no" (negative: no point) if it did not. Max. score: 4 points 0 points: PNP absent 1-4 points: PNP present Chapter 4: the DNS-score - 49

59 50 - The diabetic foot syndrome

60 Chapter 5 Diabetic Neuropathy Examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes J.W.G. Meijer, E. van Sonderen, E.E. Blaauwwiekel, A.J. Smit, J.W. Groothoff, W.H. Eisma, T.P. Links Diabetes Care 2000; 23 (6): by the American Diabetes Association; reprinted with their kind permission

61 Abstract Objective Methods Results Conclusions Existing physical examination scoring systems for distal diabetic polyneuropathy (PNP) do not fulfil all of the following criteria: validity, manageability, predictive value, and hierarchy. The aim of this study was to adapt the Neuropathy Disability Score (NDS) to diagnose PNP in diabetes mellitus (DM) so that it fulfils these criteria. A total of 73 patients with DM were examined with the NDS. Monofilaments and biothesiometry were used as clinical standards for PNP to modify the NDS. A total of 43 men and 30 women were studied; the mean duration of DM was 15 years (1-43), and the mean age was 57 years (19-90). Twenty-four patients had DM type 1 and 49 had type 2 DM. Clinically relevant items were selected from the original 35 NDS items (specific item scored positive score in > 3 patients). The resulting 8-item Diabetic Neuropathy Examination score (DNE) could accurately predict the results of the clinical standards and is strongly hierarchical (H-value 0.53). The sensitivity and specificity of the DNE at a cut-off level of 3 to 4 were 0.96 and 0.51 for abnormal monofilament scores, respectively. For abnormal biothesiometry scores, these values were 0.97 and 0.59, respectively. Reproducibility, as assessed by inter- and intrarater agreement, was good. The DNE is a sensitive and well-validated hierarchic scoring system that is fast and easy to perform in clinical practice The diabetic foot syndrome

62 5.1 Introduction Early detection of symmetric distal sensori-motor polyneuropathy (PNP) is important in patients with diabetes mellitus (DM), because preventive interventions can be applied to decrease morbidity 1. Unfortunately, no "gold standard" exists for diagnosing PNP, but a consensus panel has recommended that at least 1 measurement should be performed in 5 different diagnostic categories. One of these categories is a standardised physical examination 2,3. In our opinion, diagnostic tests should fulfil the following criteria: validation (presence of independent reference standard, adequate spectrum and number of patients, standardisation, soundly based item selection), predictive value, manageability (reproducibility, performance in clinical practice) and hierarchy. Frequently used and accepted examination scores for diabetic neuropathy are the Neuropathy Disability Score (NDS) 4, the Neuropathy Impairment Score in the Lower Limbs (NIS-LL) 5,6, various modified NDS scores 7,8, the Neuropathy Deficit Score 9, the Michigan Neuropathy Screening Instrument (MNSI) 10 and the Clinical Examination score of Valk (CE-V) 11. The NDS was designed for neuropathy in general 4. Although the score is well founded and complete, it is difficult to perform in clinical practice on patients with diabetic foot problems. Precise descriptions of how the tests should be performed and how items should be scored are lacking. The NIS- LL is a modification of the NDS specific for distal PNP, although motor activity grading is the focus and involves 64 of a maximum of 88 points 5,6. The NIS-LL has not been validated. Various other modified NDS scoring systems have been used, such as those of Veves et al. 7 and Young et al. 8. However, these instruments also have not been validated and no information is available on their predictive value regarding the results of clinical standards. The Neuropathy Deficit Score is a neurological examination score aimed at anatomical levels in the legs and arms 9. It has not been validated and no information is available about how to interpret modifications, which is also the case for the other modified NDS scoring systems 7,8. Feldman et al. 10 developed a combination of two scoring systems: the Michigan Neuropathy Screening Instrument (symptom and examination score) and the Michigan Diabetic Neuropathy Score (neurological examination and nerve conduction studies). These scores do not have a separate examination score, as advised by consensus reports 2,3. The CE-V can be used to examine sensory functions, tendon reflexes and muscle strength in the lower extremities 11. The scoring systems of Feldman et al. and Valk et al. have been validated and are easy to perform in clinical practice. None of the afore mentioned scores is known to be hierarchical. Chapter 5: the DNE-score - 53

63 The aim of this study was to adapt the NDS into a valid, easily managed, graded and accurate scoring system for diagnosing PNP, the Diabetic Neuropathy Examination (DNE) score. 5.2 Research Design and Methods Patients: Our study group consisted of 73 patients with DM. Exclusion criteria were factors that may interfere with the neurological condition of the subjects other than PNP. Fifty patients were randomly selected from the diabetes outpatient clinic of the University Hospital Groningen. Twenty-three positive control patients with obvious diabetic foot complications or clinical neuropathy were selected from the Department of Diabetes of the Rehabilitation Centre Beatrixoord. The characteristics of these 73 patients are shown in Table 1. Table 1: Patient characteristics N 73 Mean age (years)(sd) 56.9 (16.1) Min max (years) Mean duration DM (years) (SD) 14.9 (9.9) Min max (years) 1 43 Sex male female Type DM Mean HbA1c (%) (SD) 8.7 (1.4) Min max Methods: The same researcher (JWGM) examined all 73 patients. First, the NDS and NIS-LL were performed, followed by quantitative sensory tests that acted as a clinical standard. 1 NDS and NIS-LL The NDS is the most widely used and widely accepted scoring system for diabetic neuropathy; it has also been recommended in consensus reports 2,3,4. The instrument examines cranial nerves, muscle weakness, reflexes and sensation 4. The scale consists of 35 items for testing the left and right sides of 54 - The diabetic foot syndrome

64 the body; scores range from 0 to 4. A sum score is obtained with a maximum of 280 points. The NIS-LL is a modified version of the NDS to quantify diabetic PNP. The lower limb items of the NDS are used complemented with two muscle power items (toe extension and toe flexion). The NIS-LL has 14 items: 8 items evaluate muscle power (0-4 points), 2 items evaluate reflexes (0-2 points), and 4 items evaluate sensory modalities (0-2 points). All items are tested on both sides. The maximum score is 88 points. The NDS, as the most complete and accepted score, was used for item selection to develop the DNE-score. 2 Clinical Standards Semmes Weinstein Monofilaments (SWMF) and Vibration Perception Threshold (VPT) were chosen as clinical standards to study the construct validity of the scoring system for PNP. SWMF 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 The "yes-no" method was used, which means that the patient says yes each time he or she senses the application of a monofilament. Six trials were administered, when the patient was unable to respond correctly in more than 1 trial, a heavier monofilament was used. The 1, 10 and 75 gram monofilaments have been used. We present the results in four categories: category 1: 1 gram monofilament felt; category 2: 10 gram monofilament felt, 1 gram monofilament not felt; category 3: 75 gram monofilament felt, 10 gram monofilament not felt; category 4: 75 gram monofilament not felt. Vibration Perception Thresholds (VPTs) were determined using a hand-held biothesiometer (Biomedical Instruments Inc., Ohio, USA). VPT was tested at the dorsum of the hallux on the interphalangeal joint. It was performed in a standardised way 15,16. The voltage of vibration was increased until the patient could perceive a vibration. This was done three times. The mean of these three trials was used to determine the VPT. Reproducibility To test reproducibility, inter- and intrarater agreement were assessed in a separate study of 10 patients. The 6 women and 4 men, with a mean age of 50.0 years (SD15.9) had a wide range of neuropathy severity. The mean duration of DM was 11.5 years (SD 10.5); 3 participants had type 1 DM and 7 participants had type 2 DM. Two experienced physicians, an endocrinologist (EEB) and a physician for rehabilitation medicine (JWGM), both experienced in diagnosing diabetic neuropathies, rated these patients twice within one week. Chapter 5: the DNE-score - 55

65 Statistical Analyses Internal consistency of the DNE-score was assessed by calculating Cronbach's alpha, and reliability coefficient Rho 17, which is comparable to alpha. In addition to internal consistency, scalability coefficient H was computed with the probabilistic scaling programme MSP (Mokken Scaling Polychotomous items) to assess the hierarchical structure of the items 17. High values of H increase the likelihood that patients with the same scale score have difficulties or problems with the same items. The statistical package SPSS-PC (Chicago) was used to compute the descriptive statistics, factor analysis, reliability coefficient Crohnbach s alpha, Pearson's correlation coefficient r and Student's t-test. Inter- and intrarater agreement were assessed on a scale level by computing Pearson's correlation coefficients and t-test values for differences in means. 5.3 Results Items were excluded from the original NDS if they conformed to the following definition of clinical irrelevance: specific item scored positive in 3 patients or less. After examining the patients, 9 of the original 35 items remained. No relevant differences were found between the measurements made on the left and right side, so only the right-side items were used in the analyses. Factor analysis was performed on the 9 items to investigate coherence. The coherence of the 8 items was good; only item 22 (muscle strength triceps surae) had poor coherence compared to the other items. Calculation of hierarchy was performed using the MSP items. This resulted in a hierarchical scale of 8 items. Item 22 disturbed the hierarchy severely. Logistic regression analysis was performed to study whether item 22, in addition to the 8-item hierarchical scale, could predict the results of the clinical standards SWMF and VPT. Item 22 did not make any significant contribution, so it was excluded. Modification of the NDS resulted in an 8-item scale: the Diabetic Neuropathy Examination (DNE) score. The DNE-score is shown in Appendix 1. Reliability of the scale was assessed by measuring the internal consistency. According to both Cronbach's alpha (.78) and reliability coefficient Rho (.81) the scale appears to be reliable. The H-value for hierarchy was 0.53, which indicates the presence of a strong hierarchical scale 17. Table 2 shows the characteristics of the DNE-score, NDS and NIS-LL. As expected, the correlation between the DNE-score and respectively the NDS (Pearson's r.96, p<.001) and NISS-LL (Pearson's r.92, p<.001) were both high. The reliability of the scoring systems was good The diabetic foot syndrome

66 The DNE is fast and easy to perform in clinical practice; application takes about 5 minutes. Table 2: Characteristics of the NDS, NIS-LL and the DNE-score in our study population n= 73 NDS NIS-LL DNE-score Mean score (SD) 19.7 (14.5) 9.7 (7.9) 5.0 (3.6) Reliability (alpha) Number of items Maximum score Maximum scored Items not scored Less than three scores Relationship of the NDS, NIS-LL and DNE-score with the clinical standards Pearson's correlation coefficient r of SWMF with NDS, NIS-LL and DNEscore was similar with values of.76 (p<.001),.74 (p<.001) and.75 (p<.001), respectively. Pearson's correlation coefficient r for VPT with NDS, NIS-LL and DNE-score was similar with values of.73 (p<.001),.71 (p<.001) and.75 (p<.001), respectively. The NDS, NISS-LL and DNE-score predicted the results of the clinical standards very accurately (p <.001). At a cutoff point of 3 to 4, sensitivity and specificity of the DNE-score were 0.96 and 0.51, respectively, for an abnormal result using SWMF. For an abnormal result using the VPT, these values were 0.97 and 0.59, respectively. Reproducibility Comparing the scores of 2 raters obtained on 2 occasions (interval 1 week) assessed reproducibility of the DNE-score. The interrater correlation was.97 at t1 and.92 at t2, respectively. Differences in mean scores were less than 10% and not significant (p=.08 and.55, respectively). The intrarater correlation was.89 for one rater and.99 for the other. The mean scores of the two raters did not differ significantly at t1 and t2 (p=.17 and.60, respectively). Chapter 5: the DNE-score - 57

67 5.4 Discussion The NDS is a widely accepted and validated physical examination scoring system used to diagnose neuropathy. Its predictive value and reproducibility are high. It is well correlated with neurophysiological and sural nerve morphometric abnormalities in patients with diabetes mellitus 4, Because the aim of the NDS is to evaluate neuropathy in general, it is not completely suitable for use at an outpatient diabetic foot clinic. Consequently, several other scoring systems have been developed, but they do not sufficiently fulfil all of the criteria necessary for adequate diagnostic tests. One of these is NIS- LL, a score for distal diabetic polyneuropathy with 14 items. The score has not been validated, and focuses more on motor problems than on sensory problems 5,6. In this study, the NDS was modified once again with the aim of achieving a new physical examination scoring system for diagnosing distal symmetric polyneuropathy in diabetes mellitus. The new instrument is the DNE-score, a scoring system with 8 items. It was validated in DM patients with a wide spectrum of complications. The DNE-score is hierarchical, sensitive, fast, and easy to perform in clinical practice (application takes about 5 minutes). Hierarchy implies that patients with the same scale score have difficulties or problems with the same items, which makes this scoring system able to differentiate between severity levels of PNP and to compare groups or individuals over time. The NDS, NIS-LL and the other instruments for evaluating PNP have not been documented to represent a hierarchical scale. Our modifications were validated with SWMF measurements and VPTs. These are both semiquantitative, reliable measurements with proven predictive value for the development of clinical problems, such as foot ulcers and amputations. They are non-invasive, patient-friendly, independent and complementary SWMF and VPT only assess large fiber function, no small fiber tests have been used in this study. Testing the DNE-score on a random sample from the outpatient clinic in addition to a set of patients with definite neuropathy means that the results are generalisable to the complete range of patients with DM. Many clinicians prefer using electro-diagnostic techniques to diagnose diabetic PNP. Although neurophysiological examination is sensitive, specific and reproducible regarding the presence and severity of peripheral nerve involvement in patients with diabetes 18, it is not suitable for making a quick preliminary diagnosis at a diabetes outpatient clinic. No data are available on the predictive value of these techniques in relation to the development of clinical problems, such as diabetic foot disease The diabetic foot syndrome

68 Because the aim of this study was to develop a screening instrument as a tool in the detection and prevention of patients at risk for diabetic foot complications, the observed sensitivity and specificity of the DNE-score are satisfactory. Because sensitivity is of greater importance than specificity for screening instruments, the chosen cut off value results in the desired high sensitivity with an acceptable specificity. A low specificity might burden prevention education programmes. The combined use of different diagnostic tools, as advised in consensus reports, will enhance specificity. The selection of the item muscle strength of the quadriceps femoris in the DNE-score is surprising and suggests the presence of mononeuropathy. Nevertheless, all patients with quadriceps dysfunction also showed other abnormalities regarding sensation in the feet, that were not related to the same peripheral nerves, which makes mononeuropathy less probable. The ankle dorsiflexion item was excluded because of poor coherence and disturbance of hierarchy. It did not contribute to the 8 definite items. Perhaps this discrepancy in muscle strength and its assessment is because of other factors, such as limited joint mobility. The results of validation and the predictive value of the NDS, NIS-LL and DNE-score were very satisfactory. The strengths of the DNE-score are its manageability in clinical practice and its hierarchy. The DNE-score is the most efficient according to the criteria shown in Table 2. In conclusion, the DNE-score as modified from the NDS is fast and easy to perform, hierarchical, and sensitive for PNP, and patient scores are more differentiated. Chapter 5: the DNE-score - 59

69 5.5 References 1 Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994; 331: Consensus Statement, Report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988; 11: Proceedings of a Consensus Development Conference on Standardized Measures in Diabetic Neuropathy. Diabetes Care 1992; 15, suppl 3. 4 Dyck PJ, Sherman WR, Hallcher LM Service FJ, O'Brien PC, Grina LA, Palumbo PJ, Swanson CJ. Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry. Annals of Neurology 1980; 6: Dyck PJ, Melton J, O'Brien PC, Service FJ. Approaches to improve epidemiological studies of diabetic neuropathy. Insights from the Rochester Diabetic Neuropathy Study. Diabetes 1997; 46: s5-s8. 6 Bril V. NIS-LL: the primary measurement scale for clinical trial endpoints in diabetic peripheral neuropathy. Eur Neurol 1999; 41 (suppl 1): Veves A, Manes C, Murray HJ, Young MJ, Boulton AJM. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993; 16: Young MJ, Boulton AJM, Macleod AF, Williams DRR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: Young RJ, Qing Zhou Y, Rodriguez E, Prescott RJ, Ewing DJ, Clarke BF. Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy. Diabetes 1986; 35: Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. Practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17: Valk GD, Nauta JJP, Strijers RLM, Bertelsman FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med 1992; 9: Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991;13: The diabetic foot syndrome

70 13 Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG. Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Archives of Internal Medicine 1998; 158: Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: Debets P, Brouwer E. MSP: a program for Mokken Scale Analysis for Polychotomous Items, Users Manual, version iecprogramma, Groningen, the Netherlands. 18 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: Dyck PJ, Karnes JL, Daube J, O'Brien P, Service JF. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, Rizza RA, Zimmerman BR. The Rochester diabetic neuropathy study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 1991; 41: Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population based cohort: The Rochester Diabetic neuropathy study. Neurology 1993; 43: Chapter 5: the DNE-score - 61

71 Appendix 1: Diabetic Neuropathy Examination score DNE-score muscle strength 1 quadriceps femoris: extension of the knee 2 tibialis anterior: dorsiflexion of the foot reflex 3 triceps surae sensation index finger 4 sensitivity to pin pricks sensation big toe 5 sensitivity to pin pricks 6 sensitivity to touch 7 vibration perception 8 sensitivity to joint position - only the right leg and foot are tested - scoring from 0-2: 0= normal 1= mild/moderate deficit: muscle strength: MRC 3-4 reflex: decreased, but present sensation: decreased, but present 2= severely disturbed/absent: muscle strength: MRC 0-2 reflex: absent sensation: absent - maximum score: 16 points 62 - The diabetic foot syndrome

72 Chapter 6 Clinical diagnosis of diabetic polyneuropathy with the DNS and DNE score J.W.G. Meijer, E. Bosma, J.D. Lefrandt, T.P. Links, A.J. Smit, R.E. Stewart, J.H. van der Hoeven, K. Hoogenberg Submitted.

73 Abstract Objective The discriminative power of the Diabetic Neuropathy Symptom (DNS) and Diabetic Neuropathy Examination (DNE) score for diagnosing diabetic PNP, and their relation with cardiovascular Autonomic Function Testing (caft) and Electro Diagnostic Studies (EDS) are evaluated. Methods Three groups (matched for age and sex) were selected: 24 diabetic patients with neuropathic foot ulcers (diabetes ulcus group), 24 diabetic patients without clinical neuropathy or ulcers (diabetes control group) and 21 controls without diabetes (controls). In all participants the DNS- and DNE-score were assessed, and caft (Heart Rate Variability (HRV) and Baro Reflex Sensitivity (BRS)) and EDS were performed (Nerve Conduction Sum (NCS) score; muscle fiber conduction velocity: fastest/slowest ratio (F/S ratio)). Results Both the DNS and the DNE score discriminated between the diabetes ulcus and diabetes control group significantly (p<.001). The DNE score even discriminated between the diabetes control group and controls without diabetes (p<.05). Spearman's correlation coefficients between both DNS- and DNE-score and caft (HRV -.42 and -.44, respectively; BRS -.30 and -.29, respectively) and EDS (NCS.51 and.62, respectively; F/S ratio.44 and.62, respectively), were significant. Odds ratios were calculated for both DNS and DNE score with caft (HRV 4.4 and 5.7, respectively; BRS 20.7 and 14.2, respectively) and EDS (NCS 5.6 and 16.8, respectively; F/S ratio 7.2 and 18.8, respectively). Conclusions the DNS and DNE scores are capable to discriminate between patients with and without PNP, and are strongly related to caft and EDS. This further confirms the strength of the DNS and DNE scores in diagnosing diabetic PNP in daily clinical practice The diabetic foot syndrome

74 6.1 Introduction One of the major risk factors for the development of diabetic foot complications is distal symmetric sensorimotor polyneuropathy (PNP) 1,2. For diagnosing PNP, no gold standard is available. The San Antonio consensus panel has recommended that at least 1 measurement should be performed in 5 different diagnostic categories 3. These are symptom scoring, physical examination scoring, Quantitative Sensory Testing (QST), cardiovascular Autonomic Function Testing (caft) and Electro-Diagnostic Studies (EDS). Because none of the existing symptom and physical examination scores for diabetic PNP completely fulfilled methodological criteria for diagnostic tests, the Diabetic Neuropathy Symptom (DNS) score and Diabetic Neuropathy Examination (DNE) score were developed 4,5. The construct validity of these scores was studied in relation to Semmes Weinstein monofilaments and Vibration Perception Threshold testing (both forms of QST), because of their known predictive value to the development of diabetic foot complications 6-9. caft has an important prognostic value for the prediction of diabetic foot complications 8, 10,11 and mortality due to cardiovascular problems 12,13. The prognostic value of EDS is less clear, although EDS is supposed to be the most sensitive diagnostic tool for diabetic PNP 14. The relation between the DNS- and DNE-scores and caft and EDS, respectively, has not yet been studied. The objective of this study is to assess the discriminative power of the DNSand DNE-scores for diagnosing diabetic PNP, and their relation with caft and EDS, respectively. 6.2 Patients and Methods Patients All participants were recruited from the Diabetes Outpatient Clinic (University Hospital Groningen) and from the Rehabilitation Centre Beatrixoord Haren, after informed consent. To study the discriminative power of the DNS- and DNE-score, three groups of subjects were studied. Selection was performed by checking the patient records. The first group consisted of 24 diabetic patients known with previous or present neuropathic foot ulcers (group DU). These ulcers were purely neuropathic by origin, as was confirmed by their localization (plantar surface of the foot at high pressure points), and by absence of peripheral arterial disease as described below. In the second group, 24 diabetic patients unknown with clinical neuropathy or foot ulcers (group DC) were included, this was confirmed by normal sensitivity to the 10 gram Semmes Weinstein Monofilament testing (performance as described previously) 5. The third group consisted of 21 Chapter 6: Clinical diagnosis of PNP - 65

75 control subjects with normal glucose tolerance (group C). All groups were matched for sex and age (within 5 yrs), and the diabetic groups for duration and type of diabetes (type 1/ type 2; type 1 DM was considered on clinical grounds when the onset of the disease was an ketoacidosis or before the age of 40 years) as well. Subjects with a history of or clinically apparent cardiac disease, electrocardiographic abnormalities or using betablockers or calcium antagonists were excluded. Peripheral arterial disease was excluded by normal ankle-arm indices (>0.90), toe-arm indices (>0.70) and normal plethysmography (crest time 0.22 sec) in all groups. Normal glucose tolerance of the control subjects was demonstrated by a fasting capillary blood glucose < 6.1 mmol/l and a blood glucose < 7.8 mmol/l 2h after a 75 gr oral glucose tolerance test. Details of the clinical characteristics of each group are given in Table 1. Table 1: Patient Characteristics DU (n=24) DC (n=24) C (n= 21) mean age (years) 57.3 ± ± ± 9.9 sex (M/F) 14/10 13/11 10/11 mean duration of diabetes (years) 16.9 ± ± 9.8 type of diabetes (type 1/type 2) 5/19 8/16 mean HbA1c (%) 8.3 ± ± 0.8 DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy; C: controls; Data are means ± SD, or n. Methods The DNS- and DNE-score (EB), caft (JL) and EDS (JH) were performed by different researchers, blinded for the group to which the participant was allocated. The researchers were acting independently and no information about the results was exchanged during the study. An overall neuropathy sum score, according to the San Antonio consensus, was composed. Diabetic Neuropathy Symptom (DNS) score Both the DNS-score and DNE-score have been described in detail elsewhere 4,5. In short, the DNS score is a 4 item validated symptom score, with high predictive value to screen for PNP in DM 4. Symptoms of unsteadiness in walking, neuropathic pain, paraesthesia and numbness are elicited. The 66 - The diabetic foot syndrome

76 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. Diabetic Neuropathy Examination (DNE) score The DNE-score is a sensitive and validated hierarchical scoring system 5. 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. cardiovascular Autonomic Function Testing (caft) Cardiovascular autonomic function was assessed by analysis of heart rate variability (HRV) and baroreflex sensitivity (BRS). All participants were studied in the morning. All measurements took place in a quiet room with the temperature kept constant at 22 o C. 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). After 30 min of supine rest, 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 analyzed by the CARSPAN program (IEC ProGamma, Groningen, the Netherlands), as described previously 15,16. After artifact correction and stationarity check, discrete Fourier transformation of systolic blood pressure and RR interval length was performed. 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 17. The total power frequency band (TP) of HRV was defined as Hz. Because no reference values of HRV are available, the median of the control group was used, 9.2 ln(ms 2 ). BRS was determined by the transfer function method and defined as the mean modulus between systolic blood pressure and heart rate variability in the Hz frequency band with at least 0.5 coherence, expressed in ms/mmhg 15,16,18. A BRS lower than 3 ms/mmhg leads to high mortality rates in chronic heart failure and after myocardial infarction, in diabetes the prognostic value of the BRS is not yet known 19,20. In this study, a BRS < 3 ms/mmhg was considered as indicative for cardiovascular autonomic neuropathy. Electro-Diagnostic Studies (EDS) Nerve conduction studies were performed with standard surface stimulation and recording techniques using an electromyograph type Nicolet Viking IIe and IV with standard filter settings. All measurements were performed after warming in hot water (38 C) of fore arm and lower leg during at least 15 minutes. Peak-peak amplitudes were used. Motor Nerve Conduction Velocity (MNCV) and amplitudes were measured in the left median (thenar) and Chapter 6: Clinical diagnosis of PNP - 67

77 peroneal nerves (tibialis anterior). Sensory Nerve Conduction Velocities and amplitudes were measured antidromically with ring electrodes placed around the middle finger (median nerve) and stimulation lateral of the Achilles tendon (sural nerve). An overall Nerve Conduction Sum (NCS) score was defined as the number of these four nerves with an abnormal conduction velocity and amplitude, ranging from 0 (all normal) to 4 (all abnormal). Reference values from our own laboratory were used, see legend table 2. Invasive MFCV (I-MFCV) measurements were performed in the tibialis anterior muscle at rest by means of needle electrodes adapted from the method as described previously 21. In short, muscle fibers were stimulated in the distal part of the tibial anterior muscle directly by a small monopolar needle electrode (cathode) using a surface electrode as anode. Filter settings 500 Hz-10 khz, stimulation 0.2 ms, 1-2 ma. The resulting muscle fiber action potentials were detected at a known distance (50-60 mm) by a small concentric needle electrode. With this technique, action potentials supposed to represent individual muscle fibers were identified, and the resulting conduction velocities were calculated. As parameters the mean I-MFCV and the fastest/slowest ratio representing the scatter of conduction velocities were used and compared to normative values from our own laboratory. Neuropathy Sum score For this study, an overall score was composed of the 5 diagnostic categories of the San Antonio consensus: DNS-score (symptom score), DNE-score (examination score), BRS (caft) and NCS (EDS). Because SW-MF testing was used in patient selection, these data, representing QST as the fifth category of the San Antonio consensus 3, were also available. These 5 tests together formed the Neuropathy Sum score. For each abnormal test result 1 point was given, the maximum score is 5 points. Statistics The statistical package SPSS-PC 10.0 was used to compute the descriptive statistics, ANOVA, Chi-Square tests, independent samples t-test, Spearman's correlation coefficient and Odds Ratio's. Unless otherwise indicated, mean and SD are given. A p-value <.05 was considered statistically significant. 6.3 Results Table 1 shows the patient characteristics. There were no significant differences between the groups for mean age (p= 0.15) and sex (p= 0.77) and for the DU and DC groups for the duration (p= 0.23) and type of diabetes (p=0.33). The mean HbA1c of the DC group was significantly lower (p<0.01) than of the DU group The diabetic foot syndrome

78 Results of DNS- and DNE-score for the 3 groups For the DNS-score, the scores (SD) of the DU, DC and C group are 2.29 (1.23),.44 (.84) and.38 (.74), respectively. Differences between DU and both DC and C, respectively, were significant, p<0.001 in both cases, but not between DC and C. For the DNE-score, the scores (SD) of the DU, DC and C groups are 8.90 (1.98), 1.46 (2.02), and.43 (.81), respectively. Significant differences were found in all comparisons of the 3 groups, between DU and both DC and C groups, respectively, p<0.001 in both cases, and differences between DC and C p<0.05. Table 2: Results of the tests for PNP for the 3 groups DU (n=24) DC (n=24) DNS (% 1 points = abnormal) 4 96% 26% 24% DNE (% > 3 points = abnormal) 5 100% 13% 0% NCS (% 1 points = abnormal) 85% 32% 15% F/S ratio (% > 1.9 = abnormal) 91% 33% 10% BRS (% < 3 ms/mmhg) 19,20 52% 0% 11% HRVtp (%< median) 95% 57% 50% Neuropathy Sum score (% 1 point) 100% 47% 40% C (n= 21) DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy; C: controls. DNS Diabetic Neuropathy Symptom score 4 DNE Diabetic Neuropathy Examination score 5 NCS Nerve Conduction Sum score (ref value own laboratory) F/S ratio Fastest/Slowest Ratio of Muscle Fiber Conduction Velocity (ref value own laboratory) BRS Baro Reflex Sensitivity 19,20 HRVtp total power of Heart Rate Variability (abnormal defined as < median control group) Chapter 6: Clinical diagnosis of PNP - 69

79 Results of the PNP tests Table 2 shows the % of patients of the 3 groups who scored abnormal on the individual diagnostic tests and on the Neuropathy Sum score. The DNS- and DNE-score correctly identified the DU group in 96 and 100%, respectively, and the healthy controls in 76 and 100%, respectively. Almost a half (47%) of the patients of the DC group and 40% of the C group scored at least 1 point on the Neuropathy Sum score, which means that they scored abnormal on at least 1 diagnostic category of the San Antonio consensus. Table 3 shows the specified results on the Neuropathy Sum score. Table 3: The results on the Neuropathy Sum (NS) score for the 3 groups. NS score DU (22) DC (23) C (20) DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy; C: controls Relation of the DNS- and DNE-score with caft and EDS In Table 4 the relation of the DNS and DNE scores with caft (BRS and HRV) and EDS (NCS and I-MFCV) is shown. Furthermore, the Odds ratios are shown of these tests The diabetic foot syndrome

80 Table 4: Correlation (Spearmans' rho) and Odds Ratios (95% confidence interval) of DNS-score and DNE-score with EDS and caft respectively. DNS DNE NCS F/S BRS HRVtp DNS DNE NCS.67**.51** 42.7 ( ).62** 5.6 ( ) 16.8 (3.8-74) 7.2 ( ) 18.8 (5.0-71) 13.9 (3.6-53) 20.7 ( ) 14.2 (2.8-74) 4.0 ( ) ns 4.4 ( ) 5.7 ( ) 4.4 ( ) * p <.05; ** p <.001, ns: not significant DNS Diabetic Neuropathy Symptom DNE Diabetic Neuropathy Examination NCS Nerve Conduction Sum score BRS Baro Reflex Sensitivity HRVtp total power of He art Rate Variability F/S Fastest/Slowest Ratio of Muscle Fiber Conduction Velocity F/S.44**.62**.60** 3.0 ( ) ns 4.6 ( ) BRS -.30* -.29* -.22 ns -.12 ns 22.4 ( ) HRVtp -.42** -.44** -.37** -.32*.69** Chapter 6: Clinical diagnosis of PNP - 71

81 6.4 Discussion This study shows that the DNS- and DNE-score are capable to differentiate between subjects with and without neuropathy in diabetes. Previously, the construct validity of both scores already has been studied in relation to Semmes Weinstein Monofilaments and Vibration Perception Threshold testing 4,5, both Quantitative Sensory Tests known to be strong predictors of the development of diabetic foot complications. In this report, the DNS- and DNE-score are further validated with the Electro Diagnostic Studies (EDS) and cardiovascular Autonomic Function Testing (caft). There was a strong relation between the DNS- and DNE-score and EDS, both with nerve and muscle fiber conduction studies. Furthermore, the relation of the DNS- and DNE-score with caft was significant, although this was stronger for HRV than for BRS for both scores. These results further confirm the strength of the DNS- and DNE-score in diagnosing diabetic polyneuropathy. HRV and BRS are advanced measures, able to detect early abnormalities in caft The relation of HRV with the parameters for PNP (DNS- and DNE-score, NCS, F/S ratio of MFCV) was stronger than for BRS. While HRV measures the efferent part of the baroreflex arc, i.e. vagal and sympathetic nerve-mediated modulation of heart rate, BRS measures the relation between input (blood pressure sensed at the carotid arteries and aorta baroreceptors) and the output (modulations of heart rate, myocardial contractility and peripheral arterial resistance) of the baroreflex. Thus, the differences in HRV and BRS in relation to diabetic PNP may be due to the fact that BRS assesses different aspects of cardiovascular reflex function than HRV. Interestingly, it has also been proposed that PNP and caft are distinct entities with a different pathogenesis 22, thereby explaining the previously noticed variable relation between caft and PNP. The Odds ratios for the DNS- and DNE-score, respectively, with NCS, MFCV (F/S ratio), HRV and BRS are high, which means that the DNS- and DNE-score are capable to predict the results of these other diagnostic tests. Performing the DNS- and DNE-score at the outpatient clinic gives a good clue about the necessity of performing these, more laborious, expensive and less patient friendly, laboratory tests. However, in our opinion, the necessity of complementary performance of caft and EDS next to the DNS- and DNE-score as proposed in the San Antonio consensus, is debatable in clinical practice. No specific therapeutic interventions are available for neuropathy besides strict diabetes regulation, symptomatic treatment of, for example, neuropathic pain, prevention and instruction. For screening, prevention and instruction, the performance of the DNS- and DNE-score, eventually in combination with QST, may be sufficient The diabetic foot syndrome

82 As expected, performance of these various tests for diabetic PNP shows large percentages of abnormality among the group of patients with neuropathic ulcers. Although the percentage with abnormal BRS is rather low compared with the percentages of the other tests, these patients are expected to have a very poor prognosis due to their high risk of cardiovascular complications 19,20. In their treatment, hospitalisation and rehabilitation programme, this should be taken into account. Strikingly, 48% of this group with obvious neuropathy, has a BRS > 3 ms/mmhg. This supports the hypothesis that caft might develop differently from PNP, as an independent complication of diabetes. In both the diabetes group without neuropathy and the control group, abnormal tests results were found for most tests. This might be caused by lack of specificity of the tests, as shown in the control group, although it also shows that after careful and sensitive screening more abnormalities can be found, also in diabetic patients unknown with neuropathy, as expected after checking the records. The results of the DNS-score and the Neuropathy Sum score are most striking. In our previous DNS-score validation, we chose a cut-off value of 1 to define a sensitive measure for diabetic PNP. Our present values show that almost a quarter of our control group scores abnormal. The same problem will exist for other symptom scores, such as for example the NSS 14,23, because these scores do also score these four items of the DNS-score. The Neuropathy Sum score, based on the 5 diagnostic categories as advised by the San Antonio consensus 3, also shows high percentages of participants, even in the control group, with abnormal test results. Therefore, one should consider the risk of overdiagnosis by using all 5 the diagnostic categories of the San Antonio consensus. Further research should be done to characterise an optimal set of diagnostic categories for diabetic PNP. In conclusion, this report shows that the DNS- and DNE-score allow to discriminate between patients with and without diabetic PNP. Both scores are strongly related to electrodiagnostic studies and cardiovascular autonomic function testing. These results, together with the previously published results of the validation of both scores, further confirm the strength of the DNS- and DNE-score in diagnosing diabetic polyneuropathy in clinical practice. Chapter 6: Clinical diagnosis of PNP - 73

83 6.5 References 1 Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: s12-s16. 2 Mayfield JA, Reiber GE, Sanders LJ, Janisse DJ, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21 (12): American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on diabetic neuropathy (consensus statement). Diabetes Care 1988; 11: 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. Diabet Med, in press. 5 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 2000; 23 (6): Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG. Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Int Med 1998; 158: Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG. A prospective study of risk factors for diabetic foot ulcer. Diabetes Care 1999; 22 (7), Pham H, Armsytrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration. Diabetes Care 2000; 23 (5), McFadden JP, Corrall RJM, O'Brien IAD. Autonomic and sensory nerve function in diabetic foot ulceration. Clin and Exp Dermatology 1991; 16: 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 (7): Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet 1976; 1: The diabetic foot syndrome

84 13 Weston PJ, Panerai RB, McCullough A, McNally PG, James MA, Potter JF, Thurston H, Swales JD. Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index. Diabetologia 1996; 39: Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: 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: Boer de RW, Karemaker JM, Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat- to-beat model. Am.J.Physiol 1987; 253: H680-H Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RP, Gans RO, Smit AJ. Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres. Diabetologia 1999; 42: Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996; 93: Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasch C, Tavazzi L. Arterial baroreflex modulation of heart rate in chronic heart failure. Circulation 1997; 96: La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: van der Hoeven JH, van Weerden TW, Zwarts MJ. Long-lasting supernormal conduction velocity after sustained maximal isometric contraction in human muscle. Muscle and Nerve 1993; 16: Tentolouris N, Pagoni S, Tzonou A, Katsilambros N. Peripheral neuropathy does not invariably coexist with autonomic neuropathy in diabetes mellitus. Eur J Intern Med 2001; 12(1), Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O'Brien PC, Grina LA, Palumbo PJ, Swanson CJ. Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry. Annals of Neurology 1980; 6: Chapter 6: Clinical diagnosis of PNP - 75

85 76 - The diabetic foot syndrome

86 Chapter 7 Early polyneuropathy in diabetes: concurrent sensory and motor disturbances J.W.G. Meijer, F. Lange, T.P. Links, J.H. van der Hoeven Submitted.

87 Abstract Introduction Methods Results Conclusion Diabetic polyneuropathy (PNP) is supposed to be primary a disorder of sensory nerves. Hypoxic neuropathy has been hold as important pathogenetic factor. Study hypothesis: (1) PNP starts before any sign of micro- or macroangiopathy is detectable, and (2) sensory and motor dysfunction occurs concurrently and not sequentially. 12 male patients (8 type 1, 4 type 2 diabetes; mean age 35.8 yrs SD 10.6), without forms of micro- or macroangiopathy, were studied by clinical and neurophysiological testing including invasive muscle fiber conduction velocity (I-MFCV) estimation. Sensory nerve conduction velocity (SNCV) of the sural nerve was abnormal in 6 subjects. I-MFCV of the tibialis anterior muscle showed abnormal results in 6 subjects (5 had also low SNCV). Half of the subjects showed a combination of sensory and I-MFCV abnormalities, suggesting concurrent and not sequential motor and sensory involvement in early diabetic PNP, before micro- or macroangiopathy is detectable The diabetic foot syndrome

88 7.1 Introduction Distal symmetric polyneuropathy (PNP) is the most common form of diabetic neuropathy in diabetes mellitus (DM), and is supposed to be primary a disorder of sensory nerves 1. At an early stage of the disease, the disturbances are detectable by sensory nerve conduction studies, which have been taken as evidence for (sensory) PNP 2. Later on, motor dysfunction becomes evident, manifesting with clinical force loss of distally located (leg) muscles 3,4. Electromyography (EMG) may reveal chronic axonal loss, which is generally not detectable by (motor) nerve conduction studies, because axonal sprouting will compensate the loss of nerve fibers. Studies in diabetic patients with specialised EMG techniques such as macro EMG and single fiber EMG suggest a much earlier involvement of motor axons in diabetes 5-7. However, the increase of motor unit area and fiber density are both the result of axonal sprouting and reinnervation, which is only secondary to muscle fiber denervation. This suggests an earlier, subclinical start of motor neuropathy, probably together with the evolution of sensory neuropathy. In a previous study invasive muscle fiber conduction velocity (MFCV) testing was shown capable to detect muscle fiber conduction slowing due to chronic and acute neurogenic lesions. Acute axonal loss resulted in a progressive slowing of MFCV, mainly resulting from muscle fiber atrophy 8. Disturbances in the microvasculature supplying the nerve resulting in hypoxic neuropathy has been hold as important pathogenetic factor 9. This would imply a relation between angiopathy and the appearance of PNP. In this pilot study we tested the hypothesis (1) that PNP starts at a subclinical level before any sign of micro- or macroangiopathy is detectable, and (2) that sensory and motor dysfunction in DM occur concurrently and not sequentially. We investigated a group of asymptomatic diabetic patients without clinical signs of PNP, nor signs of retinopathy, nephropathy or other forms of micro- or macroangiopathy. All patients were tested by a symptom and examination score for PNP, dynamometry, and electrodiagnostic studies including MFCV testing of the tibial anterior muscle. 7.2 Patients and Methods Patients 12 male patients, (8 type 1 and 4 type 2 DM) were selected from the diabetes outpatient clinic of the University Hospital Groningen. Inclusion criteria: absence of known signs of neuropathy or retinopathy, normal clinical neurological examination, in combination with negative sores on quantitative sensory examination: Semmes Weinstein Monofilaments 10 and Vibration Perception Threshold 11 tests. The mean age was 39.9 yrs Chapter 7: Early PNP in diabetes - 79

89 (SD 12.8), with a mean duration of DM of 10.0 yrs (SD 6.1). The mean HbA1c value was 7.7 (SD 1.3). HbA1c levels were relatively constant during the 18 months preceding the study. All were normoalbuminuric, normotensive and had no other forms of micro- or macroangiopathy. Additionally, 51 age matched healthy controls were investigated to get normal values for the MFCV determination in tibialis anterior muscle. Methods After inclusion, all subjects were tested by the Diabetic Neuropathy Symptom (DNS) score, the Diabetic Neuropathy Examination (DNE) score, dynamometry and electrodiagnostic studies. DNS-score The DNS-score is a symptom score with the following items: neuropathic pain, paraesthesia, numbness and unsteadiness in walking. Items are scored as present (1 point) or absent (0 points). The maximum score is 4 points. A positive score is defined as 1point 12. DNE-score The DNE-score is a standardised physical examination score for diabetic polyneuropathy with 8 items tested on the right side, scored from 0 (no deficit) to 2 (severe deficit). The maximum score is 16 points. A positive score (suspected neuropathy) is defined as > 3 points 13. Dynamometry Hand-held dynamometry was performed according to a standardised protocol, in 10 proximal and distal arm and leg muscle groups on both sides 14. Tested muscle groups consisted of shoulder abductors, elbow flexors, elbow extensors, wrist extensors, hand grip (3 - point grip), hip flexors, hip abductors, knee extensors, knee flexors and foot extensors. All measurements were performed during isometric muscle contraction using the break technique, in which the resistance of the patient gradually is overcome. Electrodiagnostic studies The same investigator (JHvdH) performed the electrodiagnostic and force measurements. Nerve conduction studies were performed with standard surface stimulation and recording techniques using Nicolet Viking IIe and IV EMG equipment with standard filter settings. All measurements were performed after warming in hot water (38 o C) of forearm and lower legs during at least 15 minutes. Peak-peak amplitude values were used. Motor nerve conduction velocity (MNCV) was measured on the left forearm segment of the median nerve (thenar), and the left peroneal nerve (ext. dig. brevis and tibial anterior muscle). Minimal F-wave latencies were acquired 80 - The diabetic foot syndrome

90 from the same recording and distal stimulation points, from at least 8 tracings. F-wave conduction velocity (FCV) was calculated as described elsewhere 15. Sensory nerve conduction velocity (SNCV) was measured antidromically with ring electrodes placed around the thumb (median and radial nerve), middle finger (median nerve) and little finger (ulnar nerve) and stimulation at the wrist. Sural nerve was tested at both sides antidromically after stimulation lateral of the Achilles tendon, cm proximal from the active electrode. The electrodiagnostic results were defined as abnormal when lying outside the 2SD border. Reference values from our own laboratory were used. A nerve conduction sum (NCS) score, consisting of summated number of abnormal conduction velocity results (or complete absence of potentials) on the above-mentioned tests was calculated. Each abnormal test counted for 1 point, maximum score (only abnormal results) 12 points. Invasive MFCV (I-MFCV) measurements were performed in the tibialis anterior muscle at rest by means of needle electrodes adapted from the method as described previously 8. In short, muscle fibers were stimulated in the distal part of the tibial anterior muscle by a small monopolair needle electrode (cathode) using a surface electrode as anode. Filter settings 500 Hz- 10 khz, stimulation 0.2 ms, 1-2 ma, stimulation frequency 1 Hz. The uptake electrode was placed proximally at a known distance (50-60 mm) by a small concentric needle electrode (see Figure 1). Figure 1: Muscle Fiber Conduction Velocity measurement 8 Chapter 7: Early PNP in diabetes - 81