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  • 1. The Diabetic Foot Syndrome,diagnosis and consequences
  • 2. 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 16.00 uur doorJohannes Wilhelmus Gerardus Meijer geboren 21 januari 1966 te Hulst
  • 3. Promotores Prof. drs. W.H. Eisma Prof. dr. J.W. GroothoffCo-promotores Dr. T.P. Links Dr. A.J. SmitBeoordelingscommissie Prof. dr. J.H. Arendzen Prof. dr. R.O.B. Gans Prof. dr. J.A. Lutterman
  • 4. voor Miriamparanimfen H.R. Schiphorst Preuper F. de Laat
  • 5. Correspondence Rehabilitation Centre Tolbrug Tolbrugstraat 11 PO Box 90153 5200 ME s-Hertogenbosch the Netherlands tel: +31-73-6992118/2128 fax: +31-73-6992895Printed by Ponsen & Looijen BV, Wageningen, the NetherlandsCover drawings Christiaan en Roeland MeijerThe 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 BoschMeijer, Jan-Willem G.The diabetic foot syndrome, diagnosis and consequences.Thesis University of Groningen, the Netherlands – With ref. – With summary inDutch.ISBN-number 90-77113-06-1© 2002: J.W.G. Meijer, Vlijmen, the Netherlands.All rights reserved. No parts of this publication may be printed or utilized in anyform by any electronic, mechanical or other means, now known or hereafterinvented, including photocopying and recording, or in any information storage orretrieval system, without written permission of the copyright holder.
  • 6. ContentsChapter 1 Introduction and outline of the thesis 1Chapter 2 Evaluation of a screening and prevention programme for diabetic foot complications 11Chapter 3 Quality of life in patients with diabetic foot ulcers 23Chapter 4 Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score 35Chapter 5 Diabetic Neuropathy Examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes 51Chapter 6 Clinical diagnosis of diabetic polyneuropathy with the DNS and DNE score 63Chapter 7 Early polyneuropathy in diabetes: concurrent sensory and motor disturbances 77Chapter 8 Dissociation in polyneuropathy and cardiovascular autonomic neuropathy in diabetes mellitus 91Chapter 9 Discussion and conclusions 107Summary 127Samenvatting 133Northern Centre for Healthcare Research (NCH)and previous dissertations 139Dankwoord 145Curriculum Vitae 151
  • 7. Chapter 1Introduction and outline of the thesis
  • 8. 2 - The diabetic foot syndrome
  • 9. 1.1 IntroductionA very disabling long-term complication of diabetes mellitus (DM) is thediabetic foot syndrome. The diabetic foot syndrome can be defined as anarray of foot abnormalities, resulting from peripheral neuropathy, macro-angiopathy and other consequences of metabolic disturbances 1. Thesedifferent causal factors may be present alone, but mostly occur incombination in patients with DM. Neuropathy, particularly symmetric distalpolyneuropathy, is the major etiological factor, and is present in 85% of thepatients with a diabetic foot problem 2. A clinical important manifestation ofthe diabetic foot syndrome is the diabetic foot ulcer, sometimes followed byamputation.In 2000, worldwide 157 million people are suffering from DM, of whichabout 20 million in Europe 3. In 1994 the prevalence of DM in theNetherlands among men and women of 20 years and older was estimated tobe 33.4/1000, and 42.5/1000, respectively, leading to 442.300 people withDM 4. About 50% of these people are undiagnosed 4. Type 2 DM is mostfrequent, with a presence of 80-90%, type 1 DM is present in 10-20% of thepopulation 4. As a sequence of demographic changes of the Dutch society, asthere are growth of the population and changes in age and sex distribution,the prevalence of DM will increase with 35-45% during the period 1994-2015 5. This increase will be even higher due to the development of moreadequate case finding/screening techniques and the tendency of increasingincidence rates in certain population subgroups 5.An ulcer will affect 15-25% of all individuals with diabetes at least once intheir lifetime, with an annual incidence of 2 - 3% 6,7. A cross-sectional studyin 4 general practitioner practices in the Netherlands showed that theprevalence of an infected foot lesion or ulcer in patients with diabetes was3% 8. An other study showed that 5% had an ulcer or had undergone anamputation 9. Thus, diabetic foot problems are common in our society.The relative risk of diabetes related lower extremity amputation has beenreported to vary between 10 (United Kingdom) and 40 (USA) 10,11. Theincidence of amputation in the Northern part of the Netherlands has beenstudied by van Houtum et al. and Rommers et al. Van Houtum found an age-adjusted incidence rate of 8/100.000 in the non-diabetic population and345/100.000 in the diabetic population in the province of Groningen in 1991-1992, with a relative risk for patients with DM of 45 12. The percentage ofamputations due to diabetes was 62%. For the entire Dutch population, theage adjusted incidence in the non-diabetic population was 12/100.000, for thediabetic population 250/100.000, with a relative risk of 20 12. The percentageof amputations due to diabetes was 47%. Rommers et al. found an incidence Chapter 1: Introduction and outline - 3
  • 10. rate of amputations of 18-20/100.000 in the northern region of theNetherlands 13. This rate was rather constant from 1982-1994 and showed nosharp decrease in frequency despite new techniques such as used inintervention radiology and in vascular surgery. Unfortunately, thecontribution of diabetes is not known in these data.Apelqvist et al. showed that the recurrence of foot ulcers after 1, 3 and 5years of observation was 34%, 61% and 70% in diabetic patients withprevious foot ulcers, respectively. The long-term survival after amputationwas 80%, 59%, and 27% after 1, 3 and 5 years of observation. In patientswith primary healed ulcers, without the need of amputation, this was 92%,73% and 58%, respectively14. Once amputated, 30-50% of the patientsundergo 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 thecosts due to diabetic ulcers and amputation are high. In 1989, 3790 patientswere hospitalised due to diabetic foot ulcer in the Netherlands, costs ofhospital stay only already were estimated 45 million euro16. In 1992, 1810amputations were performed in diabetic patients, the medical costs wereestimated 20 million euro, costs of absenteeism and rehabilitation were nottaken into account 17. Ragnarson-Tennvall and Apelqvist studied the cost-effectiveness of the management of diabetic foot ulcers 18. Althoughmethodological aspects caused difficulties in comparing results betweencountries and settings, they state that treatment alternatives in which the limbis saved are more effective according long-term economic and quality of lifeaspects.Frequent assessment of risk factors is necessary for early detection of patientsat risk, followed by strict diabetes regulation, patient education about footcare and appropriate footwear 1. These measures can reduce or even preventamputations for diabetic foot disease 19. Bakker et al. evaluated theeffectiveness of a Dutch diabetic foot clinic 20. Co-ordinated screening,prevention and multidisciplinary treatment at this specialised clinic resultedin a decrease in number and duration of hospital admissions due to footulcers. Furthermore, a reduction was found in amputations of 43% 20.Edmonds et al. achieved healing in 86% of neuropathic ulcers and 72% ofischaemic ulcers, and a reduction of 50% of amputations, with a specialisedfoot clinic21.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 ofthe Netherlands, more specific in the province of Groningen, illustrated that4 - The diabetic foot syndrome
  • 11. there was an urgent need to evaluate the care for the diabetic foot in thatregion. In the early nineties, no specific screening and preventionprogrammes existed, and foot complications were treated by variousspecialists, without multidisciplinary attunement.At the University Hospital Groningen, the care for diabetic foot disordersbecame more organised after starting a study in 1993. In this study, theDepartments of Rehabilitation Medicine, Internal Medicine andEndocrinology were collaborating. This resulted in this thesis and in amultidisciplinary approach of the diabetic foot in the University Hospital.This present study focuses on the extent of the problem of the diabetic footsyndrome, the consequences of the diabetic foot syndrome on quality of life,the development of tests to diagnose diabetic neuropathy, and the relationbetween neuropathy and angiopathy in diabetes. Chapter 1: Introduction and outline - 5
  • 12. 6 - The diabetic foot syndrome
  • 13. 1.2 Aims of the study and outline of the thesisThis study was performed at the diabetes outpatient clinic of the Departmentof Endocrinology of the University Hospital Groningen, and at theDepartment of Diabetes and Vascular Diseases of the Rehabilitation CentreBeatrixoord, to investigate the following questions:1 How many patients from the diabetes outpatient clinic of a UniversityHospital, unknown with diabetic foot complications, are at risk to developthese complications and what is their actual state of prevention?In chapter 2 the current diabetic foot screening and prevention programme ofthe diabetes outpatient clinic of the University Hospital Groningen has beenevaluated. Therefore, 50 patients with diabetes mellitus, unknown with footcomplications, were selected at random to assess a risk-profile and thepreventional status. The aim was to get insight in the extent of the localpopulation at risk and to form a basis for further development andorganisation 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 qualityof life of patients with diabetes mellitus?In chapter 3 quality of life was measured in a group of diabetic patients withpresent or former foot ulcers and compared with diabetic patients unknownwith foot complications. Quality of life was studied on the domains physical,social and psychological functioning. Special attention was paid to mobilityand physical disabilities because of expected limitations on these items.3 Is it possible to modify the Neuropathy Symptom Score (NSS) and theNeurological Disability Score (NDS) into valid, easily managed, graded andaccurate scoring systems for diagnosing distal symmetric polyneuropathy indiabetes mellitus?Neuropathy, especially distal symmetric polyneuropathy, is a majoretiological factor in diabetic foot complications; in 85% of the diabeticpatients with ulcers neuropathy is present. Because of the lack of a goldstandard to diagnose neuropathy, the San Antonio Consensus Statement of1988 recommended to perform at least one measurement of 5 differentdiagnostic categories, including a symptom score and a physical examination Chapter 1: Introduction and outline - 7
  • 14. score. Several scores are used, the Neuropathy Symptom Score (NSS) andthe Neurological Disability Score (NDS) are the most accepted scores. Bothare scores for neuropathy in general and not specific for distal symmetricpolyneuropathy. The aim of this study was to adapt the NSS and NDS intovalid, easily managed, graded and accurate scoring systems for diagnosingdistal symmetric polyneuropathy. These studies are described in chapter 4, 5and 6, respectively.4 Is polyneuropathy present in patients with DM before any sign of micro- ormacroangiopathy is detectable? Does sensory polyneuropathy occur prior tomotor neuropathy or do they occur simultaneously?In the pathogenesis of diabetic neuropathy a vascular and a metabolichypothesis exist. In this study, presence of sensory and motor polyneuropathywas evaluated in diabetic patients without micro- or macroangiopathy.In distal symmetric polyneuropathy, sensory dysfunction seems to run aheadof motor dysfunction, because of compensating mechanisms, such ascollateral innervation and muscle fiber hypertrophy. Invasive muscle fiberconduction velocity (I-MFCV) offers sensitive information about musclefiber volume and conduction velocity, and thus of early denervation. Inchapter 7, I-MFCV was used as an indicator for early motor dysfunction indiabetic patients.5 Do cardiovascular autonomic neuropathy tests reflect diabeticpolyneuropathy or diabetic vasculopathy?The frequently used Ewing Battery is known to have a high predictive valuein the development of diabetic foot complications. The San AntonioConsensus Statement recommends cardiovascular autonomic neuropathy(CAN) tests, as one of the five different categories for diagnosing diabeticneuropathy. However, evidence exists that the association with otherdiagnostic categories for neuropathy is weak, and that CAN is more stronglyrelated to vasculopathy in diabetes mellitus. Recently, new methods havebeen developed to measure CAN, such as Heart Rate Variability (HRV) andBaroreflex Sensitivity (BRS). In chapter 8 these tests for cardiovasculardysfunction were studied, and compared with conventional tests for distalsymmetric polyneuropathy and vascular examination.8 - The diabetic foot syndrome
  • 15. 1.3 References1 Syllabus Richtlijnen diabetische retinopathie, diabetische nefropathie, diabetische voet en hart en vaatziekten bij diabetes mellitus. Richtlijnen NDF/CBO september 1998. Banda Heerenveen BV, the Netherlands.2 Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: 12-16.3 Post D, Tuinstra J, Groothoff JW. Zorgconsumptie van patiënten met diabetes mellitus. Tijdschrift voor Gezondheidswetenschappen 2000; 78 (6): 354-60.4 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. 85-1468. Washington: US Government Printing Office, 1985: XV 1-21.7 Most R, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care 1983; 6: 87-91.8 Crebolder HFJM. De huisarts en de diabetische voet. In: Consensus bijeenkomst diabetische voet. Utrecht: CBO, 1985: 2-11.9 Verhoeven S, Ballegooije E van, Casparie AT. Impact of late complications in type II diabetes in a dutch population. Diabet Med 1991; 8: 435-8.10 Gujral JS, McNally PG, OMalley BP, Burden AC. Ethnic differences in the incidence of lower extremity amputation secondary to diabetes mellitus. Diabet Med 1993; 10: 271-74.11 Connel FA, Shaw C, Will J. Lower extremity amputations among persons with diabetes mellitus. Washington, 1988. MMWR 1991; 40: 737-39.12 Houtum van WH, Lavery LA. Regional variation in the incidence of diabetes-related amputations in the Netherlands. Diabetes Res and Clin Practice 1996; 31: 125-32.13 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: 92-99.14 Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. J of Internal Medicine 1993; 233: 485-91. Chapter 1: Introduction and outline - 9
  • 16. 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: 24-31.16 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): 215-18.17 Houtum van WH, Lavery LA, Harkless LB. The cost of diabetes- related lower extremity amputations in the Netherlands. Diabet Med 1995; 12: 777-781.18 Ragnarson-Tennvall G, Apelqvist J. Cost-effective management of diabetic foot ulcers, a review. Pharmaco-economics 1997; 12 (1): 42- 53.19 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: 602-13.20 Bakker K, Dooren J. Een gespecialiseerde voetenpolikliniek voor diabetespatienten vermindert het aantal amputaties en is kostenbesparend. NTvG 1994; 138(11): 565-69.21 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): 763-71.10 - The diabetic foot syndrome
  • 17. 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: 132-38.© 2001 by ISPO; reprinted with their kind permission
  • 18. AbstractIntroduction 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.Methods 50 diabetic patients not known to have foot complications were selected at random. Risk factors and preventive measures were inventarised with the Coleman risk- categorisation system and the Preventive Measures Scale, respectively.Results 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.Discussion 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.12 - The diabetic foot syndrome
  • 19. 2.1 IntroductionFoot complications have an enormous impact on the quality of life of patientswith diabetes mellitus and the financial cost is considerable 1,2. Frequentassessment of risk factors (neuropathy, foot deformity, history of ulcerationand angiopathy) is necessary for the early detection of patients at risk fordeveloping foot disease and for preventing amputation. Better patienteducation about foot care and appropriate footwear are expected to prevent atleast half of the amputations for diabetic foot disease 3-7.At the time of this study, standardised diabetes patient education with theusual attention to diabetic foot care was being given at the universityoutpatient clinic. This individual education is repeated every two years andthe feet are examined once a year or more frequently on indication.The aim of this study was to evaluate the clinics current screening andprevention programme by assessing the risk profile and the actual state ofprevention in a sample of patients, not known to have diabetic footcomplications, at the outpatient clinic. The information was intended to forma basis for further development and organisation of diabetic foot care at thehospital and rehabilitation centre.2.2 Patients and MethodsPatientsAt the diabetes outpatient clinic of the University Hospital Groningen, 55patients who had been suffering from diabetes mellitus for at least one year,but did not have any documented foot complications, were selected atrandom. Exclusion criteria were: causes of neuropathy other than diabetesmellitus, other neurological diseases or peripheral nerve disorders, high dosebenzodiazepine or analgesic use, cognitive or psychological problems as faras they might interfere with the test results, the presence or a history of footulceration and foot amputation.Five patients refused to take part in this research project.MethodsThe same specialist (JWGM) examined all 50 patients. In the same session,risk factors and preventive measures were assessed using a risk-categorisation 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
  • 20. 1 Colemans risk categorisationNo generally accepted risk profile is available to determine a patients risk ofdeveloping foot problems. The American Diabetes Association (ADA)recommends assessment of the four major risk factors: neuropathy, footdeformity, ulceration and angiopathy 8.As risk profile, Colemans risk-categorisation system was chosen 9, whichcovers these major risk factors. Four different risk categories are used (seeTable 1). In risk category 0 the only risk factor present is foot deformity. Incategory 1 neuropathy is present. In category 2 the presence of neuropathy iscombined with foot deformity, while in category 3 angiopathy or an ulcer arepresent.Table 1: Risk profile according to Coleman 9risk category 0 1 2 3Neuropathy - + + +Foot deformity -/+ - + +Ulceration and/or vascular laboratory - - - +findings implying angiopathyNumber of patients (%) 20 10 4 16 (40%) (20%) (8%) (32%)1a NeuropathyAccording to the recommendations of the ADA, the presence of neuropathywas determined with Semmes Weinstein Monofilaments (SWMF) and theVibration Perception Threshold (VPT) 10. These are semi-quantitative,reliable instruments, complementary to each other, with proven predictivevalue for the development of clinical problems, such as foot ulcers and theneed for amputation 11-18. Both were applied 6 times to two locations on bothfeet. Insensitivity to the 10 gram SWMF was scored as absence of protectivesensibility. The VPT was determined with a hand-held biothesiometer(Biomedical Instruments Inc., Ohio, USA) and compared to the referencevalues published by Young et al.17. Neuropathy was defined as a disturbedVPT and/or insensitivity to the 10-gram SWMF at one location or more.1b Foot deformityFoot deformity was defined as comprising at least one of the followingobvious deformities: claw toes, overlying toes, prominent bony parts andhallux rigidus or valgus.14 - The diabetic foot syndrome
  • 21. 1c UlcerationPatients with ulceration or a history of ulceration were excluded from thisstudy.1d AngiopathyIn Colemans system, angiopathy is defined as vascular laboratory findingsindicating significant angiopathy. Ankle/brachial indexes at the arteriadorsalis pedis and arteria tibialis posterior and toe/brachial indexes at thehallux on both sides using laser-doppler flowmetry, were measured.Ankle/brachial indexes of below 0.90 and toe/brachial indexes of below 0.75were considered abnormal 19. Angiopathy was diagnosed if one or moreabnormal value was observed.2 The Preventive Measures ScaleAccording to recommendations of the American Diabetes Association,diabetic patients should be educated regarding their risk factors andappropriate management 10. Assessment of a persons current knowledge andcare practices should be obtained. Patients should understand the implicationsof the loss of protective sensation, the importance of foot monitoring on adaily basis, the proper care of the foot, including nail and skin care, and theselection of appropriate footwear. It is known that the type of evidence for theeffectiveness of these specific interventions varies, ranging from evidencebased (randomised controlled trials) for prescription of adequate footwear toexpert or consensus opinions of the other interventions.In literature there is no valid score available to quantify the preventive statusof these patients. Therefore, a panel of medical specialists of the UniversityHospital, all members of the Diabetic Foot working group, developed thePMS on expert and consensus opinion regarding the recommendations of theADA, several education programmes, guidelines for shoes, and theliterature9,10,20-22.The PMS has four sub-scales: (1) patient knowledge (7 items), (2) carepractice (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 basedon self-reporting, 3 is based on observation. The PMS is standardised, self-reporting questions could be answered yes or no. Observation criteria for sub-scale 3 were described in detail before starting the study. Adequate measuresreceived 0 points, inadequate measures received 1 point, thus the maximumscore was 31 points. The PMS is shown in Appendix 1. Chapter 2: Evaluation of screening and prevention - 15
  • 22. StatisticsThe statistical package SPSS-PC was used for all the analyses, includingcomputation of the descriptive statistics, Spearmans Correlation Coefficientand Oneway Multiple Range Test.2.3 ResultsCharacteristics of the 50 participants are shown in Table 2. The mean agewas 51.4 years (min 18, max 89 yrs), while the mean duration of DM was14.1 years (min 1, max 36 yrs). The group consisted of 32 men and 18women; 22 had type 1 DM and 28 had type 2 DM.Table 2: Patient characteristicsN 50mean age (years) (SD) 51.4 (16.2)min – max (years) 18 – 89mean duration diabetes (years) (SD) 14.1 (9.1)min – max (years) 1 – 36sexmale : female 32:18type of diabetestype 1 : type 2 22 : 28mean HbA1c (%) (SD) 8.6 (1.4)min – max 6.6 - 13.51 Colemans risk categorisation60% of the patients had scores that placed them in risk categories 1-3. Thesepatients 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 deformitywithout any other risk factors) (Table 1).2 Preventive measuresTable 3 presents the mean scores on the sub-scales of the PreventiveMeasures Scale for each risk category. A large percentage of the patientswere not taking any preventive measures in any of the four sub-scales. Foot-16 - The diabetic foot syndrome
  • 23. care behaviour and foot-care knowledge were inadequate. The scores forfoot-care behaviour were even worse than those for foot-care knowledge.Basal preventive demands of shoes, such as fitting, presence of seamlessinsides 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 measuresscale (Spearmans correlation coefficient 0.24). There were no significantdifferences in the scores on the preventive measures scale between the fourrisk categories.Table 3: Preventive Measures ScaleThe mean percentage of patients in each category who were not performingthe preventive measurerisk category 0 1 2 3number of patients 20 10 4 161 Patient Knowledge: 39.2 40.0 37.5 46.02 Patient Care Practice: 56.7 47.8 56.1 52.03 Condition of Feet and Shoes: 56.8 55.2 40.1 63.34 Preventive Measures by Health Workers: 68.0 50.0 50.0 61.22.4 DiscussionUsing Colemans risk-categorisation system, 60 per cent of the study groupwere found to be at serious risk of developing diabetic foot complications,despite the availability of a screening and education programme. The samplewas recruited at a university hospital outpatient clinic and did not have anydocumented foot disorders. Foot-care knowledge and foot-care behaviourwere inadequate. The scores for preventive foot-care behaviour were worsethan those for foot-care knowledge; there was no relation between the sub-scale prevention and risk category. Protective measures by shoe adaptationswere insufficient. This means that the screening and prevention programme,even though it follows generally prescribed procedures, is inadequate and thatpatients do not comply sufficiently with preventive self-care. This might be Chapter 2: Evaluation of screening and prevention - 17
  • 24. exacerbated by the fact that doctors and patients are inclined to underestimatefoot care. In both doctors and patients thresholds need to be overcome inexamining the feet. In doctors, time is scarce and foot inspection takes time.Many patients have visual problems, which complicate inspection, and somehave cosmetic objections towards wearing orthopaedic footwear.The study group was not fully representative of the entire population at theoutpatient clinic, because of the exclusion criteria used. The study group wasyounger, did not have any documented foot problems, had a shorter durationof diabetes mellitus and there were relatively more male patients. Theobjection might be raised that the study sample was small and, because it wasuniversity-hospital-based, it was not representative. However, the percentageat risk was so high that valid conclusions can be drawn about the need forpreventive care, even in this small sample. Similar risk estimates for thegeneral population will underestimate the situation, because patients with (ahistory of) foot ulcers were excluded and because everyone had receivedstandardised diabetes patient education.Several validated tests to diagnose and evaluate neuropathy are available indifferent diagnostic categories, such as symptom scoring, physicalexamination, quantitative sensory testing, electrodiagnostic studies andautonomic function testing. According to a consensus statement one test fromeach of these five diagnostic categories has to be used to diagnose andevaluate neuropathy 23. In clinical practice, certainly at an outpatient clinic,this is not feasible for screening purposes. The ADA recently recommendedthe use of psychophysical somatosensory threshold tests (especially VPT byBiothesiometry and SWMF testing) because these tests provide the bestdiscrimination in the clinical setting to identify the loss of sensation 10. Bothrecommended tests have been used in this study. However, there is still nocombination of tests available with the optimal predictive value to diabeticfoot ulcer. By using only these two methods still cases will be missed duringscreening, so the percentage at risk will even be higher than 60%.It is questionable whether the highest risk category should be defined by thepresence of angiopathy. Several studies have shown that neuropathy played alarger role in the development of ulceration and the need for amputation thanangiopathy 7,20,24-26. This means that for the entire 60% (categories 1-3:neuropathy present) the risk is high and preventive foot care is of greatimportance.Because there was no score available in literature, the Preventive MeasuresScale was developed to standardise the quantification of the preventivemeasures being taken by patients. Validation of the PMS was beyond the18 - The diabetic foot syndrome
  • 25. scope of this study. The PMS is not broad enough to evaluate educationprogrammes, because information about the social system, coping, behaviourand health locus of control are lacking. However, the PMS does provide asimple, standardised instrument to assess the preventive measures beingtaken by patients. Three sub-scales are based on self-report. Patients mightrespond socially desirable, which means that the real situation of preventionis even worse than reported.In view of the findings of this evaluation, the screening and preventionprogramme has to be revised. Because our programme closely followsgenerally accepted programmes, this need for revision will hold for manyinstitutions. In our opinion, the screening programme needs to be adapted tofollow 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 tobe followed by preventive measures and regular check-ups. For this purpose,a multidisciplinary diabetic foot team and intensive education programmeshave been started at the University Hospital and rehabilitation centre. Theeducation programme offers information and individual or group traininggiven by a multidisciplinary rehabilitation team. The major goal of thisprogramme is to increase the level of preventive self-care.Physicians, podiatrists and shoe-technicians need to be aware that they willhave to provide adequate footwear to an enormous number of patients at risk.Furthermore they should underpin their work, specifically the indications andeffects of adaptations and their preventive value.Using a simple risk-categorisation system combined with improvedprevention strategies for patients at risk of developing diabetic foot problems,we are attempting to balance the presence of risk factors and the applicationof preventive measures. It is clear that patients, health care workers andhealth insurance companies will have to invest a great deal of time andmoney 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
  • 26. 2.5 References1 Bakker K, Dooren J. Een gespecialiseerde voetenpolikliniek voor diabetespatiënten vermindert het aantal amputaties en is kostenbesparend. NTvG 1994; 11: 565-69.2 Ollendorf DA, Kotsanos JG, Wishner WJ. Potential economic benefits of lower-extremity amputation prevention strategies in diabetes. Diabetes Care 1998; 21:1240-45.3 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: 602-613.4 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: 763-71.5 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: 129-40.6 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: 111-17.7 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: 75-82.8 American Diabetes Association. Preventive foot care in people with diabetes. Diabetes Care 2000; 23: s55-56.9 Coleman WC. Footwear in a management program for injury prevention. In: Levin ME, ONeal LW, Bowker JH (eds). The Diabetic Foot, 5th edition. St. Louis: Mosby-Year Book, 1993, P 533-36.10 Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21: 2161-77.11 Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J of Neur, Neurosurg and Psych 1979; 42: 793-803.12 Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non- diabetic subjects. BMJ 1984; 288: 1793-95.13 Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Lepr Rev 1986; 57: 261-67.14 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: 1057-61.20 - The diabetic foot syndrome
  • 27. 15 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inex- pensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: 63-68.16 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: 709-11.17 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.18 Valk GD, De Sonnaville JJJ, van Houtum WH. The assessment of diabetic polyneuropathy in daily clinical practice. Muscle and Nerve 1997; 20: 116-18.19 Conier SA. Role of pressure measurements. In: Bernstein EF (ed). Vascular Diagnosis, 4th edition. St. Louis: Mosby, 1993, p 486-512.20 Boulton AJM. Peripheral neuropathy and the diabetic foot. The Foot 1992; 2: 67-72.21 Edmonds ME, Foster AVM. Diabetic Foot Clinic. In: Levin ME, ONeal LW, Bowker JH (eds). The Diabetic Foot, 5th edition. St. Louis: Mosby-Year Book, 1993, p 599-603.22 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: 854-860.23 American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on Diabetic neuropathy (Consensus Statement). Diabetes Care 1988; 11: 592-97.24 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: 335-37.25 Pecaro RE, Reiber GE, Burgess EM. Causal pathways to amputation: basis for prevention. Diabetes Care 1990; 13: 513-21.26 Boulton AJM. The pathogenesis of diabetic foot problems: an overview. Diabet Med 1996; 13: 12-16.27 CBO/NDF. Diabetische retinopathie, diabetische nefropathie, diabetische voet, hart en vaatziekten bij diabetes mellitus. Heerenveen, the Netherlands: Banda, 1998. Chapter 2: Evaluation of screening and prevention - 21
  • 28. Appendix 1: Preventive Measures Scale1: Patient Foot-care Knowledge: 7 itemsDo 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 itemsDo 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 itemsObservation criteria: scored as:condition of nails inadequate: fungal infections, inadequate trimming, ingrown nailscondition of skin inadequate: dry crackled skin, maceration, callus, tinea pedisstockings adequate: seamlessfitting of stockings inadequate: pinch off effectsinside of shoes adequate: seamlessfitting of shoes adequate: widest part at MTP-I, length longest toe to shoe 1.5-2 cm, sufficient room at toesshoe counter adequate: fixation of heel and foot, no slippingsole adequate: rigid protecting against penetration traumadistributing inlay adequate: distribution of pressure over entire plantar surfacerocker bottom adequate: right place, decreasing pressure plantar forefoot4: Preventive Measures by Health Care Workers: 5 itemsDo 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
  • 29. 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): 336-340.© 2001 by Taylor and Francis; reprinted with their kind permission
  • 30. AbstractAim To compare Quality of Life (QoL) between diabetic patients with (former or present) and without foot ulcers.Methods 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).Results 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 Spearmans r: -.66, -.56 and WSQ -.63, -.64, -.67 and -.71, respectively).Discussion 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.24 - The diabetic foot syndrome
  • 31. 3.1 IntroductionA disabling long-term complication of diabetes mellitus (DM) is the diabeticfoot ulcer (DFU), caused by the presence of neuropathy, angiopathy and/orfoot 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) inpatients with DFUs. Rijken et al. 3 studied the association of foot pain withseveral other parameters in the field of impairments, disabilities and qualityof life in 29 patients, without controls. There were no patients with ulcersincluded. Several clinical variables and four unvalidated functional variableswere assessed on fatigue, functional ability, walking distance and quality oflife. In this study foot pain was related to fatigue, disability in walking and alower level of quality of life.Carrington et al. 4 examined 13 diabetic patients with ulcers, 13 diabeticpatients with a unilateral amputation and 26 controls. They assessedpsychological adjustment to illness (PAIS), anxiety and depression (HAD)and life satisfaction (QoL ladder) and concluded that the psychological statusof mobile amputees is better than that of the diabetic foot ulcer patients, butnot as good as diabetic controls. They did not assess mobility.Brod 5 studied quality of life in diabetic patients with foot ulcers and theircaregivers, 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. Anegative impact on all domains of QoL was experienced because of thelimitations in mobility caused by the ulcer. The conclusions were groupfindings and not based on individual assessments.In conclusion, QoL in diabetic patients with foot ulcers is greatly influencedby physical (especially mobility), social and psychological impairments anddisabilities. However, it is not clear which specific domains of QoL are mostaffected by DFUs.The aim of this study was to evaluate the QoL of individual patients withpresent or former DFUs by comparing them to DM patients not known tohave DFUs. QoL was defined as "the physical, social and psychologicalfunctioning of the patients as being influenced by disease or therapy", andwas investigated using the sub-items mobility, activities of daily living andgeneral QoL 6-8. Chapter 3: Quality of life - 25
  • 32. 3.2 Patients and MethodsPatientsA cross-sectional patient-control study was performed on patients who wereadmitted to the Diabetes Department of the Rehabilitation Centre Beatrixoordbetween 1993 and 1997. Two groups were composed, a study group withpatients with DM who had been hospitalised because of DFUs and a controlgroup with patients without any foot problems, who had a diabetes durationof 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 ororthopaedic problems, cardiac or pulmonary problems), diabetes relatedproblems (severe retinopathy, nephropathy, amputation above the level of thetoes, 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 departmentfor various reasons (dysregulation, amputation, instruction and prevention,ulcers etc). To select patients and controls, the records were read by JT andchecked by JWGM. Referring to the in- and exclusion criteria mentioned, 31patients were initially selected for the study group and 53 for the controlgroup. To get informed about the actual state of the patients, their generalpractitioners were contacted to check in- and exclusion criteria just beforestarting the study. This led to the exclusion of 12 patients of the study groupand 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 totake part in the study, resulting in 14 participants of the study group and 24 ofthe control group, as shown in Table 1.Table 1: Patient selection Study group Control groupinitially selected 31 53 5 died 3 diedcheck general -12 5 comorbidity -20 15 comorbiditypractitioner 2 moved house 2 moved houseselected 19 33 -5 refused -9 refusedparticipated 14 2426 - The diabetic foot syndrome
  • 33. MethodsRisk profiles for diabetic foot complications were determined and QoL wasassessed. The same observer examined all the patients (JT).1 Risk ProfileThe risk profile test from the Dutch consensus report on the diabetic foot wasused to assess the risk of developing foot complications 1. This profileemploys the known risk factors neuropathy, angiopathy, foot deformity andulceration. Risk is graded from 0 (no risk) to 3 (highest risk). In grade 0, noneof the 4 risk factors are present. In grade 1 the only risk factor present isneuropathy; in grade 2 neuropathy is present combined with angiopathy orfoot deformity, while in grade 3 there is an existing or previous ulcer 1.Neuropathy was diagnosed with Semmes Weinstein Monofilaments. Inabilityto feel the 10-gram filament at 4 plantar locations on the foot was defined asthe presence of neuropathy 9-11. Angiopathy was defined as symptomaticarterial disease (Fontaine class 2 or higher) and/or absence of arterial footpulsations. Foot deformity was defined as the presence of halluxvalgus/rigidus, prominent bony parts or pressure areas. Ulceration waspresent when there were Wagner stage 1 to 5 abnormalities 12.2 Quality of LifeQoL was assessed with the RAND-36, the Barthel Index and the Walkingand Walking Stairs Questionnaire (WSQ).2.1 RAND-36The RAND-36 is a general questionnaire for measuring the influence ofhealth on QoL (physical, psychological and social aspects) 13. It has proven tobe valid and reliable 13. There are 8 domains: physical and social functioning,emotional and physical impairment of role, mental health, vitality, pain andexperienced health. For each domain there is a minimum score of 0 and amaximum score of 100. The higher the score, the better the quality of life.2.2 Barthel IndexThe Barthel index is a questionnaire on skills/disabilities of activities of dailyliving (ADL), which consists of 10 questions ranging from bowel and bladdercontrol items to mobility and personal care items 14,15. The maximum score is20 points (normal); less than 10 points means severely impaired ADL.2.3 Walking and Walking Stairs QuestionnaireA reliable and valid preliminary version of the Walking and Walking StairsQuestionnaire (WSQ) was used to evaluate mobility 16,17. This questionnaireconsists of 62 items, divided into 4 hierarchical scales: using stairs (16 items), Chapter 3: Quality of life - 27
  • 34. walking indoors (18 items), walking outdoors (20 items) and walkingvelocity (8 items). Each scale has a maximum of 100 points; the higher thescore, the better the mobility.StatisticsThe statistical package SPSS-PC was used to compute descriptive statistics,Spearmans 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:MeanA − MeanB SS A + SSB , where Sp = Sp (N A − 1) + (N B − 1)MeanA = mean of group A, MeanB = mean of group B, Sp = Pooled standard deviation,SSA = sum of squares of group A, SSB = sum of squares of group B, NA = total of group A,NB = total of group BInterpretation of the ES: no or trivial effect < 0.20; small effect = 0.20 – 0.49; mediumeffect = 0.50 – 0.79; large effect = > 0.79 19.3.3 ResultsPatient characteristics are shown in Table 2. The two groups were found to becomparable 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) groupswere compared to the patients who actually participated in the two groups onthe items sex distribution, age, known duration and type of diabetes. In theparticipating control group, the mean duration of diabetes was significantlylonger than that in the excluded group. In the study group with foot ulcersthere were significantly more men than in the group of excluded patients. Noother significant differences were found between the subjects selectedinitially and those who actually participated.28 - The diabetic foot syndrome
  • 35. Table 2: Patient characteristics study group control groupn 14 24Sex (male : female) 10 : 4 13 : 11Age (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 : 11 10 : 141 Risk ProfileA significant difference was found in the risk profile between the two groups(p-value < .0001). The study group had a higher risk of developing footcomplications (mean score of 3.00; SD 0.0) than the control group (meanscore 0.58; SD 1.10).2 Quality of Life2.1 RAND-36Patients in the study group scored both relevantly and significantly lower(experienced a lower QoL) than the controls on the domains physicalfunctioning, social functioning, physical role and health experience, as shownin 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). Thepatients also experienced problems with working, especially a lowerproductivity (1.1). There were no differences in complaints about pain. Chapter 3: Quality of life - 29
  • 36. Table 3: RAND-36 study group control group mean ± SD mean ± SDPhysical functioning 52.1 ± 31.7 ** 90.0 ± 15.9Social functioning 80.4 ± 27.6 * 96.4 ± 7.8Physical role 42.9 ± 34.6 ** 83.3 ± 29.2Emotional role 92.3 ± 14.6 ns 84.7 ± 31.1Mental health 75.7 ± 19.5 ns 77.2 ± 15.6Vitality 71.2 ± 16.0 ns 72.3 ± 15.9Pain 68.7 ± 28.4 ns 76.2 ± 14.3Health experience 51.1 ± 23.1 * 66.4 ± 14.9* ** ns p < .05, p < .001, not significant2.2 Barthel IndexThe study group scored 19.2 points (SD 1.5), and the control group scored19.8 points (SD 0.5) (not significant).2.3 WSQIn all four categories, the study group had significantly lower scores than thecontrol group, which means that the patients with foot ulceration experiencedmore disabilities on mobility than the controls. The study group scored 80.0points for using stairs versus 96.7 points in the controls (p<.001); for walkingindoors the scores were 54.8 and 90.3 (p<.001), respectively. For walkingoutdoors, 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 upand down (more effort (1.4), more time (1.1)) and for walking small distancesin (1.1) and outdoors (1.5).30 - The diabetic foot syndrome
  • 37. 3 Relation between Risk Profile and Quality of LifeIn Table 4 the significant correlations between risk profile and QoL areshown for the entire study population. The severity of the risk profile wassignificantly related to QoL on all the scales of the WSQ and on the physicalfunctioning and impairment of physical role domains of the RAND-36. Therewas no significant correlation between risk profile and social functioning,self-perceived health and the other domains of the RAND-36 or the BarthelIndex.Table 4: Relation between Risk Profile and Quality of Life (Spearmans 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 < .0013.4 DiscussionThis study addressed the interrelations between physical, social andpsychological dimensions of QoL in DM patients. The obvious physicallimitations of patients with DFUs, reflected by the WSQ and by the physicalfunctioning domain of the RAND-36, greatly affected QoL, and wereprobably causing limitations in social functioning.On an individual level, there were highly relevant and significant differencesfor 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 Rijken3, we didnot find a relation between having a DFU and complaints of pain. Whereasother studies found more psychological complaints in patients with foot Chapter 3: Quality of life - 31
  • 38. disease4, this was not found in our study for the item psychologicalfunctioning. Very few of our patients had an acute phase of foot disease.Perhaps they had learnt to accept their disabilities and had found a newpsychological balance.In conclusion, an existing or previous ulcer has an obvious negative influenceon the physical and social aspects of quality of life in patients with diabetesmellitus. This is in line with the findings of earlier studies 3,5.In a general population of patients with diabetes, psychological and socialaspects contributed to the overall QoL, while physical complaints had lessinfluence 20. This suggests that having a diabetic foot changes the spectrum offactors that influence QoL, with an increase in the impact of limitationsrelated 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 physicaldisabilities on quality of life, by decreasing mobility of patients, is verysignificant and relevant for workers in the field of rehabilitation.Despite the fact that the clinical situation was stable in all the patients withDFUs at the time of the study, their mobility and physical functioning werelimited. The significant correlation between risk profile and QoL suggeststhat the decrease in physical functioning and mobility in the patients with footdisease was caused by physical restrictions due to the DFU itself, or due tosigns and symptoms of risk factors, such as neuropathy or angiopathy. Thisdecrease might have been further strengthened by restrictions imposed bypreventive patient education (for example patients are advised to walk onlyshort distances). Our data emphasize the necessity to pay attention to mobilityin 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. Physicaldisabilities, due to the presence of risk factors or ulcers, are responsible forthis decrease in quality of life.In our opinion, combining diabetic foot prevention programmes with arehabilitation programme for patients with DFUs can increase quality of life.Such a programme might provide physical training for these patients (toenhance their condition and decrease disabilities), increase awareness aboutadaptations and equipment to enhance mobility (prescription of specialfootwear, walking aids or electric trikes and stair-lifts) and offer vocationaltherapy.This study was sponsored by a grant from the Vereniging Beatrixoord,Haren, the Netherlands32 - The diabetic foot syndrome
  • 39. 3.5 References1 Centraal Begeleidingsorgaan voor de Intercollegiale Toetsing, Nederlandse Diabetes Federatie. Richtlijnen NDF/CBO de Diabetische Voet. Heerenveen:Banda, 1998.2 Palumbo PJ, Melton LJ. Peripheral vascular disease and diabetes. In: Harris MI, Hamman RF eds. Diabetes in America. NIH publ. No. 85- 1468. Washington: US Government Printing Office, 1985; XV: 1-21.3 Rijken PM, Dekker J, Dekker E et al. Clinical and functional correlates of foot pain in diabetic patients. Disability and Rehabilitation 1998; 20(9): 330-36.4 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: 19-25.5 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): 365-72.6 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: 1074.7 Revicki DA. Quality of life and non-insulin-dependent diabetes mellitus. Diabetes spectrum 1990; 3: 260.8 World Health Organisation. The first ten years of the World Health Organisation. Geneva: WHO, 1959: 459.9 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: 854-60.10 Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: 261-67.11 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: 709-11.12 Wagner FW. The dysvascular foot: a system for diagnosis and treatment. Foot and Ankle 1981; 2: 64-122.13 Zee K van der, Sanderman R. Het meten van de algemene gezondheidstoestand met de RAND-36. Noordelijk Centrum voor Gezondheidsvraagstukken, Rijksuniversiteit Groningen, 1993: 1-28.14 Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965; 14: 61-65.15 Wade DT, Collin C. The Barthel ADL Index: A standard measure of physical disability? International Disability Studies 1988; 10: 64-67. Chapter 3: Quality of life - 33
  • 40. 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: 34-8.17 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: 663-69.18 J.H.Zar , Biostatistical Analyses, 1999, New Jersey.19 J.Cohen, Statistical Power Analysis for the Behavioral Scienes, New York, 1969.20 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): 1876-85.34 - The diabetic foot syndrome
  • 41. 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.© 2002 by Blackwell Ltd and Diabetes UK;reprinted with their kind permission
  • 42. AbstractAims 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.Methods 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).Results 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 DNS- score, respectively, with the clinical standards was good (Spearman r = 0.21 - 0.60). Both scores had a comparable predictive value. Reproducibility of the DNS-score was good (Cohen weighted Kappa .78-.95). The DNS-score was easier to perform and therefore preferred above the NSS.Conclusions 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.36 - The diabetic foot syndrome
  • 43. 4.1 IntroductionDistal symmetric polyneuropathy (PNP) is a very common complication ofdiabetes and is considered to be a major causal factor in the majority of footulcers in diabetic patients 1,2. To diagnose PNP, the San Antonio consensusreport advises that at least one measurement should be performed in 5different diagnostic categories 3. One of these categories is symptom scoring.In our opinion, the value of systematic assessment of symptoms is oftenmisunderstood in clinical practice, and is not based on standardised scoring ofa specific set of questions. Diagnosis is usually based on QuantitativeSensory Testing or Physical Examination. However, symptoms are importantto evaluate, because they reflect the complaints of the patient, they may be ofadditional diagnostic or prognostic value and treatment might be possible 4.As diagnostic tests, symptom scores should fulfil the criteria as described byJaeschke et al. 5. The scores have to be validated (presence of an independentreference standard, adequate spectrum and number of patients,standardisation, soundly based item selection), they should be of predictivevalue and manageable in clinical practice (reproducibility, performance inclinical practice) 5.Several scores have been developed to assess symptoms of diabeticneuropathy.The Neuropathy Symptom Score (NSS) 4, 6-8 and the Neuropathy SymptomProfile (NSP) 9 both assess diabetic neuropathy. The NSS is the most widelystudied and accepted score, and known to be valid and sensitive 4, 6-8. TheNeuropathy Symptom Profile contains 34 test categories. It is validated andcan be read and scored by computer 9. Because both scores assess neuropathyin general, they are rather extensive in clinical practice. The MichiganNeuropathy Screening Instrument (MNSI) 10 and the modified NSS scores ofVeves and Young 11,12 have been developed specifically for distal diabeticpolyneuropathy. The MNSI is a combination of a symptom score (15 items)and a physical examination score 10. The combination is valid and has a highpredictive value. However, there is no separate symptom score, as advised byconsensus reports 3. No information is available to review the modificationsof the NSS scores of Veves and Young 11,12. The Diabetes SymptomChecklist type 2 (DSC-type 2) 13 and the McGill Pain Questionnaire 14 arescores for diabetes in general and pain, respectively. The DSC-type 2 hasbeen validated both as an entire score and for neuropathy symptoms alone 13.Of the items concerning neuropathy, only numbness and tingling sensationsat both hand and feet were associated with other diagnostic standards fordiabetic neuropathy 15. The McGill Pain Questionnaire scores for painfuldiabetic leg problems 14, but no data is available about validity and predictivevalue. The Diabetic Neuropathy Symptom score (DNS-score), developed at Chapter 4: the DNS-score - 37
  • 44. our hospital, consists of 4 items chosen on clinical relevance and experience,as the most typical and clinically relevant for distal symmetric PNP indiabetes. This score has not been validated or published before.Because none of these scoring systems fulfil Jaeschkes criteria for diagnostictests 5, the aim of this study was to validate the DNS-score for diagnosingdistal symmetric PNP in diabetes, and to compare its score-characteristicswith the NSS.4.2 Patients and MethodsPatients:Our study group consisted of 73 patients with diabetes, covering the entirespectrum of secondary complications. Informed consent was obtained fromall participating patients. Exclusion criteria were factors that may interferewith the neurological condition of the subjects other than PNP.Fifty of these 73 patients were randomly selected from the diabetes outpatientclinic of the University Hospital Groningen. The other 23 patients, all knownwith obvious diabetic foot complications or clinical neuropathy, wereselected from the Department of Diabetes at the Rehabilitation Centre Beat-rixoord.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) 19 – 90 Mean duration DM (years) (SD) 14.9 (9.9) Min – max (years) 1 – 43 Sex Male – female 43 – 30 Type DM 1- 2 24 – 49 Mean HbA1c (%) (SD) 8.7 (1.4) Min – max 6.6 – 13.5 Retinopathy 40% Nephropathy 42% Peripheral vascular disease 38% Present or former ulcer 20%38 - The diabetic foot syndrome
  • 45. Methods:The same researcher (J.-W.G.M.) examined all 73 patients. First, thesymptom scores were performed followed by clinical standards; a physicalexamination score ( the Diabetic Neuropathy Examination (DNE) score) andquantitative sensory tests (Semmes Weinstein Monofilaments and vibrationperception thresholds), respectively.1 Symptom Scores1.1 NSSThe NSS consists of 17 items, 8 focusing on muscle weakness, 5 on sensorydisturbances and 4 on autonomic symptoms 4,6. Items that are answerednegative/absent are scored 0, presence scored as 1 point. Maximum score ofthe NSS is 17 points 4, 6-8.1.2 DNS-scoreAn expert panel of the University Hospital (Groningen, the Netherlands)developed a 4 item symptom score for diabetic PNP. The panel consisted of adiabetologist/endocrinologist, a specialist for internal vascular diseases, aneurologist and a physician for rehabilitation medicine; all experienced indiagnosing diabetic neuropathy. The DNS-score consists of the followingitems: (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 StandardsThe Diabetic Neuropathy Examination (DNE) score, Semmes-WeinsteinMonofilaments (SWMF) and Vibration Perception Threshold (VPT) werechosen as clinical standards to study the construct validity of the symptomscoring systems for PNP.2.1 DNE-scoreThe DNE-score is a validated, hierarchical physical examination score todiagnose distal symmetric PNP in diabetes 16. It exists of 8 items; 2 itemstesting muscle strength, 1 item testing a tendon reflex and 5 items testingsensation. The maximum score is 16 points. A score of > 3 points is definedas disturbed/abnormal.2.2 Semmes-Weinstein Monofilaments (SWMF)SWMFs were tested on the plantar surface of the hallux and central at theheel (when necessary after removal of excessive callus). This method wasperformed standardised according to generally accepted guidelines 17-20. The Chapter 4: the DNS-score - 39
  • 46. "yes-no" method was used. This means that the patient says yes each timethat 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 heaviermonofilament was taken. The 1, 10 and 75 gram monofilaments have beenused 17-20. This resulted in four categories: category 1: 1 gram monofilamentfelt; category 2: 10 gram felt, 1 gram not felt; category 3: 75 gram felt, 10gram not felt; category 4: 75 gram not felt. In categories 1 and 2 sensitivity ispresent, therefore they are scored as normal. Categories 3 and 4 are scored asabnormal.2.3 Vibration Perception Threshold (VPT)VPTs were determined using a hand-held biothesiometer (Biomedical Instru-ments Inc., Ohio, USA). VPT was tested at the dorsum of the hallux on theinterphalangeal joint and at the lateral malleolus. It was performed in astandardised way 21-23. The voltage of vibration was increased until the patientcould perceive a vibration. This was done three times. The mean of thesethree was used to determine the VPT. Age-adjusted reference values wereused 21-23. Values higher than the mean+2*SD (reference value) wereconsidered as abnormal.ReproducibilityIn order to test reproducibility of the DNS-score, inter- and intrarateragreement were assessed in a separate study on 10 patients. The 6 womenand 4 men, with a mean age of 50.0 years (SD15.9) had a wide range ofneuropathy severity. The mean duration of DM was 11.5 years (SD 10.5); 3participants had type 1 DM and 7 had type 2 DM. Two doctors, anendocrinologist and a physician for rehabilitation medicine, both experiencedin diagnosing diabetic neuropathies, rated these patients twice with aninterval of one week.Statistical AnalysesInternal consistency of the symptom scores was assessed by calculatingCronbachs alpha, and reliability coefficient Rho, which is comparable toalpha. The statistical package SPSS-PC was used to compute the descriptivestatistics, reliability coefficient Crohnbach’s alpha, Spearmans correlationcoefficient r, Students t-test and ROC curves 24. Inter- and intrarateragreement was assessed using Cohen’s weighted Kappa 25,26.40 - The diabetic foot syndrome
  • 47. 4.3 ResultsIn 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 alower association between the items. Correlation (Spearman r) between thesetwo 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) .74 .64 Number of items 17 4 Maximum score 10 4 Non used items 4 0Relationship of the NSS and DNS-score with the Clinical StandardsSpearmans correlation coefficient r for the DNE-score with the NSS andDNS-score was similar with values of .56 and .60 (both p<.001),respectively. Spearmans correlation coefficient r for the SWMF with theNSS and DNS-score was .21 (not significant) and .25 (p<.05), respectively.For VPT, Spearmans correlation coefficient r with the NSS and DNS-scorewas .46 and .56 (both p<.001), respectively.The NSS and the DNS-score predicted the results of the clinical standardsadequately, as shown in Table 3. Chapter 4: the DNS-score - 41
  • 48. Table 3 Relation Clinical Standards - Symptom Scoresgroup 0= normal on clinical standard, group 1= disturbed on clinical standardDNE-score: N mean NSS (SD) mean DNS (SD) 0 24 .92 (1.47) .42 (.93) 1 48 2.42 (2.07) 1.52 (1.24) p .002 p .000Semmes Weinstein Monofilaments Hallux: N mean NSS (SD) mean DNS (SD) 0 45 1.42 (1.42) .84 (1.04) 1 25 2.64 (2.63) 1.56 (1.41) p .014 p .019Vibration Perception Threshold Hallux: N mean NSS (SD) mean DNS (SD) 0 39 1.28 (1.47) .67 (.98) 1 32 2.63 (2.34) 1.69 (1.30) p .004 p .000Sensitivity / SpecificityFigure 1 shows the ROC-curves of, respectively, the NSS and DNS-score ascompared with the DNE-score. For NSS and DNS-score the areas under thecurve are .75 and .78, respectively. Using the SWMF at the hallux thesevalues 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% andspecificity 78% regarding the DNE-score. Regarding SWMF sensitivity was81% and specificity 56%, for VPT sensitivity was 81% and specificity 58%.42 - The diabetic foot syndrome
  • 49. Figure 1: ROC-curves of NSS and DNS-score, respectively, in relation to theDNE-score. 1,00 ,75 ,50 sensitivity ,25 Referenc e Li DNS -score 0,00 NSS 0,00 ,25 ,50 ,75 1,00 1-specificityReproducibility of the DNS-scoreThe intrarater agreement showed Cohen’s weighted Kappa’s for both ratersof .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
  • 50. 4.4 DiscussionThe NSS is a validated and widely accepted symptom score for diabeticneuropathy 4, 6-8. The most frequent form of neuropathy in diabetes and majorrisk factor for diabetic foot disease is distal symmetric PNP 1. Several itemsof the NSS are seldom scored, because the NSS has not been developedspecifically for distal PNP. Large groups of diabetic patients need to bescreened regularly to diagnose PNP early as part of prevention of diabeticfoot ulcers. Consequently, several other scoring systems and modificationshave been developed, but they do not sufficiently fulfil all the criterianecessary for adequate diagnostic tests. In this study, the DNS-score wasvalidated with the aim of achieving a manageable symptom scoring systemfor diagnosing distal symmetric diabetic PNP in clinical practice andepidemiological studies.We compared the score-characteristics of the DNS-score with the originalNSS. Furthermore, the construct validity of the NSS and DNS-score has beenstudied by comparing the scores with the clinical standards chosen: the DNE-score, SWMF and VPT. We conclude that both symptom scores adequatelyfulfil the criteria for diagnostic tests, as mentioned in the introduction. Weprefer the DNS-score for further use as symptom score, because thedifferences between the scores on validity and predictive value are small andnot 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 inclinical practice with a high reproducibility.Diagnostic tests can be discriminative (diagnosis), predictive (prognosis) orevaluative (follow up). The DNS-score is validated with clinical standards ondiscriminative and predictive values. For evaluation of treatment or followup, the score might be too short with only four items. However, in the NSSthe number of items related to PNP is also very limited.Unfortunately the exact weight of the different categories, individual or incombination, in diagnosing diabetic PNP and predicting diabetic footcomplications, is not yet known.Sensitivity and specificity of the DNS-score were high regarding the DNEscore, SWMF and VPT. Because the DNS-score will be used for screeningpurposes, sensitivity is preferred above specificity. A score of 1 or morepoints on the DNS-score is very sensitive for presence of diabetic PNP. Incombination with the results of the other diagnostic categories of the SanAntonio Consensus, this gives an indication of type and severity of PNP.44 - The diabetic foot syndrome
  • 51. Controversy exists about the use of symptom scoring in diagnosing PNP indiabetes. Because symptoms of neuropathy (pain, numbness and tingling) arepresent in 30-40% of all people with diabetes, Mayfield et al. concluded thatthe presence or absence of symptoms should not be used to assess the risk ofulcers or amputation 27. Valk et al. found that symptoms of neuropathic painand paraesthesia were neither correlated with the results of physicalexamination nor with the results of neurophysiological examination 15. Inanother study they concluded that only symptoms of numbness and tinglingsensations in hand and feet (items of the DSC-type 2), were associated withthe clinical examination, but not with neurophysiological examination 28.Franse et al. studied whether a patient history could replace the ClinicalNeurological Examination (CNE). The individual symptoms wereinsufficiently predictive for the presence of polyneuropathy. They concludedthat individual symptoms could not replace the CNE 29. Dyck et al. found anassociation between complaints of diabetic neuropathy, abnormalities of theclinical examination and abnormalities of nerve conduction 7. In our reportsignificant and clinically relevant correlations have been shown between thesymptom scores and the DNE-score, SWMF and VPT, respectively; whichare all accepted tests with known predictive value for diabetic footcomplications. Therefore, as the consensus advises, we state that symptomscoring deserves to be a part of the diagnostic set, complementary to otherdiagnostic categories for diabetic PNP 3.It is known that the reliability of symptom scores may be poorer than thereliability of the other diagnostic categories 3,4,8. This might be caused by thesubjectivity of the scores, leading to a poor reproducibility. The consensusadvises to score dichotomous to enhance reliability 3. In the DNS-score, ashort and dichotomous symptom score, the reproducibility is high.In conclusion, the DNS-score, a symptom score specific for distal symmetricPNP in diabetes, has now been validated, and is fast and easy to perform inclinical practice. As the consensus advises, this scale has to be usedcomplementary to other diagnostic categories as for example standardisedphysical examination (for example the DNE-score) and quantitative sensorytesting. Further prospective studies are necessary with the DNS-score, theDNE-score and other diagnostic tests, to assess the predictive value of thescales and items. Chapter 4: the DNS-score - 45
  • 52. 4.5 References1 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: 854-860.3 Consensus Statement: Report and recommendations of the San Anto- nio conference on diabetic neuropathy. Diabetes Care 1988; 11: 592- 97.4 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: 21-32.5 Jaeschke R, Guyatt G, Sacket DL. Users guides to the medical literature: how to use an article about a diagnostic test. JAMA 1994; 271: 389-391.6 Dyck PJ, Sherman WR, Hallcher LM Service FJ, OBrien 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: 590-96.7 Dyck PJ, Karnes JL, Daube J, OBrien P, Service JF. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: 861-80.8 Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, OBrien 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: 799-807.9 Dyck PJ, Karnes J, OBrien PC, Swanson CJ. Neuropathy Symptom Profile in health, motor neuron disease, diabetic neuropathy, and amyloidosis. Neurology 1986; 36: 1300-08.10 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: 1281-89.11 Veves A, Manes C, Murray HJ, Young MJ, Boulton AJM. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993; 16: 1187-89.12 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: 150-54.46 - The diabetic foot syndrome
  • 53. 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: 253-61.14 Masson EA, Hunt L, Gem JM, Boulton AJM. A novel approach to the diagnosis and assessment of symptomatic diabetic neuropathy. Pain 1989; 38: 25-28.15 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: 29-34.16 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: 750-53.17 Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: 261-67.18 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inex- pensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: 63-68.19 Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: 68-71.20 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: 289-92.21 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: 793-803.22 Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non- diabetic subjects. BMJ 1984; 288: 1793-95.23 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.24 Hanley JA, McNeil BJ. A method of comparing the areas under the receiver operating characteristic curves derived from the same cases. Radiology 1983; 148: 839-43.25 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33: 159-74. Chapter 4: the DNS-score - 47
  • 54. 26 Altman DG, ed. Practical statistics for medical research. London: Chapman and Hall, 1997.27 Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21: 2161-77.28 Valk GD, Nauta JJP, Strijers RLM, Bertelsman FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med 1992; 9: 716-21.29 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: 105-10.48 - The diabetic foot syndrome
  • 55. 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 distributionThe questions should be answered "yes" (positive: 1 point) if a symptom occurred moretimes a week during the last 2 weeks or "no" (negative: no point) if it did not.Max. score: 4 points0 points: PNP absent1-4 points: PNP present Chapter 4: the DNS-score - 49
  • 56. 50 - The diabetic foot syndrome
  • 57. 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): 750-753.© 2000 by the American Diabetes Association;reprinted with their kind permission
  • 58. AbstractObjective 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.Methods 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.Results 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.Conclusions The DNE is a sensitive and well-validated hierarchic scoring system that is fast and easy to perform in clinical practice.52 - The diabetic foot syndrome
  • 59. 5.1 IntroductionEarly detection of symmetric distal sensori-motor polyneuropathy (PNP) isimportant in patients with diabetes mellitus (DM), because preventive inter-ventions can be applied to decrease morbidity 1. Unfortunately, no "goldstandard" exists for diagnosing PNP, but a consensus panel has recommendedthat at least 1 measurement should be performed in 5 different diagnosticcategories. 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 numberof patients, standardisation, soundly based item selection), predictive value,manageability (reproducibility, performance in clinical practice) andhierarchy. Frequently used and accepted examination scores for diabeticneuropathy are the Neuropathy Disability Score (NDS) 4, the NeuropathyImpairment Score in the Lower Limbs (NIS-LL) 5,6, various modified NDSscores 7,8, the Neuropathy Deficit Score 9, the Michigan NeuropathyScreening 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 iswell founded and complete, it is difficult to perform in clinical practice onpatients with diabetic foot problems. Precise descriptions of how the testsshould be performed and how items should be scored are lacking. The NIS-LL is a modification of the NDS specific for distal PNP, although motoractivity 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 scoringsystems 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 informationis available on their predictive value regarding the results of clinicalstandards. The Neuropathy Deficit Score is a neurological examination scoreaimed at anatomical levels in the legs and arms 9. It has not been validatedand no information is available about how to interpret modifications, which isalso the case for the other modified NDS scoring systems 7,8. Feldman et al. 10developed a combination of two scoring systems: the Michigan NeuropathyScreening Instrument (symptom and examination score) and the MichiganDiabetic Neuropathy Score (neurological examination and nerve conductionstudies). These scores do not have a separate examination score, as advisedby 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 scoringsystems of Feldman et al. and Valk et al. have been validated and are easy toperform in clinical practice. None of the afore mentioned scores is known tobe hierarchical. Chapter 5: the DNE-score - 53
  • 60. The aim of this study was to adapt the NDS into a valid, easily managed,graded and accurate scoring system for diagnosing PNP, the DiabeticNeuropathy Examination (DNE) score.5.2 Research Design and MethodsPatients:Our study group consisted of 73 patients with DM. Exclusion criteria werefactors that may interfere with the neurological condition of the subjects otherthan PNP. Fifty patients were randomly selected from the diabetes outpatientclinic of the University Hospital Groningen. Twenty-three positive controlpatients with obvious diabetic foot complications or clinical neuropathy wereselected from the Department of Diabetes of the Rehabilitation CentreBeatrixoord. The characteristics of these 73 patients are shown in Table 1.Table 1: Patient characteristicsN 73Mean age (years)(SD) 56.9 (16.1)Min – max (years) 19 – 90Mean duration DM (years) (SD) 14.9 (9.9)Min – max (years) 1 – 43Sexmale – female 43 – 30Type DM1- 2 24 – 49Mean HbA1c (%) (SD) 8.7 (1.4)Min – max 6.6 – 13.5Methods:The same researcher (JWGM) examined all 73 patients. First, the NDS andNIS-LL were performed, followed by quantitative sensory tests that acted asa clinical standard.1 NDS and NIS-LLThe NDS is the most widely used and widely accepted scoring system fordiabetic neuropathy; it has also been recommended in consensus reports 2,3,4.The instrument examines cranial nerves, muscle weakness, reflexes and sen-sation 4. The scale consists of 35 items for testing the left and right sides of54 - The diabetic foot syndrome
  • 61. the body; scores range from 0 to 4. A sum score is obtained with a maximumof 280 points.The NIS-LL is a modified version of the NDS to quantify diabetic PNP. Thelower limb items of the NDS are used complemented with two muscle poweritems (toe extension and toe flexion). The NIS-LL has 14 items: 8 itemsevaluate 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 onboth sides. The maximum score is 88 points.The NDS, as the most complete and accepted score, was used for itemselection to develop the DNE-score.2 Clinical StandardsSemmes Weinstein Monofilaments (SWMF) and Vibration PerceptionThreshold (VPT) were chosen as clinical standards to study the constructvalidity of the scoring system for PNP. SWMF were tested on the plantarsurface of the hallux and centrally at the heel (when necessary after removalof excessive calluses). This method was standardised according to generallyaccepted guidelines 12-15.The "yes-no" method was used, which means thatthe patient says yes each time he or she senses the application of amonofilament. Six trials were administered, when the patient was unable torespond correctly in more than 1 trial, a heavier monofilament was used. The1, 10 and 75 gram monofilaments have been used. We present the results infour categories: category 1: 1 gram monofilament felt; category 2: 10 grammonofilament felt, 1 gram monofilament not felt; category 3: 75 grammonofilament felt, 10 gram monofilament not felt; category 4: 75 grammonofilament not felt.Vibration Perception Thresholds (VPTs) were determined using a hand-heldbiothesiometer (Biomedical Instruments Inc., Ohio, USA). VPT was tested atthe dorsum of the hallux on the interphalangeal joint. It was performed in astandardised way 15,16. The voltage of vibration was increased until the patientcould perceive a vibration. This was done three times. The mean of thesethree trials was used to determine the VPT.ReproducibilityTo test reproducibility, inter- and intrarater agreement were assessed in aseparate study of 10 patients. The 6 women and 4 men, with a mean age of50.0 years (SD15.9) had a wide range of neuropathy severity. The meanduration of DM was 11.5 years (SD 10.5); 3 participants had type 1 DM and7 participants had type 2 DM. Two experienced physicians, anendocrinologist (EEB) and a physician for rehabilitation medicine (JWGM),both experienced in diagnosing diabetic neuropathies, rated these patientstwice within one week. Chapter 5: the DNE-score - 55
  • 62. Statistical AnalysesInternal consistency of the DNE-score was assessed by calculatingCronbachs alpha, and reliability coefficient Rho 17, which is comparable toalpha. In addition to internal consistency, scalability coefficient H wascomputed with the probabilistic scaling programme MSP (Mokken ScalingPolychotomous items) to assess the hierarchical structure of the items 17.High values of H increase the likelihood that patients with the same scalescore have difficulties or problems with the same items.The statistical package SPSS-PC (Chicago) was used to compute thedescriptive statistics, factor analysis, reliability coefficient Crohnbach’salpha, Pearsons correlation coefficient r and Students t-test.Inter- and intrarater agreement were assessed on a scale level by computingPearsons correlation coefficients and t-test values for differences in means.5.3 ResultsItems were excluded from the original NDS if they conformed to thefollowing definition of clinical irrelevance: specific item scored positive in 3patients or less. After examining the patients, 9 of the original 35 itemsremained. No relevant differences were found between the measurementsmade on the left and right side, so only the right-side items were used in theanalyses.Factor analysis was performed on the 9 items to investigate coherence. Thecoherence of the 8 items was good; only item 22 (muscle strength tricepssurae) had poor coherence compared to the other items.Calculation of hierarchy was performed using the MSP items. This resultedin a hierarchical scale of 8 items. Item 22 disturbed the hierarchy severely.Logistic regression analysis was performed to study whether item 22, inaddition to the 8-item hierarchical scale, could predict the results of theclinical standards SWMF and VPT. Item 22 did not make any significantcontribution, so it was excluded.Modification of the NDS resulted in an 8-item scale: the Diabetic NeuropathyExamination (DNE) score. The DNE-score is shown in Appendix 1.Reliability of the scale was assessed by measuring the internal consistency.According to both Cronbachs alpha (.78) and reliability coefficient Rho (.81)the scale appears to be reliable. The H-value for hierarchy was 0.53, whichindicates the presence of a strong hierarchical scale 17.Table 2 shows the characteristics of the DNE-score, NDS and NIS-LL. Asexpected, the correlation between the DNE-score and respectively the NDS(Pearsons r .96, p<.001) and NISS-LL (Pearsons r .92, p<.001) were bothhigh. The reliability of the scoring systems was good.56 - The diabetic foot syndrome
  • 63. The DNE is fast and easy to perform in clinical practice; application takesabout 5 minutes.Table 2: Characteristics of the NDS, NIS-LL and the DNE-score in our studypopulationn= 73 NDS NIS-LL DNE-scoreMean score (SD) 19.7 (14.5) 9.7 (7.9) 5.0 (3.6)Reliability (alpha) .88 .87 .78Number of items 70 28 8Maximum score 280 88 16Maximum scored 56 32 13Items not scored 44 1 0Less than three scores 8 3 0Relationship of the NDS, NIS-LL and DNE-score with the clinical standardsPearsons correlation coefficient r of SWMF with NDS, NIS-LL and DNE-score was similar with values of .76 (p<.001), .74 (p<.001) and .75 (p<.001),respectively. Pearsons correlation coefficient r for VPT with NDS, NIS-LLand 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 theresults of the clinical standards very accurately (p < .001).At a cutoff point of 3 to 4, sensitivity and specificity of the DNE-score were0.96 and 0.51, respectively, for an abnormal result using SWMF. For anabnormal result using the VPT, these values were 0.97 and 0.59, respectively.ReproducibilityComparing the scores of 2 raters obtained on 2 occasions (interval 1 week)assessed reproducibility of the DNE-score. The interrater correlation was .97at t1 and .92 at t2, respectively. Differences in mean scores were less than10% and not significant (p=.08 and .55, respectively). The intraratercorrelation was .89 for one rater and .99 for the other. The mean scores of thetwo raters did not differ significantly at t1 and t2 (p=.17 and .60,respectively). Chapter 5: the DNE-score - 57
  • 64. 5.4 DiscussionThe NDS is a widely accepted and validated physical examination scoringsystem used to diagnose neuropathy. Its predictive value and reproducibilityare high. It is well correlated with neurophysiological and sural nervemorphometric abnormalities in patients with diabetes mellitus 4,18-21. Becausethe aim of the NDS is to evaluate neuropathy in general, it is not completelysuitable for use at an outpatient diabetic foot clinic. Consequently, severalother scoring systems have been developed, but they do not sufficiently fulfilall 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 hasnot been validated, and focuses more on motor problems than on sensoryproblems 5,6.In this study, the NDS was modified once again with the aim of achieving anew physical examination scoring system for diagnosing distal symmetricpolyneuropathy in diabetes mellitus. The new instrument is the DNE-score, ascoring system with 8 items. It was validated in DM patients with a widespectrum of complications. The DNE-score is hierarchical, sensitive, fast, andeasy to perform in clinical practice (application takes about 5 minutes).Hierarchy implies that patients with the same scale score have difficulties orproblems with the same items, which makes this scoring system able todifferentiate between severity levels of PNP and to compare groups orindividuals over time. The NDS, NIS-LL and the other instruments forevaluating 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 predic-tive value for the development of clinical problems, such as foot ulcers andamputations. They are non-invasive, patient-friendly, independent and com-plementary 12-16. SWMF and VPT only assess large fiber function, no smallfiber tests have been used in this study. Testing the DNE-score on a randomsample from the outpatient clinic in addition to a set of patients with definiteneuropathy means that the results are generalisable to the complete range ofpatients with DM.Many clinicians prefer using electro-diagnostic techniques to diagnosediabetic PNP. Although neurophysiological examination is sensitive, specificand reproducible regarding the presence and severity of peripheral nerveinvolvement in patients with diabetes 18, it is not suitable for making a quickpreliminary diagnosis at a diabetes outpatient clinic. No data are available onthe predictive value of these techniques in relation to the development ofclinical problems, such as diabetic foot disease.58 - The diabetic foot syndrome
  • 65. Because the aim of this study was to develop a screening instrument as a toolin the detection and prevention of patients at risk for diabetic footcomplications, the observed sensitivity and specificity of the DNE-score aresatisfactory. Because sensitivity is of greater importance than specificity forscreening instruments, the chosen cut off value results in the desired highsensitivity with an acceptable specificity. A low specificity might burdenprevention education programmes. The combined use of different diagnostictools, as advised in consensus reports, will enhance specificity.The selection of the item muscle strength of the quadriceps femoris in theDNE-score is surprising and suggests the presence of mononeuropathy.Nevertheless, all patients with quadriceps dysfunction also showed otherabnormalities regarding sensation in the feet, that were not related to thesame peripheral nerves, which makes mononeuropathy less probable. Theankle dorsiflexion item was excluded because of poor coherence anddisturbance of hierarchy. It did not contribute to the 8 definite items. Perhapsthis discrepancy in muscle strength and its assessment is because of otherfactors, such as limited joint mobility.The results of validation and the predictive value of the NDS, NIS-LL andDNE-score were very satisfactory. The strengths of the DNE-score are itsmanageability in clinical practice and its hierarchy. The DNE-score is themost efficient according to the criteria shown in Table 2.In conclusion, the DNE-score as modified from the NDS is fast and easy toperform, hierarchical, and sensitive for PNP, and patient scores are moredifferentiated. Chapter 5: the DNE-score - 59
  • 66. 5.5 References1 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: 854-860.2 Consensus Statement, Report and recommendations of the San Anto- nio conference on diabetic neuropathy. Diabetes Care 1988; 11: 592- 97.3 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, OBrien 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: 590-96.5 Dyck PJ, Melton J, OBrien 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): 8-13.7 Veves A, Manes C, Murray HJ, Young MJ, Boulton AJM. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993; 16: 1187-89.8 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: 150-54.9 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: 192-97.10 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: 1281-89.11 Valk GD, Nauta JJP, Strijers RLM, Bertelsman FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med 1992; 9: 716-21.12 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inex- pensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991;13: 63-68.60 - The diabetic foot syndrome
  • 67. 13 Birke JA, Sims DS. Plantar sensory threshold in the ulcerative foot. Leprosy Review 1986; 57: 261-67.14 Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: 68-71.15 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: 289-92.16 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.17 Debets P, Brouwer E. MSP: a program for Mokken Scale Analysis for Polychotomous Items, Users Manual, version 1.50. iecProgramma, Groningen, the Netherlands.18 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: 21-32.19 Dyck PJ, Karnes JL, Daube J, OBrien P, Service JF. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: 861-80.20 Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, OBrien 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: 799-807.21 Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, OBrien 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: 817-24. Chapter 5: the DNE-score - 61
  • 68. 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 points62 - The diabetic foot syndrome
  • 69. Chapter 6 Clinical diagnosisof 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.
  • 70. AbstractObjective 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). Spearmans 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.64 - The diabetic foot syndrome
  • 71. 6.1 IntroductionOne of the major risk factors for the development of diabetic footcomplications is distal symmetric sensorimotor polyneuropathy (PNP) 1,2. Fordiagnosing PNP, no gold standard is available. The San Antonio consensuspanel has recommended that at least 1 measurement should be performed in 5different diagnostic categories 3. These are symptom scoring, physicalexamination scoring, Quantitative Sensory Testing (QST), cardiovascularAutonomic Function Testing (cAFT) and Electro-Diagnostic Studies (EDS).Because none of the existing symptom and physical examination scores fordiabetic PNP completely fulfilled methodological criteria for diagnostic tests,the Diabetic Neuropathy Symptom (DNS) score and Diabetic NeuropathyExamination (DNE) score were developed 4,5. The construct validity of thesescores was studied in relation to Semmes Weinstein monofilaments andVibration Perception Threshold testing (both forms of QST), because of theirknown predictive value to the development of diabetic foot complications 6-9.cAFT has an important prognostic value for the prediction of diabetic footcomplications 8, 10,11 and mortality due to cardiovascular problems 12,13. Theprognostic value of EDS is less clear, although EDS is supposed to be themost sensitive diagnostic tool for diabetic PNP 14. The relation between theDNS- and DNE-scores and cAFT and EDS, respectively, has not yet beenstudied.The objective of this study is to assess the discriminative power of the DNS-and DNE-scores for diagnosing diabetic PNP, and their relation with cAFTand EDS, respectively.6.2 Patients and MethodsPatientsAll participants were recruited from the Diabetes Outpatient Clinic(University Hospital Groningen) and from the Rehabilitation CentreBeatrixoord Haren, after informed consent. To study the discriminativepower of the DNS- and DNE-score, three groups of subjects were studied.Selection was performed by checking the patient records. The first groupconsisted of 24 diabetic patients known with previous or present neuropathicfoot ulcers (group DU). These ulcers were purely neuropathic by origin, aswas confirmed by their localization (plantar surface of the foot at highpressure points), and by absence of peripheral arterial disease as describedbelow. In the second group, 24 diabetic patients unknown with clinicalneuropathy or foot ulcers (group DC) were included, this was confirmed bynormal 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
  • 72. control subjects with normal glucose tolerance (group C). All groups werematched for sex and age (within 5 yrs), and the diabetic groups for durationand type of diabetes (type 1/ type 2; type 1 DM was considered on clinicalgrounds when the onset of the disease was an ketoacidosis or before the ageof 40 years) as well. Subjects with a history of or clinically apparent cardiacdisease, electrocardiographic abnormalities or using betablockers or calciumantagonists were excluded. Peripheral arterial disease was excluded bynormal ankle-arm indices (>0.90), toe-arm indices (>0.70) and normalplethysmography (crest time 0.22 sec) in all groups. Normal glucosetolerance of the control subjects was demonstrated by a fasting capillaryblood glucose < 6.1 mmol/l and a blood glucose < 7.8 mmol/l 2h after a 75 groral 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 ± 11.4 52.2 ± 12.0 58.2 ± 9.9sex (M/F) 14/10 13/11 10/11mean duration of diabetes (years) 16.9 ± 12.0 13.1 ± 9.8type of diabetes (type 1/type 2) 5/19 8/16mean HbA1c (%) 8.3 ± 1.1 7.5 ± 0.8DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy;C: controls; Data are means ± SD, or n.MethodsThe DNS- and DNE-score (EB), cAFT (JL) and EDS (JH) were performedby different researchers, blinded for the group to which the participant wasallocated. The researchers were acting independently and no informationabout the results was exchanged during the study. An overall neuropathy sumscore, according to the San Antonio consensus, was composed.Diabetic Neuropathy Symptom (DNS) scoreBoth the DNS-score and DNE-score have been described in detail elsewhere4,5 . In short, the DNS score is a 4 item validated symptom score, with highpredictive value to screen for PNP in DM 4. Symptoms of unsteadiness inwalking, neuropathic pain, paraesthesia and numbness are elicited. The66 - The diabetic foot syndrome
  • 73. presence of a symptom is scored as 1 point; the maximum score is 4 points. Ascore of one or higher is defined as positive for PNP.Diabetic Neuropathy Examination (DNE) scoreThe DNE-score is a sensitive and validated hierarchical scoring system 5. Thescore contains 2 items concerning muscle strength, 1 concerning reflexes and5 concerning sensation, with a total of 8 items. Each item is scored from 0 to2 (0 is normal and 2 severely disturbed). The maximum score is 16 points. Ascore 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 ratevariability (HRV) and baroreflex sensitivity (BRS). All participants werestudied in the morning. All measurements took place in a quiet room with thetemperature kept constant at 22oC. Blood pressure was monitored by aFinapres (Ohmeda 2300, Inglewood, Col., USA) and heart rate by an ECGmonitor (Hewlett-Packard 78351T, Palo Alto, Ca., USA). After 30 min ofsupine rest, the Finapres and ECG signal were sampled at 100 Hz and storedon a personal computer during 15 min. Offline, 300 seconds of eachrecording was analyzed by the CARSPAN program (IEC ProGamma,Groningen, the Netherlands), as described previously 15,16. After artifactcorrection and stationarity check, discrete Fourier transformation of systolicblood pressure and RR interval length was performed. HRV analysis wasperformed in accordance with the guidelines of the Task Force of theEuropean Society of Cardiology and the North American Society of Pacingand Electrophysiology 17. The total power frequency band (TP) of HRV wasdefined as 0.02-0.40 Hz. Because no reference values of HRV are available,the median of the control group was used, 9.2 ln(ms2). BRS was determinedby the transfer function method and defined as the mean modulus betweensystolic blood pressure and heart rate variability in the 0.07-0.14 Hzfrequency band with at least 0.5 coherence, expressed in ms/mmHg 15,16,18. ABRS lower than 3 ms/mmHg leads to high mortality rates in chronic heartfailure and after myocardial infarction, in diabetes the prognostic value of theBRS is not yet known 19,20. In this study, a BRS < 3 ms/mmHg wasconsidered as indicative for cardiovascular autonomic neuropathy.Electro-Diagnostic Studies (EDS)Nerve conduction studies were performed with standard surface stimulationand recording techniques using an electromyograph type Nicolet Viking IIeand IV with standard filter settings. All measurements were performed afterwarming in hot water (38°C) of fore arm and lower leg during at least 15minutes. 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
  • 74. peroneal nerves (tibialis anterior). Sensory Nerve Conduction Velocities andamplitudes were measured antidromically with ring electrodes placed aroundthe middle finger (median nerve) and stimulation lateral of the Achillestendon (sural nerve). An overall Nerve Conduction Sum (NCS) score wasdefined as the number of these four nerves with an abnormal conductionvelocity 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 tibialisanterior muscle at rest by means of needle electrodes adapted from themethod as described previously 21. In short, muscle fibers were stimulated inthe distal part of the tibial anterior muscle directly by a small monopolarneedle electrode (cathode) using a surface electrode as anode. Filter settings500 Hz-10 kHz, stimulation 0.2 ms, 1-2 mA. The resulting muscle fiberaction potentials were detected at a known distance (50-60 mm) by a smallconcentric needle electrode. With this technique, action potentials supposedto represent individual muscle fibers were identified, and the resultingconduction velocities were calculated. As parameters the mean I-MFCV andthe fastest/slowest ratio representing the scatter of conduction velocities wereused and compared to normative values from our own laboratory.Neuropathy Sum scoreFor this study, an overall score was composed of the 5 diagnostic categoriesof the San Antonio consensus: DNS-score (symptom score), DNE-score(examination score), BRS (cAFT) and NCS (EDS). Because SW-MF testingwas used in patient selection, these data, representing QST as the fifthcategory of the San Antonio consensus 3, were also available. These 5 teststogether formed the Neuropathy Sum score. For each abnormal test result 1point was given, the maximum score is 5 points.StatisticsThe statistical package SPSS-PC 10.0 was used to compute the descriptivestatistics, ANOVA, Chi-Square tests, independent samples t-test, Spearmanscorrelation coefficient and Odds Ratios. Unless otherwise indicated, meanand SD are given. A p-value < .05 was considered statistically significant.6.3 ResultsTable 1 shows the patient characteristics. There were no significantdifferences between the groups for mean age (p= 0.15) and sex (p= 0.77) andfor 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.68 - The diabetic foot syndrome
  • 75. Results of DNS- and DNE-score for the 3 groupsFor 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 andboth DC and C, respectively, were significant, p<0.001 in both cases, but notbetween 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 werefound in all comparisons of the 3 groups, between DU and both DC and Cgroups, respectively, p<0.001 in both cases, and differences between DC andC p<0.05.Table 2: Results of the tests for PNP for the 3 groups DU DC C (n= 21) (n=24) (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%DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy;C: controls.DNS Diabetic Neuropathy Symptom score4DNE Diabetic Neuropathy Examination score5NCS 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 Sensitivity19,20HRVtp total power of Heart Rate Variability (abnormal defined as < median control group) Chapter 6: Clinical diagnosis of PNP - 69
  • 76. Results of the PNP testsTable 2 shows the % of patients of the 3 groups who scored abnormal on theindividual diagnostic tests and on the Neuropathy Sum score. The DNS- andDNE-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 1point on the Neuropathy Sum score, which means that they scored abnormalon 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 0 1 2 3 4 5DU (22) 1 12 6 3DC (23) 12 7 3 1C (20) 12 6 2DU: diabetic patients with neuropathic ulcer; DC: diabetic patients without neuropathy;C: controlsRelation of the DNS- and DNE-score with cAFT and EDSIn Table 4 the relation of the DNS and DNE scores with cAFT (BRS andHRV) and EDS (NCS and I-MFCV) is shown. Furthermore, the Odds ratiosare shown of these tests.70 - The diabetic foot syndrome
  • 77. DNS DNE NCS F/S BRS HRVtp DNS .67** .51** .44** -.30* -.42** DNE 42.7 (8.4-215) .62** .62** -.29* -.44** NCS 5.6 (1.7-18.2) 16.8 (3.8-74) .60** -.22ns -.37** F/S 7.2 (2.3-22.3) 18.8 (5.0-71) 13.9 (3.6-53) -.12ns -.32* BRS 20.7 (2.5-172) 14.2 (2.8-74) 4.0 (0.7-24.4)ns 3.0 (0.7-11.7)ns .69** HRVtp 4.4 (1.5-12.8) 5.7 (1.8-17.8) 4.4 (1.3-14.7) 4.6 (1.5-14.2) 22.4 (2.7-186) * 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 interval) of DNS-score and DNE-score with EDS and cAFT respectively.Chapter 6: Clinical diagnosis of PNP - 71 F/S Fastest/Slowest Ratio of Muscle Fiber Conduction Velocity Table 4: Correlation (Spearmans rho) and Odds Ratios (95% confidence
  • 78. 6.4 DiscussionThis study shows that the DNS- and DNE-score are capable to differentiatebetween subjects with and without neuropathy in diabetes. Previously, theconstruct validity of both scores already has been studied in relation toSemmes Weinstein Monofilaments and Vibration Perception Thresholdtesting 4,5, both Quantitative Sensory Tests known to be strong predictors ofthe development of diabetic foot complications. In this report, the DNS- andDNE-score are further validated with the Electro Diagnostic Studies (EDS)and cardiovascular Autonomic Function Testing (cAFT). There was a strongrelation between the DNS- and DNE-score and EDS, both with nerve andmuscle fiber conduction studies. Furthermore, the relation of the DNS- andDNE-score with cAFT was significant, although this was stronger for HRVthan for BRS for both scores. These results further confirm the strength of theDNS- and DNE-score in diagnosing diabetic polyneuropathy.HRV and BRS are advanced measures, able to detect early abnormalities incAFT 10-13. The relation of HRV with the parameters for PNP (DNS- andDNE-score, NCS, F/S ratio of MFCV) was stronger than for BRS. WhileHRV measures the efferent part of the baroreflex arc, i.e. vagal andsympathetic nerve-mediated modulation of heart rate, BRS measures therelation between input (blood pressure sensed at the carotid arteries and aortabaroreceptors) and the output (modulations of heart rate, myocardialcontractility and peripheral arterial resistance) of the baroreflex. Thus, thedifferences in HRV and BRS in relation to diabetic PNP may be due to thefact that BRS assesses different aspects of cardiovascular reflex function thanHRV. Interestingly, it has also been proposed that PNP and cAFT are distinctentities with a different pathogenesis 22, thereby explaining the previouslynoticed 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- andDNE-score are capable to predict the results of these other diagnostic tests.Performing the DNS- and DNE-score at the outpatient clinic gives a goodclue about the necessity of performing these, more laborious, expensive andless patient friendly, laboratory tests. However, in our opinion, the necessityof complementary performance of cAFT and EDS next to the DNS- andDNE-score as proposed in the San Antonio consensus, is debatable in clinicalpractice. No specific therapeutic interventions are available for neuropathybesides strict diabetes regulation, symptomatic treatment of, for example,neuropathic pain, prevention and instruction. For screening, prevention andinstruction, the performance of the DNS- and DNE-score, eventually incombination with QST, may be sufficient.72 - The diabetic foot syndrome
  • 79. As expected, performance of these various tests for diabetic PNP shows largepercentages of abnormality among the group of patients with neuropathiculcers. Although the percentage with abnormal BRS is rather low comparedwith the percentages of the other tests, these patients are expected to have avery poor prognosis due to their high risk of cardiovascular complications19,20 . In their treatment, hospitalisation and rehabilitation programme, thisshould be taken into account. Strikingly, 48% of this group with obviousneuropathy, has a BRS > 3 ms/mmHg. This supports the hypothesis thatcAFT might develop differently from PNP, as an independent complicationof diabetes.In both the diabetes group without neuropathy and the control group,abnormal tests results were found for most tests. This might be caused bylack of specificity of the tests, as shown in the control group, although it alsoshows that after careful and sensitive screening more abnormalities can befound, also in diabetic patients unknown with neuropathy, as expected afterchecking the records. The results of the DNS-score and the Neuropathy Sumscore are most striking. In our previous DNS-score validation, we chose acut-off value of ≥ 1 to define a sensitive measure for diabetic PNP. Ourpresent values show that almost a quarter of our control group scoresabnormal. The same problem will exist for other symptom scores, such as forexample the NSS 14,23, because these scores do also score these four items ofthe DNS-score. The Neuropathy Sum score, based on the 5 diagnosticcategories as advised by the San Antonio consensus 3, also shows highpercentages of participants, even in the control group, with abnormal testresults. Therefore, one should consider the risk of overdiagnosis by using all5 the diagnostic categories of the San Antonio consensus. Further researchshould be done to characterise an optimal set of diagnostic categories fordiabetic PNP.In conclusion, this report shows that the DNS- and DNE-score allow todiscriminate between patients with and without diabetic PNP. Both scores arestrongly related to electrodiagnostic studies and cardiovascular autonomicfunction testing. These results, together with the previously published resultsof the validation of both scores, further confirm the strength of the DNS- andDNE-score in diagnosing diabetic polyneuropathy in clinical practice. Chapter 6: Clinical diagnosis of PNP - 73
  • 80. 6.5 References1 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): 2161-77.3 American Diabetes Association, American Academy of Neurology. Report and recommendations of the San Antonio Conference on diabetic neuropathy (consensus statement). Diabetes Care 1988; 11: 592-97.4 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): 750-53.6 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.7 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: 289-92.8 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), 1036-42.9 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), 606-11.10 McFadden JP, Corrall RJM, OBrien IAD. Autonomic and sensory nerve function in diabetic foot ulceration. Clin and Exp Dermatology 1991; 16: 193-96.11 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): 1173-77.12 Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet 1976; 1: 601-03.74 - The diabetic foot syndrome
  • 81. 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: 1385-91.14 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: 21-32.15 Robbe HW, Mulder LJ, Ruddel H, Langewitz WA, Veldman JB, Mulder G. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987; 10: 538-543.16 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-H689.17 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; 42:1345-1349.18 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; 93:1043-1065.19 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: 3450-58.20 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: 478- 84.21 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: 312-20.22 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), 20-27.23 Dyck PJ, Sherman WR, Hallcher LM, Service FJ, OBrien 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: 590-96. Chapter 6: Clinical diagnosis of PNP - 75
  • 82. 76 - The diabetic foot syndrome
  • 83. Chapter 7 Early polyneuropathy in diabetes:concurrent sensory and motor disturbancesJ.W.G. Meijer, F. Lange, T.P. Links, J.H. van der Hoeven Submitted.
  • 84. AbstractIntroduction 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.Methods 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.Results 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).Conclusion 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.78 - The diabetic foot syndrome
  • 85. 7.1 IntroductionDistal symmetric polyneuropathy (PNP) is the most common form ofdiabetic neuropathy in diabetes mellitus (DM), and is supposed to be primarya disorder of sensory nerves 1. At an early stage of the disease, thedisturbances are detectable by sensory nerve conduction studies, which havebeen taken as evidence for (sensory) PNP 2. Later on, motor dysfunctionbecomes evident, manifesting with clinical force loss of distally located (leg)muscles 3,4. Electromyography (EMG) may reveal chronic axonal loss, whichis generally not detectable by (motor) nerve conduction studies, becauseaxonal sprouting will compensate the loss of nerve fibers. Studies in diabeticpatients with specialised EMG techniques such as macro EMG and singlefiber 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 resultof axonal sprouting and reinnervation, which is only secondary to musclefiber denervation. This suggests an earlier, subclinical start of motorneuropathy, probably together with the evolution of sensory neuropathy. In aprevious study invasive muscle fiber conduction velocity (MFCV) testingwas shown capable to detect muscle fiber conduction slowing due to chronicand acute neurogenic lesions. Acute axonal loss resulted in a progressiveslowing of MFCV, mainly resulting from muscle fiber atrophy 8.Disturbances in the microvasculature supplying the nerve resulting inhypoxic neuropathy has been hold as important pathogenetic factor 9. Thiswould imply a relation between angiopathy and the appearance of PNP. Inthis pilot study we tested the hypothesis (1) that PNP starts at a subclinicallevel before any sign of micro- or macroangiopathy is detectable, and (2) thatsensory and motor dysfunction in DM occur concurrently and notsequentially. We investigated a group of asymptomatic diabetic patientswithout clinical signs of PNP, nor signs of retinopathy, nephropathy or otherforms of micro- or macroangiopathy. All patients were tested by a symptomand examination score for PNP, dynamometry, and electrodiagnostic studiesincluding MFCV testing of the tibial anterior muscle.7.2 Patients and MethodsPatients12 male patients, (8 type 1 and 4 type 2 DM) were selected from thediabetes outpatient clinic of the University Hospital Groningen. Inclusioncriteria: absence of known signs of neuropathy or retinopathy, normalclinical neurological examination, in combination with negative sores onquantitative sensory examination: Semmes Weinstein Monofilaments 10and Vibration Perception Threshold 11 tests. The mean age was 39.9 yrs Chapter 7: Early PNP in diabetes - 79
  • 86. (SD 12.8), with a mean duration of DM of 10.0 yrs (SD 6.1). The meanHbA1c value was 7.7 (SD 1.3). HbA1c levels were relatively constantduring 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 getnormal values for the MFCV determination in tibialis anterior muscle.MethodsAfter inclusion, all subjects were tested by the Diabetic NeuropathySymptom (DNS) score, the Diabetic Neuropathy Examination (DNE)score, dynamometry and electrodiagnostic studies.DNS-scoreThe DNS-score is a symptom score with the following items: neuropathicpain, paraesthesia, numbness and unsteadiness in walking. Items are scoredas present (1 point) or absent (0 points). The maximum score is 4 points. Apositive score is defined as ≥ 1point 12.DNE-scoreThe DNE-score is a standardised physical examination score for diabeticpolyneuropathy with 8 items tested on the right side, scored from 0 (nodeficit) to 2 (severe deficit). The maximum score is 16 points. A positivescore (suspected neuropathy) is defined as > 3 points 13.DynamometryHand-held dynamometry was performed according to a standardisedprotocol, in 10 proximal and distal arm and leg muscle groups on both sides14 . Tested muscle groups consisted of shoulder abductors, elbow flexors,elbow extensors, wrist extensors, hand grip (3 - point grip), hip flexors, hipabductors, knee extensors, knee flexors and foot extensors. All measurementswere performed during isometric muscle contraction using the ”break”technique, in which the resistance of the patient gradually is overcome.Electrodiagnostic studiesThe same investigator (JHvdH) performed the electrodiagnostic and forcemeasurements. Nerve conduction studies were performed with standardsurface stimulation and recording techniques using Nicolet Viking IIe and IVEMG equipment with standard filter settings. All measurements wereperformed after warming in hot water (38 oC) of forearm and lower legsduring at least 15 minutes. Peak-peak amplitude values were used. Motornerve conduction velocity (MNCV) was measured on the left forearmsegment of the median nerve (thenar), and the left peroneal nerve (ext. dig.brevis and tibial anterior muscle). Minimal F-wave latencies were acquired80 - The diabetic foot syndrome
  • 87. from the same recording and distal stimulation points, from at least 8tracings. F-wave conduction velocity (FCV) was calculated as describedelsewhere 15. Sensory nerve conduction velocity (SNCV) was measuredantidromically with ring electrodes placed around the thumb (median andradial nerve), middle finger (median nerve) and little finger (ulnar nerve) andstimulation at the wrist. Sural nerve was tested at both sides antidromicallyafter stimulation lateral of the Achilles tendon, 10-12 cm proximal from theactive electrode. The electrodiagnostic results were defined as abnormalwhen lying outside the 2SD border. Reference values from our ownlaboratory were used.A nerve conduction sum (NCS) score, consisting of summated number ofabnormal conduction velocity results (or complete absence of potentials) onthe above-mentioned tests was calculated. Each abnormal test counted for 1point, maximum score (only abnormal results) 12 points.Invasive MFCV (I-MFCV) measurements were performed in the tibialisanterior muscle at rest by means of needle electrodes adapted from themethod as described previously 8. In short, muscle fibers were stimulated inthe distal part of the tibial anterior muscle by a small monopolair needleelectrode (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 uptakeelectrode was placed proximally at a known distance (50-60 mm) by a smallconcentric needle electrode (see Figure 1).Figure 1: Muscle Fiber Conduction Velocity measurement 8 Chapter 7: Early PNP in diabetes - 81
  • 88. After optimal positioning action potentials, supposed to represent individualmuscle fibers, were identified, and the resulting conduction velocities werecalculated. As parameters the mean I-MFCV and the fastest/slowest ratiorepresenting the scatter of conduction velocities were used. Concentric needleEMG was performed directly afterwards with the same uptake electrode atthe same location.StatisticsThe statistical package SPSS-PC was used to compute the descriptivestatistics. To test significance of differences between the study and referencegroups and the correlation, the student T test and Spearmans correlationcoefficient have been used. Statistical significance was accepted at a level of5%.7.3 ResultsThe individual patient results of the main parameters are shown in Table 1.DNS- and DNE-score and dynamometryTwo out of 12 patients scored positive on the DNS-score, respectively 1patient 1 point and 1 patient 2 points. There were no patients who scoredmore than 3 points on the DNE-score. The positive scores on the DNS- andDNE-score were related to sensory or autonomic function. Force values asmeasured with hand-held dynamometry, were within the normal range in allsubjects, in proximal as well as in distal muscle groups.Electrodiagnostic studies:Table 1 shows some results of the individual patients. Median MNCV wasabnormal in 2 subjects (subject 6 and 11). Amplitudes were all within thenormal range. Peroneal MNCV of the tibialis anterior muscle was abnormalin 1 patient (subject 6), amplitudes were all within the normal range. F-wavesof the median nerve were abnormal in 3 subjects (subject 6, 11 and 12), theperoneal nerve showed 1 abnormal F wave result (subject 6). Sensory testingshowed abnormal SNCV or no responses at all in at least one nerve of thehand (median, radial or ulnar nerve) in 8 patients (1, 3, 6, 7, 8, 9, 11 and 12).The mean, median and fastest I-MFCV were normal in all patients, theslowest I-MFCV was abnormal in subject 12. In 6 patients the F/S ratio wasabnormal, 5 of these patients also had abnormal sural nerve SNCV.82 - The diabetic foot syndrome
  • 89. Table 1: Patient Characteristicspat nr age type DM duration HbA1c DNS DNE SNCV MNCV NCS MFCV (yrs) DM (yrs) (%) sural EDB slowest F/S ratiorv <1 <4 CV > 40 CV > 41 <1 >1.8 < 1.91 42 1 17 8.4 0 2 39* 42 5* 2.0 2.2*2 47 1 14 7.1 1* 2 43 44 0 3.2 1.33 24 1 4 8.4 0 0 38* 40* 6* 2.0 2.1*4 43 1 8 7.9 0 0 41 43 1* 2.3 1.75 33 1 6 7.9 0 0 47 43 0 3.2 1.56 20 1 14 10.6 0 0 28* 30* 10* 1.9 2.1*7 26 1 15 6.9 0 0 42 45 2* 2.7 1.68 32 1 20 7.7 0 0 39* 34* 5* 2.3 1.9*9 56 2 12 8.4 0 1 38* 46 5* 1.9 2.0*10 44 2 3 6.0 2* 0 48 46 0 2.9 1.611 55 2 5 6.3 0 0 36* 38* 7* 2.2 1.712 57 2 2 6.5 0 1 41 44 4* 1.3* 3.0* reference values (rv):sncv sural: sensory nerve conduction velocity of the sural nerve CV: 47.4 SD 3.6mncv EDB: motor nerve conduction velocity of the extensor digitorum brevis muscle CV: 47.3 SD 3.0MFCV: muscle fiber conduction velocity of the tibialis anterior muscle slowest: 2.6 SD 0.4 F/S ratio: 1.47 SD 0.2CV: conduction velocityNCS: nerve conduction sum score Chapter 7: Early PNP in diabetes - 83
  • 90. As shown in Table 2, mean values of mean and fastest MFCV were notsignificantly different between patients and controls. There was a significantdifference for the F/S ratio and slowest MFCV.Table 2: Results of I-MFCV measurements in tibialis anterior muscle controls patients -1I-MFCV ms 3.17 (±0.40) 3.27 (±0.40)F/S ratio 1.47 (±0.20) 1.89 (±0.46) *I-MFCV (fastest) ms-1 3.78 (±0.49) 4.16 (±0.31)I-MFCV (slowest) ms-1 2.60 (±0.40) 2.32 (±0.57) ** :significant difference (p<.05)Needle EMG findings were abnormal in 1 patient (increase of MUPduration). Signs of denervation (fibrillations and positive waves) were notfound in any of the patients.Figure 2 shows the relation between the nerve conduction sum score and theSNCV of the left sural nerve (r -.97, p<.001), MNCV of the extensordigitorum brevis muscle (r -.67, p<.05) and the mean I-MFCV (r -.79, p<.01).Furthermore, the relation between SNCV of the left sural nerve and the meanI-MFCV is shown (r -.80, p<.01).Figure 2a: Relation of NCS-score with the SNCV of the left sural nerve 50 40 r -.97, p<.001 30 SENSURLI 20 -2 0 2 4 6 8 10 12 NCS84 - The diabetic foot syndrome
  • 91. Figure 2b: Relation of NCS-score with the MNCV of the extensor digitorumbrevis muscle 50 40 r -.67, p<.05 30PEREDB 20 -2 0 2 4 6 8 10 12 NCSFigure 2c: Relation of NCS-score with the mean I-MFCV 4,0 3,8 3,6 3,4 r -.79, p<.01 3,2 3,0MFCSMEAN 2,8 2,6 -2 0 2 4 6 8 10 12 NCS Chapter 7: Early PNP in diabetes - 85
  • 92. Figure 2d: Relation of the mean I-MFCV with the SNCV of the left suralnerve 50 40 r -.80, p<.01 30SENSURLI 20 2,6 2,8 3,0 3,2 3,4 3,6 3,8 4,0 MFCSMEAN86 - The diabetic foot syndrome
  • 93. 7.4 DiscussionWe investigated a group of male diabetic patients without clinical signs ofPNP, nor signs of retinopathy, nephropathy or other forms of micro- ormacroangiopathy to study the sequence of changes in early distal symmetricpolyneuropathy. The main findings were (1) half of the patients showedelectrodiagnostic sensory nerve involvement before any sign of micro- ormacroangiopathy was detectable, and (2) 5 out of 6 patients with sensoryinvolvement had concurrent abnormalities on MFCV testing. This findingsuggests combined sensory and motor involvement in early diabetic PNP.The pathophysiology of PNP in DM is until now not completely clear 16.Hypoxic neuropathy, caused by disturbances in the microvasculaturesupplying the nerve, has been hold as important pathogenetic factor 9. Thiswould imply a relation between angiopathy and the appearance of PNP.However, none of our patients showed signs of angiopathy. This suggeststhat PNP in these cases is the first detectable consequence ofmicroangiopathy, or, alternatively, that PNP in DM is (partly) caused byother factors. Animal studies suggest a multifactorial cause, involving closelyinterrelated metabolic alterations occurring sequentially. Endoneurialischaemia forms in this view only one of the elements in the pathwaysleading to PNP 17. The abnormalities in motor and sensory conduction andMFCV in our patients, without any sign of angiopathy, argues in favour ofthe second hypothesis.Although five patients scored some positive items on the DNS- and DNE-score, none of them was known with clinical signs of PNP, and force valueswere within the normal range. There was no correlation between DNS- andDNE-scores and electrodiagnostic studies. This means that the abnormalitiesfound by electrodiagnosis are mainly at subclinical level. The unimpairedforce, as measured with dynamometry, points to normal motor function inour patient group as well.Diabetic PNP is characterised by axonal loss, and secondary demyelinationand remyelination. Loss of motor neurons causes denervation and musclefiber atrophy. Collateral reinnervation and muscle fiber hypertrophycompensates denervation and preserves muscle strength despite of loss of upto 90% of the motor units 18. Conventional concentric needle EMG testingmay reveal partial denervation as an early sign of motor axon loss. However,spontaneous muscle activity (fibrillations, positive sharp waves) are seldomfound in, slight, slow progressive PNP. Qualitative motor unit actionpotential (MUAP) changes at visual inspection are difficult to interpret in Chapter 7: Early PNP in diabetes - 87
  • 94. borderline cases. Studies with specialised EMG techniques such as macroEMG 5 and single fiber EMG (sfEMG) 6,7 suggests a much earlierinvolvement of motor axons in diabetes. The increase in motor unit area bymacro EMG and the increase of fiber density as shown by sfEMG are theresult of axonal sprouting and reinnervation, manifesting the reshaping of themotor unit. Using these techniques, a close relation between the degree ofreinnervation and distal muscle strength was found in advanced neuropathy19,20 . However, such techniques are not capable in showing denervation ofsingle muscle fibers. Increased jitter values as found with sfEMG point toinstability of the neuromuscular junction. Although a highly sensitivemethod, increased jitter, as a measure of end-plate function, does notdiscriminate between dying back neuropathy and early reinnervation, andmerely reflects dynamic changes in metabolic status 7. Invasive MFCVtesting, on the contrary, is designed to detect abnormalities in muscle fiberconduction 21. This method was shown highly sensitive to detect muscle fiberconduction changes due to chronic neurogenic lesions. Axonal loss results ina progressive slowing of MFCV, which has been attributed to muscle fiberatrophy. Additionally, high conduction velocities indicate hypertrophicmuscle fibers. Slow conducting fibers and the (related) increase of fast/slow(F/S) ratio, can therefore be used as marker for the presence of muscle fibersdiameter changes 8. Our findings of an increased F/S-ratio in combinationwith the decrease of the slowest I-MFCV in the study group strongly suggeststhe presence of hypotrophic muscle fibers in the anterior tibialis muscle,however, without clear increase in fast conducting fibers. This indicatesmotor axon loss at a stage when compensatory motor unit reshaping is not yetpresent. In that respect invasive MFCV determination offers a highlysensitive method to detect early motor neuropathy.In conclusion, we showed in clinically asymptomatic DM patients that (1)half of the subjects had sensory nerve involvement before any sign of micro-or macroangiopathy was detectable, and (2) that almost all patients withsensory involvement had abnormalities on MFCV testing, despite normalconcentric needle EMG and normal force. This finding suggests concurrentsensory and motor involvement in early diabetic PNP.88 - The diabetic foot syndrome
  • 95. 7.5 References1 Feldman EL, Russel JW, Sullivan KA, Golovoy D. New insights into the pathogenesis of diabetic neuropathy. Curr Opin Neurol 1999;12(5):553-63.2 American Diabetes Association, American Academy of Neurology: Report and recommendations of the San Antonio Conference on Diabetic Neuropathy (Consensus Statement). Diabetes Care 1988; 11: 592-97.3 Brown MJ, Asbury AK. Diabetic neuropathy. Ann Neurol 1984; 15(1): 2-12.4 Thomas PK. Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 1997; 46: S 54-57.5 Stalberg E. Macroelectromyography in reinnervation. Muscle Nerve1982; 5(9s): S135-38.6 Shields RW. Single-fiber electromyography is a sensitive indicator of axonal degeneration in diabetes. Neurology 1987; 37(8): 1394-97.7 Bril V, Werb MR, Greene DA, Sima AA. Single-fiber electromyography in diabetic peripheral polyneuropathy. Muscle Nerve 1996; 19(1):2-9.8 van der Hoeven JH, Zwarts MJ, van Weerden TW. Muscle fiber conduction velocity in amyotrophic lateral sclerosis and traumatic lesions of the plexus brachialis. Electroenceph clin Neurophysiol 1993; 89: 304-310.9 Dyck PJ, OBrien P. Meaningful degrees of prevention or improvement of nerve conduction in controlled clinical trials of diabetic neuropathy. Diabetes Care 1989; 12: 649-65210 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 Intern Med 1998; 158: 289-92.11 Bloom S, Till S, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non-diabetic subjects. BMJ 1984; 288: 1793-95.12 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.13 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): 750-53. Chapter 7: Early PNP in diabetes - 89
  • 96. 14 van der Ploeg RJO, Fidler V, Oosterhuis HJGH. Hand-held dynamometry: reference values.J Neurol Neurosurg Psych 1991; 54: 244-47.15 Kohara N, Kimura J, Kaji R, Goto Y, Ischii J, Takiguchi M, Nakai M. F-wave latency serves as the most reproducible measure in nerve conduction studies of diabetic polyneuropathy: multicentre analysis in healthy subjects and patients with diabetic polyneuropathy. Diabetologia 2000; 43 (7): 915-21.16 Cameron NE, Cotter MA. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 1997; 46: s31-37.17 Sima AA, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia 1999; 42 (7): 773-88.18 McComas AJ, Sica RE, Campbell MJ, Upton AR. Functional compensation in partially denervated muscles. J Neurol Neurosurg Psychiatry 1971; 34: 453-60.19 Andersen H, Poulsen PL, Mogensen CE, Jakobsen J. Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications. Diabetes 1996; 45 (4): 440-45.20 Andersen H, Stalberg E, Gjerstad MD, Jakobsen J. Association of muscle strength and electrophysiological measures of reinnervation in diabetic neuropathy. Muscle and Nerve 1998; 21 (12): 1647-54.90 - The diabetic foot syndrome
  • 97. Chapter 8 Dissociation in polyneuropathy andcardiovascular autonomic neuropathy in diabetes mellitus J.W.G. Meijer, J.D. Lefrandt, T.P. Links, W.H. Eisma, J. Trip, A.J. Smit Submitted.
  • 98. AbstractIntroduction Cardiac autonomic neuropathy (CAN) tests, recommended as one of the diagnostic categories for diabetic polyneuropathy (PNP), may be more a reflection of cardiovascular abnormalities than of PNP in diabetes.Aim To test the agreement between several CAN tests and other neuropathy, and vascular categories over a broad range of diabetic patients.Methods In a random sample of 45 diabetic patients (18 type 1, 27 type 2; diabetes duration 11.8 years), the Ewing battery, short-term heart rate variability and baroreflex sensitivity as CAN tests were compared with PNP examination (DNE) and symptom (DNS) scores and with monofilaments (MF) and vibration perception threshold (VPT). CAN tests were also related to ankle- and toe- brachial index (A/TBI) and to laser Dopplerflow (LDF) measures (Tmax) at the foot.Results A weak relation of the Ewing test score to the MF scores and VPT (r= .33 with MF hallux, and .32 with VPT hallux) was not significant after age correction, while no association was evident with DNE- and DNS-scores. For HFnu the relation remained significant after age correction with the DNE-score (r= .41), monofilament scores and VPT (r= .37 and .32, respectively). BRS was not associated to peripheral neuropathy scores. CAN tests were not related to A/TBI. HFnu was associated to LDF- Tmax (r=.47), the DNE-score was related to Vmax (r= - .42). No other relation was found with microcirculation.Conclusion CAN tests are weakly related to MF, VPT and DNE- score, and even less to DNS-score for diabetic PNP. Some CAN tests might both reflect microvascular angiopathy and diabetic PNP.92 - The diabetic foot syndrome
  • 99. 8.1 IntroductionBecause no ‘gold standard’ exists for diagnosing diabetic polyneuropathy(PNP) in clinical practice, a consensus panel from the San AntonioConference on Diabetic Neuropathy recommended that 1 measurementshould be performed of 5 diagnostic categories 1. One of these categories isAutonomic Function Testing, to diagnose autonomic neuropathy (ANP). Theconsensus recommended the Ewing Battery for this category 1,2.Disadvantages of this battery are its limited reproducibility and sensitivity,and the requirement of active co-operation of the patient 3. Recently, newertechniques like measurement of heart rate variability (HRV), QT intervalprolongation and dispersion, and baroreflex sensitivity (BRS) have beenreported to detect ANP, or more specifically Cardiovascular AutonomicNeuropathy (CAN), in an early stage 4-6. The diagnostic use of Ewing tests,and even more so HRV and BRS measurements, assumes that thesehemodynamic tests assess primarily the presence and degree of CAN, or atleast dysfunction, as a component of diabetic neuropathy.However, considerable evidence suggests that CAN testing is influenced byother factors than neuropathy alone. CAN, as measured by one of thetechniques above, is dissociated from other manifestations of ANP likegastrointestinal motor dysfunction 7. We recently reported on the importantindependent contribution of microalbuminuria to HRV and BRSabnormalities in diabetes, as confirmed by others 8-11. Di Carli elegantlydemonstrated the close link between cardiac sympathetic innervation andimpaired vasodilator response of coronary resistance vessels, both measuredusing PET scanning, in diabetics 12. Long-term effects of converting enzymeinhibition on autonomic modulation, tested with HRV, were found indiabetes patients with autonomic neuropathy 13, 14. Vascular structure, definedas aortic stiffness measured by pulse wave velocity is strongly related to theE/I ratio during the Ewing deep breathing test in type 1 diabetes mellitus 15.We also found carotid intimal-medial thickness to be strongly related to BRSin hypertension 16. HRV and BRS have been found to be strong independentpredictors of cardiovascular mortality in conditions like congestive heartfailure and after myocardial infarction 17. Thus, evidence exists thatfunctional or structural vascular abnormalities have an important effect onseveral autonomic neuropathy tests. Although overt cardiac abnormalitieswere already longer known to affect Ewing test results, more subtlecardiovascular abnormalities, very prevalent in diabetes mellitus, might thusalso affect one of the test categories for diabetic polyneuropathy. Chapter 8: Dissociation in PNP and CAN - 93
  • 100. The aim of our study was to test the relation between several cardiacautonomic neuropathy tests, other diagnostic categories for diabeticneuropathy, and vascular functioning, over a broad range of patients withdiabetes mellitus, prone to or suffering from diabetic foot disease.8.2 Patients and MethodsPatientsOur study group consisted of 45 patients with diabetes mellitus, both type 1and 2. Exclusion criteria were factors that may interfere with theneurological condition of the subjects other than PNP, a history or clinicallyapparent cardiac disease, electrocardiographic abnormalities or the use ofbetablokkers or calcium antagonists. The patients were randomly selectedfrom the diabetes outpatient clinic of the University Hospital (Groningen, theNetherlands). The characteristics of the patients are shown in Table 1. Theparticipants all gave informed consent and the study was conductedaccording to recommendations of the Declaration of Helsinki.Table 1: Patient Characteristicsn = 45Sex:Male : Female 32 : 13Mean age (yrs)(SD) 52.3 (13.8)Min-max (yrs) 18-78Mean duration DM (yrs)(SD) 11.8 (8.8)Min – max (yrs) 1 – 36Type of DM1:2 18 : 27Mean HbA1c (%)(SD) 8.7 (1.5)Min – max 6.8 – 13.5MethodsThe following tests were performed in all patients: (1) cardiovascularautonomic neuropathy (CAN) tests, (2) a diabetic PNP symptom and physicalexamination score, (3) Quantitative Sensory Tests (QST), and (4) a vascularexamination. Tests (2) and (3) were performed by the same researcher (J.-W.G.M.), (1) and (4) in a separate session by technicians, unaware of theresults of the PNP scores and QST.94 - The diabetic foot syndrome
  • 101. (1) Cardiovascular Autonomic Neuropathy (CAN) testsTo assess CAN, the Ewing test battery, Heart Rate Variability and BaroreflexSensitivity were tested. The tests were performed in a quiet room with atemperature of 22 0C. The patients rested in the supine position. Bloodpressure was monitored by a Finapres (Ohmeda 2300, Inglewood, Col.,USA) and heart rate by an ECG monitor (Hewlett-Packard 78351T, PaloAlto, Ca., USA) during all tests. The Finapres-cuff was put on the rightmiddle finger.Ewing test batteryThe Ewing test battery consists of 5 tests: deep breathing, Valsalvamanoeuvre, isometric handgrip and standing up (influence on heart rate andblood pressure, respectively) 2. The execution and interpretation of the testmanoeuvres has been described in detail elsewhere3, 18,19. Autonomicneuropathy was classified categorically as follows: 1 = all tests within normalrange, 2 = 1 abnormal and 1 or 2 in the borderline range, 3 = 2 or more testsabnormal.Heart rate variabilityHRV analysis was performed in accordance with the guidelines of the TaskForce of the European Society of Cardiology and the North AmericanSociety of Pacing and Electrophysiology 20. The Finapres and ECG signalwere sampled at 100 Hz and stored on a personal computer during 15 min.Offline, 300 seconds of each recording was analysed by the CARSPANprogramme (IEC ProGamma, Groningen, the Netherlands), as describedpreviously 21. After artefact correction and stationarity check, discrete Fouriertransformation of systolic blood pressure and RR interval length wasperformed. Time domain and frequency domain HRV parameters can beanalysed, we only addressed frequency domain parameters in the presentstudy.Because absolute values of low and high frequency are related to totalfrequency power and heart rate, we also used normalised low and highfrequency units, LFnu and HFnu, calculated as low frequency * 100 %/ totalfrequency and high frequency * 100 %/ total frequency, respectively.Baroreflex sensitivity measurementTo assess baroreflex sensitivity (BRS) blood pressure and heart rate weremeasured beat-to-beat by Finapres. BRS was determined by the ‘transferfunction’ method 21 using the CARSPAN programme, as previouslydescribed in more detail8. Chapter 8: Dissociation in PNP and CAN - 95
  • 102. (2) PNP symptom and physical examination scoreThe Diabetic Neuropathy Symptom (DNS) score and the DiabeticNeuropathy Examination (DNE) score were performed.The DNS-scoreBoth the DNS-score and DNE-score have been described in detail elsewhere22,23 . In short, the DNS score is a 4 item validated symptom score, with highpredictive value to screen for PNP in DM 23. Symptoms of unsteadiness inwalking, neuropathic pain, paraesthesia and numbness are elicited. Thepresence of a symptom is scored as 1 point; the maximum score is 4 points. Ascore of one or higher is defined as positive for PNP.The DNE-scoreThe DNE-score is a sensitive and validated hierarchical scoring system fordiabetic PNP 23. The score contains 2 items concerning muscle strength, 1concerning reflexes and 5 concerning sensation, with a total of 8 items. Eachitem is scored from 0 to 2 (0 is normal and 2 severely disturbed). Themaximum score is 16 points. A score of more than 3 points is defined aspositive for PNP.(3) Quantitative Sensory Tests (QST)Semmes-Weinstein monofilaments (SWMFs) and Vibration PerceptionThreshold (VPT) testing were used to assess QST. SWMFs were tested onthe plantar surface of the hallux and centrally at the heel (when necessaryafter removal of excessive calluses). This method was standardised accordingto generally accepted guidelines 24, 25. The "yes/no" method was used, whichmeans that the patient says "yes" each time that he or she senses theapplication of a monofilament. Six trials were administered. The 10-gmonofilament was used. We present the results in 2 categories: category 1:10-g monofilament felt (=normal) and category 2: 10-g monofilament not felt(= abnormal).VPTs were determined using a hand-held biothesiometer (BiomedicalInstruments, Newbury, OH). VPT was tested at the dorsum of the hallux onthe interphalangeal joint. It was performed in a standardised way as describedelsewhere 26-28. The voltage of vibration was increased until the patient couldperceive a vibration. This was done 3 times. The mean of these 3 trials wasused to determine the VPT. Age-adjusted reference values were used 27, 28.96 - The diabetic foot syndrome
  • 103. (4) Vascular examination:Toe and ankle pressuresAnkle and toe pressures were measured using standard procedures asdescribed in detail previously29. The ratio of the ankle and toe pressure andthe simultaneously recorded brachial systolic blood pressure was the ankle-brachial (ABI), and toe-brachial index (TBI), respectively.Laser Doppler flow measurementsA post-occlusive reactive hyperaemia (PORH) procedure with laser Dopplerskin blood flow was performed and analysed according to previouslydescribed methods, with a Diodopp LDF meter at the pulpar side of theextremity of one of the toes30. We used in PORH after occlusion the maximalblood flow (Vmax) and the time to reach this maximum (Tmax) for analysis.We also tried to establish the half time of the period after reaching thismaximum till flow values had reached baseline skin blood flow again, butoften this was not possible because flow did not reach baseline levels againand showed considerable variability after the occlusion period. Therefore, wedid not further take this parameter into account in our analysis.Statistical analysesThe statistical package SPSS-PC 10.0.07 (Chicago) was used to compute thedescriptive statistics, factor analysis, Pearsons and Spearman’s correlationcoefficient r, and Student-t test. Mean, standard deviation, minimum andmaximum are given. For BRS a logarithmic transformation was used(lnBRS) to obtain a normal distribution for further analysis. In cases withnormal distribution of variables Pearson’s correlation was assessed, in case ofnon-normal distribution or of categorical values Spearman’s correlation wasused. The number of 45 patients is sufficient to detect an r of 0.3 with apower of 80 % and P < 0.05. No further subgroup analysis was performed. Chapter 8: Dissociation in PNP and CAN - 97
  • 104. 8.3 ResultsThe group scores for CAN, PNP and vascular tests are shown in Table 2.Table 2: Group scores for CAN, PNP and vascular tests. Means and SD RangeCAN tests: Ewing score 23 / 12 / 8 HRV lnHFnu .53 .22 .14-.88 HRV lnLFnu .47 .22 .12-.86 HRV LFHF -.66 1.02 -3.4-1.9 lnBRS 1.8 .72 .11- 3.3PNP scores: DNS 1.0 1.2 0-4 DNE 4.4 3.1 0-11QST: SW-MF Hallux 29n/16a SW-MF Heel 27/n18a VPT Hallux 22.2 15.2 2-50 VPT Malleolus med 23.4 13.9 4-50Vascular tests: ABI 117 21 10-174 TBI 82.6 20 10-131 LDF-tMax ( n = 19) 22.9 15.2 1.3-52.8The group scores are expressed as numbers in categories, or as mean, SD and range forCAN tests (Ewing score, categories 1, 2 and 3, resp.); HRV expressed as lnHFnu, lnLFnuand lnLFHF; and lnBRS), PNP scores (DNS-, DNE-score), QST (SW-MF, VPT) andvascular measurements (ABI, TBI, LDF=tMax and t1/2).Interrelationships between CAN testsThe score of the Ewing autonomic neuropathy tests was not related to theHRV measure HFnu or any other HRV measure, but was strongly related tolnBRS (Spearman’s r = -0.57, p < 0.0001). lnBRS was modestly related toHFnu, but more strongly related to other HRV measures (ln total powerPearson’s r = 0.89; with lnHF 0.83, respectively).CAN tests compared to PNP symptom and physical examination scoresThe sum scores of the Ewing autonomic neuropathy tests were not related toany of the PNP scores, without or with correction for age.98 - The diabetic foot syndrome
  • 105. Using several HRV measures, a relation was found between Hfnu and theDNE- score (r=0.41 after age correction). Other HRV measures were notrelated to any of the PNP scores. For lnBRS, without or with correction forage, no significant relations were found with any of the PNP scores.CAN tests compared to QSTThe sum scores of the Ewing autonomic neuropathy tests were not related tothe results of the tests with monofilaments at the hallux, a weak relation(Spearman’s r = 0.33, p = 0.02) was found with monofilaments at the heel,which became non-significant after correction for age. With VPT at thehallux comparable results were found (r = 0.32, p = 0.02 in bivariate analysis,loss of significance after correction for age).Of several HRV measures HFnu was modestly related to monofilament andVPT scores (after correction for age, monofilaments hallux and heel 0.37 and0.36, respectively; VPT hallux 0.32; all P < 0.05).For lnBRS, after correction for age, no significant relations were found withmonofilament or VPT scores.CAN tests compared to toe and ankle pressuresThe sum scores of the Ewing autonomic neuropathy tests and lnBRS werenot related to toe or ankle pressures. HFnu was related to the toe-arm-index,but this relation was not present any more after correction for age (withoutcorrection for age r = 0.39, p = 0.01; after age correction r = -0.23, n.s.). Norelation of HFnu was found with ankle pressures.CAN tests, PNP symptom and physical examination, and QST scorescompared to LDF measurementsBecause of technical problems with the laser Doppler equipment during asubstantial period of the study LDF measurements could be obtained in only19 persons. This group was otherwise comparable to the other participants.Within this group a significant relation was found between total power andhigh frequency power (Hfnu) in the heart rate variability measurement andthe Tmax LDF value (r = 0.44, and 0.47, respectively, both p < 0.05). Thisrelation remained present after correction for age. No relation was found withbaseline flow or maximal flow during PORH.As for the PNP scores and QST, the DNE score was related to V max (r = -0.42). No relations were found with the baseline LDF signal. Chapter 8: Dissociation in PNP and CAN - 99
  • 106. 8.4 DiscussionThis study shows that several so-called cardiac autonomic neuropathy (CAN)tests are not, or only very weakly, related to the QST (SWMF and VPT) andthe PNP physical examination score (DNE-score), and even less to the PNPsymptom score. The assumption that CAN tests may also be a reflection ofdiabetic microangiopathy was confirmed in the relations of some of the CANscores with laser Doppler flow measures. No relation existed between CANscores and toe or ankle pressures. However, toe or ankle pressures are amarker for macrovascular disease, and not of other forms of vasculopathy indiabetes, especially microangiopathy.A complex interrelationship between neuropathy and angiopathy exists indiabetes mellitus. Ample evidence supports a role for functional andstructural vascular abnormalities in the pathogenesis of diabeticpolyneuropathy: Veves demonstrated endothelial dysfunction in patients withdiabetic neuropathy and diabetic foot disease 31. Conversely, their analysisshows neuropathy as the most important contributing factor in explainingendothelial dysfunction. Jude showed increased levels of cell adhesionmolecules, partly of endothelial origin, in diabetic polyneuropathy 32.Histologically, Dyck et al showed microscopic vasculitis in patients withdiabetic lumbosacral radiculo/plexus neuropathy 33. On the other handneuropathy is considered to be an essential factor in the pathogenesis ofmicroangiopathy in diabetes. This is also supported by our results, whichshowed that LDF measures were not only related to CAN scores but also toother neuropathy symptom scores. Loss of shunt control by mainlysympathetic denervation is held responsible for increased baseline skin flowand decreased flow reserve in skin blood flow in diabetes. Unfortunately, thesmall number of LDF measurements in our group did allow only limitedassessment of the relations. Hilz et al 34 recently described the use of laserDoppler flowmetry with assessment of abnormal reaction to arousal stimulias a complement to sympathetic skin response testing for the diagnosis ofautonomic neuropathy.In our study several measures of CAN were assessed concomitantly. Severalauthors consider the Ewing tests to be moderately sensitive for CAN, andpropose that sensitivity may be improved with HRV measures or BRS. In thecomparison of different CAN tests the interrelations were modest, furtherillustrating the limitations of the Ewing tests in assessing CAN. Recently,Tank et al also found marked discrepancies between BRS and conventionalCAN test results 35.100 - The diabetic foot syndrome
  • 107. In our analysis of relations between CAN tests and other neuropathy tests, wecorrected for age, because Gerritsen et al found that this is one of thestrongest determinants of autonomic function 36.The observation that CAN reflects both neuropathy as well asmicrocirculatory abnormalities increases the value of CAN tests for riskassessment for diabetic foot disease. Toyry described that the development ofautonomic and peripheral neuropathies is divergent in type 2 diabetes andsuggests different pathophysiological mechanisms 37. Boyko et al confirmedautonomic neuropathy, tested as orthostatic blood pressure fall, as anindependent predictor of diabetic foot disease in a large population ofdiabetes patients 38. Aso et al showed that HRV parameters were moredisturbed in patients with neuropathic foot disease compared to an otherwisematched group of patients with neuropathy but without neuropathic footcomplications 39. It is at this moment difficult to draw conclusions on thevalue of CAN tests in the follow up of interventions intended to lower therisk of diabetic foot disease. Reversibility of CAN abnormalities, measuredas HRV, was shown by Burger 40, but is not known whether this is alsoassociated with a decrease in risk for diabetic foot problems. Another merit ofCAN testing is its prognostic value for all-cause and cardiovascular mortalityin diabetes36, which has also been found for other conditions like post-infarction17.Our results are for the most part in line with those of Ducher who also foundthe Ewing tests to be related to HRV and BRS41. Discrepancies like those forthe BRS may be due to differences in the methods used, for example Ducherused the sequential technique for BRS assessment instead of our resultsobtained with transfer function analysis.In conclusion, our study shows that CAN tests are very weakly related to theclinical standards for diabetic distal neuropathy (SW-MF and VPT, DNE-score), and even less to the DNS-score. Some of the CAN scores, especiallyHRV measures, were related to microcirculatory parameters. This supportsthe assumption that CAN scores are equally associated with diabeticmicrovascular angiopathy as with diabetic polyneuropathy. It should be keptin mind that a close interrelationship exists between neuropathy andmicrocirculatory abnormalities in diabetes mellitus. Chapter 8: Dissociation in PNP and CAN - 101
  • 108. 8.5 References1 Consensus Statement: Report and recommendation of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988; 11:592-597.2 Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med. 1980; 92:308-311.3 Reyners AK, Hazenberg BP, Haagsma EB, Tio RA, Reitsma WD, Smit AJ.The assessment of autonomic function in patients with systemic amyloidosis: methodological considerations. Amyloid 1998; 5:193-199.4 Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care 2000; 23:1381-1383.5 Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia 1999; 42:68-75.6 Frattola A, Parati G, Gamba P, Paleari F, Mauri G, Di Rienzo M, Castiglioni P, Mancia G. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia 1997; 40: 1470-1475.7 Annese V, Bassotti G, Caruso N, De Cosmo S, Gabbrielli A, Modoni S, Frusciante V, Andriulli A. Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus. J Clin Gastroenterol 1999; 29: 171-177.8 Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RP, Gans ROB, Smit AJ. Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres. Diabetologia 1999; 42: 1345-1349.9 Rutter MK, McComb JM, Brady S, Marshall SM. Autonomic neuropathy in asymptomatic subjects with non-insulin-dependent diabetes mellitus and microalbuminuria. Clin Auton Res 1998; 8: 251- 257.10 Wirta OR, Pasternack AI, Mustonen JT, Laippala PJ, Reinikainen PM. Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus. J Intern Med 1999; 245: 329- 335.102 - The diabetic foot syndrome
  • 109. 11 Clarke CF, Eason M, Reilly A, Boyce D, Werther GA. Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria. Diabet Med 1999; 16: 550-554.12 Di Carli MF, Bianco-Batlles D, Landa ME, Kazmers A, Groehn H, Muzik O, Grunberger G. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999; 100: 813-819.13 Athyros VG, Didangelos TP, Karamitsos DT, Papageorgiou AA, Boudoulas H, Kontopoulos AG. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 1998; 53: 201-209.14 Lluch I, Hernandez A, Real JT, Morillas C, Tenes S, Sanchez C, Ascaso JF. Cardiovascular autonomic neuropathy in type 1 diabetic patients with and without peripheral neuropathy. Diabetes Res Clin Pract 1998;42:35-40.15 Ahlgren AR, Sundkvist G, Wollmer P, Sonesson B, Lanne T. Increased aortic stiffness in women with type 1 diabetes mellitus is associated with diabetes duration and autonomic nerve function. Diabetic Med 1999; 16: 291-297.16 de Vries R, Lefrandt JD, Terpstra WF, Smit AJ, May J. Increased intima media thickness of the carotid artery negatively affects baroreflex function in mild to moderate hypertensive subjects. Presented at the ‘Tenth European Meeting on Hypertension’ of the European Society of Hypertension, Goteborg, May 2000.17 La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351: 478-84.18 Wieling W, Karemaker JF, Borst C, Dunning AJ. Testing for autonomic neuropathy: heart rate response to forced breathing. Clin Physiol 1985; 5 Suppl 5:28-33.19 Imholz BP, van Montfrans GA, Settels JJ, van der Hoeven GM, Karemaker JM, Wieling W. Continuous non-invasive blood pressure monitoring: reliability of Finapres device during the Valsalva manoeuvre. Cardiovasc res 1988; 22: 390-397.20 Task Force of the European Society of Cardiology and the Northern American Society of Pacing and Electrophysiology. Heart Rate Variability: Standards of measurement, physiological interpretation and clinical use. Circulation 1996; 93: 1043-65. Chapter 8: Dissociation in PNP and CAN - 103
  • 110. 21 Robbe HW, Mulder LJ, Ruddel H, Langewitz WA, Veldman JB, Mulder G: Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987; 10: 538-543.22 Meijer JWG, Smit AJ, van Sonderen E, Groothoff JW, Eisma WH, Links TP: Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score. Diabetic Medicine, in press.23 Meijer JWG, van Sonderen E, Blaauwwiekel EE, Smit AJ, Groothoff JW, Eisma WH, Links TP: Diabetic Neuropathy Examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 23 (6): 750-53, 2000.24 Kumar S, Fernando DJS, Veves A, Knowles EA, Young MJ, Boulton AJM. Semmes Weinstein Monofilaments: a simple, effective and inex- pensive screening device for identifying diabetic patients at risk of foot ulceration. Diab Res and Clin Pract 1991; 13: 63-68.25 Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower extremity complications: use of Semmes Weinstein monofilaments. Physical Therapy 1996; 76: 68-71.26 Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J of Neur, Neurosurg and Psych 1979; 42: 793-803.27 Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer to measure individual vibration thresholds and their variation in 519 non- diabetic subjects. BMJ 1984; 288: 1793-95.28 Young MJ, Breddy L, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibratory perception thresholds. Diabetes Care 1994; 17: 557-60.29 Andriessen MP, Barendsen GJ, Wouda AA, de Pater L. The effect of six months intensive physical training on the circulation in the legs of patients with intermittent claudication. VASA 1989; 18: 56-62.30 Van de Ven LLM, Van Leeuwen JTM, Smit AJ. The influence of chronic treatment with betablockade and angiotensin converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication. A comparative cross-over trial. VASA 1994; 23: 357-362.31 Veves A, Akbari CM, Primavera J, Donaghue VM, Zacharoulis D, Chrzan JS, DeGirolami U, LoGerfo FW, Freeman R. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 1998; 47: 457-463104 - The diabetic foot syndrome
  • 111. 32 Jude EB, Abbott CA, Young MJ, Anderson SG, Douglas JT, Boulton AJ. The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy. Diabetologia 1998; 41(3): 330-336.33 Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999; 53: 2113- 2121.34 Hilz MJ, Hecht MJ, Berghoff M, Singer W, Neundoerfer B. Abnormal vasoreaction to arousal stimuli--an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry. J Clin Neurophysiol 2000; 17: 419.35 Tank J, Neuke A, Molle A, Jordan J, Weck M. Spontaneous baroreflex sensitivity and heart rate variability are not superior to classic autonomic testing in older patients with type 2 diabetes. Am J Med Sci 2001; 322: 24-30.36 Gerritsen J, Dekker JM, TenVoorde BJ, Kostense PJ, Heine RJ, Bouter LM, Heethaar RM, Stehouwer CD. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care 2001; 24: 1793-1798.37 Toyry JP, Partanen JV, Niskanen LK, Lansimies EA, Uusitupa MI. Divergent development of autonomic and peripheral somatic neuropathies in NIDDM. Diabetologia 1997; 40: 953-8.38 Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG. A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care 1999; 22: 1036-1042.39 Aso Y, Fujiwara Y, Inukai T, Takemura Y. Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration. Diabetes Care 1998; 21:1173-1177.40 Burger AJ, Weinrauch LA, DElia JA, Aronson D. Effect of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 1999; 84: 687-691.41 Ducher M, Cerutti C, Gustin MP, Abou-Amara S, Thivolet C, Laville M, Paultre CZ, Fauvel JP. Non-invasive exploration of cardiac autonomic neuropathy. Four reliable methods for diabetes? Diabetes Care 1999; 22: 1387-1388. Chapter 8: Dissociation in PNP and CAN - 105
  • 112. 106 - The diabetic foot syndrome
  • 113. Chapter 9Discussion and conclusions
  • 114. 108 - The diabetic foot syndrome
  • 115. 9.1 General discussion9.1.1 The diabetic foot syndromeDefinitionThe World Health Organisation defines the diabetic foot as an infection,ulceration and/or destruction of deep tissues associated with neurologicalabnormalities and various degrees of peripheral vascular disease in the lowerlimb. In the Dutch consensus the diabetic foot is defined as a diversity of footabnormalities caused by neuropathy, macro-angiopathy, limited jointmobility and other consequences of metabolic disturbances, mostly occurringin combination, in patients with diabetes mellitus 1. Both definitions aredescriptions of causal factors and resulting foot disorders. This emphasisesthat the diabetic foot is more a syndrome rather than a diagnosis. Tocommunicate in clinical practice, we would therefore recommend anadditional description of the present causal factors and the resulting footdisorders, instead of using the term diabetic foot.CausesDiabetic foot lesions frequently result from a combination of two or morerisk factors occurring together. Neuropathy has a central role and is present in90% of diabetic patients with foot lesions 2. Other risk factors for thedevelopment of ulcers, foot disintegration or amputation are alteredbiomechanics due to limited joint mobility and/or foot form deformity 3, andperipheral vascular disease 2,4. Traumata, sometimes shoe-related, andpsychological factors, like perception of risks based on symptoms, and ownbelieves on efficacy of self care 5, act in concert with these risk factors in themajority of diabetic foot ulcers.ConsequencesThe diabetic foot syndrome causes a major burden on the quality of life of thediabetic patient and to the health care system.Impact on quality of lifeThe impact of diabetic foot ulcers on quality of life is large, especially onphysical functioning, social functioning and mobility, as described in chapter3. Physical disabilities seem to be primarily responsible for the decrease in Chapter 9: Discussion and conclusions - 109
  • 116. quality of life. In the care for patients with a diabetic foot disorder, theseaspects are underexposed. Parallel to the medical care for the diabetic footulcer, including metabolic control and preventive measures, attention shouldbe given to a rehabilitation programme. Such a programme should be offeredto decrease disabilities on mobility and social functioning by providing forexample physical training and advice about adaptations. There is no literatureavailable about the effect of these programmes on quality of life. So, anevaluation of this issue will be necessary.Impact on the health care systemPrevalencePolyneuropathy (PNP) is a frequently occurring complication of DM. Theepidemiological data vary because of the use of different definitions,diagnostic tests and study populations.Of the population studied at the outpatient clinic of the University HospitalGroningen, sixty percent was at risk to develop diabetic foot disorders, due tothe presence of PNP eventually combined with other risk factors (chapter 2).In this study, which was performed in 1995, Colemans risk categorisationsystem 6 was used. In 1998 the Dutch diabetic foot consensus was presented1 . The risk classification system of Coleman differs slightly from the systemadvised in the Dutch consensus. Coleman defines high risk (category 3) asulceration and/or vascular laboratory findings implying angiopathy. In theDutch consensus the highest risk category is defined as a present or formerulcer. The macrovascular abnormalities as found in the vascular laboratoryare overestimated in Colemans system. Macrovascular factors only play amoderate role in the development of diabetic foot problems 2. Nowadays, wewould prefer the classification system of the Dutch consensus.In the Diabetes Control and Complications Trial (DCCT) 7, PNP wasdetectable in 39% of the subjects, which is lower than in our studypopulation. This can be explained by difference in characteristics of the studypopulations: the DCCT population was younger, had a shorter duration ofdiabetes, and only patients with type 1 DM were included 7.Veves et al. studied risk factors for foot problems in outpatient clinics ofhospitals in 4 different European countries 8. Prevalence rates of PNP variedfrom 8-54%, depending on location of study and diagnostic test used. Theprevalence of PNP in our studied patient group is even higher. In our studyPNP was defined as the sum-score of insensitivity to the 10 gram SWMFand/or disturbed VPT. Veves did not compose an overall sum-score, heshowed separate data of SWMF and VPT 8.In 1988 a Dutch study was performed in general practices among type 2diabetic patients. Neuropathy was defined as presence of one or more signsand symptoms, and was found in 68% of these patients 9. This percentage isonly a little higher than the data of our study.110 - The diabetic foot syndrome
  • 117. Compared to foreign clinics, a rather high percentage of patients are at risk atour diabetes outpatient clinic, although the results from the Dutch generalpractices are comparable. Reliable comparison is impossible due todifferences in diagnostic definitions of neuropathy and different studypopulations used.UnderdiagnosisMost of our patients at risk for the development of foot ulcers areundiagnosed in that capacity and adjust insufficient preventive measures.Both factors contribute to the high relative risk of amputations in diabeticpatients in the province of Groningen, as found by van Houtum et al. 10. VanHoutum gives as possible explanation of the regional differences, differencesin severity of diabetes, in local treatment philosophies or the availability ofsub-specialities. However, careful systematic screening is necessary to statethat risk profiles and prevention of diabetic patients in other parts of thecountry will differ from Groningen. Even, no evidence is present of adifference in severity of diabetes or a less availability of sub-specialitiesbetween provinces of the Netherlands. Further study of the underlyingmechanisms explaining the relatively high risk for amputation in patientswith diabetes in the province of Groningen is necessary.PreventionDiabetic foot care has not yet been become standard care in the Netherlands.Although more attention is devoted to the diabetic foot syndrome,implementation seems to be difficult in clinical practice.In the Dutch primary health care system, nurse practitioners, specialisednurses or doctors assistants are involved in the prevention and care fordiabetic foot disorders. Also, a Diabetes Service of the General Practitionerslaboratory is supportive to general practitioners for screening purposes. Inthis organisation of care, a brief consultation of specialists has to be easilyavailable and follow fluently. The ongoing development of transmural careprojects will facilitate this development.In the clinical setting, the multidisciplinary approach to the care for thediabetic foot syndrome is not yet accepted unquestioningly, partially causedby its difficult organisation structure. However, education and frequentoutpatient clinic controls could be well performed by trained nurses ordoctors assistants. An experienced staff should be available on demand, totake adequate action and intervention in observed abnormalities.This thesis is the outcome of multidisciplinary co-operation. It alsoendeavours the development of instruments to make the expertise of thespecialist available to other workers in the field. Particularly at the outpatientclinics, early diagnosis of neuropathy, an important causal factor of thediabetic foot syndrome, contributes to risk profiles and early intervention. Chapter 9: Discussion and conclusions - 111
  • 118. The instruments developed in this thesis are not reserved to neurologists orother physicians, but especially can be used by nurses and paramedics.When diabetic foot problems are present, systematic documentation of theeffect of treatment should be performed. Besides standard medicalparameters like physical examination or laboratory scores, also quality of lifemeasurements have to be assessed. Evaluation of quality of life, morespecifically the domain of mobility, is an underestimated part in clinicalpractice. The activities of the multidisciplinary working group for the diabeticfoot are a base for a complementary approach to cover all aspects of thediabetic foot syndrome, and for further development of transmuralprogrammes.We state that patient care for the diabetic foot syndrome should primarily beimproved by further attunement between the specialists concerned, and thegeneral practitioners, how to reach the population at risk and how to offerthem adequate prevention.9.1.2 Diabetic neuropathyClassificationDiabetic neuropathy is not a single entity, but a diverse group of disorders. Inclinical practice, the classification of diabetic neuropathy by Brown isfrequently used: (1) distal symmetric polyneuropathy, with sensory, motor,and autonomic involvement, respectively, (2) proximal motor neuropathy,and (3) focal and multifocal neuropathies, existing of cranial neuropathiesand mono-neuropathies 11.Distal symmetric polyneuropathy (PNP) is the most commonly recognisedform of diabetic neuropathy 12. The legs are more commonly involved thanthe arms. Sensory, motor as well as autonomic fibres are concerned. Distalsymmetric PNP is chronically progressive, while proximal and cranialneuropathies tend to resolve spontaneously in time. The mono-neuropathiescan have both clinical courses 13.CausesThe pathogenesis of diabetic neuropathy has not yet been fully elucidated 14.Hyperglycaemia is the best studied factor. The Diabetes Control andComplications Trial (DCCT) showed that glycaemic control is extremelyimportant in preventing and delaying progression of neuropathy 15.Hyperglycaemia can directly cause early functional alterations in Schwann112 - The diabetic foot syndrome
  • 119. cells (myelin), nodes of Ranvier, or axons. These functional alterationsinitiate the risk for progressive disease in these tissues 16.Abnormal metabolic pathways in DM, such as for example polyol pathwayabnormalities, can also lead to functional derangement of the peripheral nervecells 17. However, this is not supported by the controversial results of trialswith aldose reductase inhibitors, acting on derangement of the polyolpathway 17,18. The mechanism seems to be more complex and multicausal,due to for example glycation of nerve proteins, the involvement of fatty acidmetabolism within the vasculature, and oxidative stress 19,20.Another hypothesis is the vascular genesis. Due to vascular disease, themicrovascular supply of the nerve will fail and intraneural hypoxia will exist.This induces fiber changes, leading to the development of neuropathy 17,21.Despite evidence that microvascular disease plays an important role in thepathogenesis of neuropathy, it is unclear if advanced neuropathy developsdirectly via hyperglycaemia or secondary via microangiopathy. In chapter 7,we studied diabetic patients without clinical signs of microangiopathy orcomplications due to DM. The majority of these patients had abnormalities inboth nerve and muscle fiber conduction, parameters of sub-clinical sensoryand motor neuropathy. Because no presence of microangiopathy was found,this finding argues in favour of a direct metabolic hypothesis.TreatmentMany clinical trials have been conducted to test the possible beneficial effectsof different treatment modes. However, yet, no medication has beenindisputably proved to be effective in the treatment of PNP in patients withDM 18. Treatment of neuropathy has three aims; firstly, prevention throughreduction of putative risk factors such as hyperglycaemia, secondly, earlydiagnosis and prophylaxis of the complications of DM with special attentionto the diabetic foot, and thirdly palliation of symptoms.DiagnosisTo fully classify diabetic neuropathy, the San Antonio Conference onDiabetic Neuropathy recommends at least one measure from each of thefollowing categories: (a) clinical symptoms, (b) clinical examination, (c)electrodiagnostic studies, (d) quantitative sensory testing and (e) autonomicfunction testing 22. The consensus panel further states that standardisationwould be beneficial and recommends that future efforts should be directedtowards the development of common interstudy methodologies.Unfortunately, even 14 years later, no consensus is available about Chapter 9: Discussion and conclusions - 113
  • 120. diagnosing diabetic neuropathy in clinical practice. Because therecommendations are too extended and not suitable in clinical practice anenormous amount of studies with different diagnostic methods is used. In ouropinion the consensus advises from San Antonio 1988 should be revised.(a) Clinical symptomsAlthough controversy exists about the use of symptom scoring in diagnosingdiabetic neuropathy 23-25, several authors concluded that symptoms have to beevaluated because of their additional diagnostic or prognostic value inresearch and patient care 26-27. Several scores have been developed forsymptom scoring. None of them completely fulfilled the criteria fordiagnostic tests, such as validation, predictive value and manageability, asdescribed in chapter 4. Most scores have not been validated, some others aretoo extended and, therefore, not manageable in clinical practice. Informationabout the predictive value is scarce.In chapter 4 the development of the Diabetic Neuropathy Symptom (DNS)score, a modification of the Neuropathy Symptom Score (NSS) 28, has beendescribed. The DNS-score is specific for distal symmetric PNP, the mostfrequent form of diabetic neuropathy. The DNS-score is shorter and easier toperform in clinical practice. It is validated with clinical standards ondiscriminative and predictive values, for diagnosis and prognosis,respectively. For evaluative purposes or follow up, the DNS-score might betoo short. However, in the NSS the number of items related to PNP is alsovery limited. The NSS covers symptoms due to the entire spectrum ofneuropathy and will be preferred in case of suspicion of other forms ofdiabetic neuropathy.(b) Clinical examinationConcerning the examination scores to diagnose diabetic neuropathy, alsonone of them completely fulfilled the criteria for diagnostic tests, as is theproblem with symptom scores. Physical examination scores are very capablein predicting diabetic foot complications. Pham et al. found that clinicalexamination (modified Neurological Disability Score (NDS)) and a 10 grammonofilament test are the two most sensitive tests in identifying patients atrisk for foot ulceration 29. This was supported by a study of Abbott et al, whoconcluded that particularly a modified NDS score was the best predictor fordiabetic foot ulceration 30. Nevertheless, the application of standard clinicalexamination in clinical practice is poor. In a study from 1994, in only 57% ofthe patients with diabetes, admitted with foot complications, a neurologicalexamination was performed 31. Although the Dutch consensus composed in1998 advises regular screening of patients with DM, we do not think that theclinical application of physical examination has changed. The lack ofmanageable scores, insufficient facilities, and the limited knowledge or even114 - The diabetic foot syndrome
  • 121. motivation of the physicians for diabetic foot problems contributes toinsufficient and/or inadequate care for the diabetic foot even in 2002.The generally accepted Neurological Disability Score (NDS) 28 is tooextensive and modified versions are not validated. Therefore, we developedthe Diabetic Neuropathy Examination (DNE) score, a validated modificationof the NDS, easy to perform in clinical practice and very suitable fordiscriminative, evaluative and predictive purposes. Because the DNE-score isspecific for distal symmetric polyneuropathy, use of the NDS is preferred incase of suspicion of presence of other forms of neuropathy.(c) Quantitative Sensory Testing (QST)QST is used to characterise and quantify human cutaneous sensation. QST isnon-invasive, with high predictive values to the development of foot ulcers 32-35 . Manageability, defined as time and equipment needed to perform the test,differs between the several methods used. QST measures show larger intra-and inter-individual variability than nerve conduction velocities 36-39.Standardisation and correction for age, sex and height is important in QST 39-41 . There is no consensus about which stimuli, testing procedures and criteriafor diagnosis should be used in QST 42. In chapter 5 the most frequently usedand generally accepted tests are described, namely Vibration PerceptionThreshold (VPT) testing with the Biothesiometer and Semmes WeinsteinMonoFilaments (SWMF) testing. SWMF are very easy to perform, althoughfor evaluative purposes several filaments have to be used which is more timeconsuming. Both VPT and SWMF can be used for discrimination andprediction of PNP. For evaluation we prefer VPT above SWMF because VPTis a continuous variable and SWMF score dichotomous. The large variabilityof both scores limits the value for clinical evaluations. Thermal DetectionThreshold (TDT) testing can be indicated in neurological clinics, because it isone of the only methods to assess small unmyelinated fiber functioning 43-45.(d) cardiovascular Autonomic Function Testing (cAFT)cAFT is used to document autonomic failure, defined as an impaired functionof the peripheral autonomic nervous system. The most extensively studiedand validated tests of autonomic function are the tests of the cardiovascularreflexes which have been studied by Ewing et al. 46. More recently, HeartRate Variability (HRV) and Baro Reflex Sensitivity (BRS) were developed,as more sensitive tests for cAFT 47,48. The Ewing tests and HRV have a valuein the prediction of diabetic foot ulcers 49,50, BRS seems to be more related tomicroalbuminuria with a high predictive value for cardiovascularcomplications 51,52, as shown in chapter 6 and 8. There seems to be ahierarchy in sensitivity of these measures. For example, an abnormality ofHRV alone may be the earliest stage. An abnormality of Valsalva response asperformed in the Ewing tests, may define an intermediate stage, and the Chapter 9: Discussion and conclusions - 115
  • 122. presence of postural hypotension may occur in a more severe stage 53. Allthese methods have been validated. As for manageability, the tests are timeconsuming and a special laboratory, staff and software is necessary. Thesetests can be used for discrimination, prediction and evaluation. AlthoughcAFT testing should be performed to diagnose diabetic PNP according theSan Antonio consensus 22, we have shown in chapter 8 that these tests aremore related to microcirculatory abnormalities than to clinical standards fordiabetic PNP (SWMF and VPT), and even less to the DNS- and DNE-score.We assume that cAFT tests more reflect microvascular angiopathy thandiabetic PNP. Further research on this item is necessary. For now we believethere is only an indication for clinical use of cAFT on specific clinicalindication, as for example the determination of the cardiovascular prognosis.(e) Electro Diagnostic Studies (EDS)Electrodiagnostic assessments are sensitive, specific and reproduciblemeasures of the presence and severity of peripheral nerve involvement inpatients with diabetes 53. EDS can be performed as nerve conduction andmuscle fiber conduction studies, and as electromyography. The predictivevalue of EDS in the development of foot ulcers is not obvious. Manageabilityis confined because it is time consuming, and the necessity of an experiencedstaff and specific laboratory equipment. As in cAFT, EDS can be used fordiscrimination, prediction and evaluation. In clinical practice we believe thatEDS should be used when uncertainty in diagnosis exists, and to distinguishfrom other neurological problems.In chapter 6 we combined the results of scores of the 5 diagnostic categoriesfor diabetic PNP of the San Antonio consensus 22. In both a diabetes groupwithout neuropathy and in the control group, abnormal test results werefound (abnormal score on at least 1 diagnostic category) in 47% and 40%,respectively. The risk of overdiagnosis by using all 5 diagnostic categoriesshould be considered, further research to characterise an optimal set ofdiagnostic categories for diabetic PNP is necessary.Table 1 shows the indications for use of the specific diagnostic tests for threehealth care settings and for the different diagnostic purposes. All fivediagnostic categories of the San Antonio consensus are mentioned 22. Theseguidelines are experience based, with reference to the literature mentionedabove.116 - The diabetic foot syndrome
  • 123. Table 1: Clinical Guidelines Diagnosis Diabetic Polyneuropathy general practice diabetes clinic neurology clinic D P F D P F D P FSS DNS + + +/- + + +/- - - - NSS - - - oi - oi + + +ES DNE + + + + + + + + + NDS - - - oi - oi oi - oiQST SWMF + + + + + - + + - VPT - - - + + +/- + + +/- TDT - - - - - - + + +/-EDS - - - oi - oi oi - oicAFT - - - oi oi oi oi oi oiSS Symptom Score D: Diagnosis- DNS Diabetic Neuropathy Symptom score P: Prognosis- NSS Neuropathy Symptom Score F: Follow upES Examination Score o.i.: on indication- DNE: Diabetic Neuropathy Examination score- NDS: Neurological Disability ScoreQST Quantitative Sensory Testing- SWMF: Semmes-Weinstein Monofilaments- VPT: Vibration Perception Threshold- TDT: Thermal Detection ThresholdEDS Electro Diagnostic TestingcAFT cardiovascular Autonomic Function TestingFourteen years after the San Antonio Consensus, progress has been made inthe development and validation of diagnostic tests for diabetic neuropathy,more specifically PNP, in all 5 diagnostic categories. Several validated andmanageable tests are available. The problem now is how to compose, fordifferent clinical practices or research settings, a well based, optimal set ofcomplementary tests. Further research should be focussed on this. Chapter 9: Discussion and conclusions - 117
  • 124. 9.2 The diabetic foot syndrome and rehabilitationIntroductionRehabilitation is the care for a person with congenital or acquired physicalimpairments of the loco-motor system and processes of control, by co-ordinated patient centred treatment. The primary goal is increasing orcompensating functions and activities to optimise participation and quality oflife. Treatment is individually based although group therapy is alsoperformed. The rehabilitation programme is mono- or multidisciplinary,different disciplines can be involved. The rehabilitation concept as described,can also be implemented in treatment programmes of other medicalspecialists.The diabetic foot is an acquired problem of the feet in patients with diabetesmellitus. A combination of vascular and neurological impairments with orwithout foot-deformity may result in ulcers and sometimes amputation.Consequently, patient activities, participation in the society and quality of lifeis limited. The physical limitations with the consequences on mobility andsocial functioning are evident, as shown in this thesis. Therefore, arehabilitation programme is necessary to optimise patient mobility. Othertargets are education and prevention, or training diabetic patients on otheritems of activities and participation (sports, work etc).The role of the physician for rehabilitation medicine in diabetic foot careThe physician for rehabilitation medicine participates in the development of adiabetic foot prevention, screening and treatment programme. It is widelyknown and generally accepted that these programmes are effective inpreventing ulcers and amputations, and that they are cost effective54-57.Therefore, each hospital should be obligated to develop such a programme,initiated and co-ordinated by the diabetologists or one of the other medicalspecialists involved. A physician for rehabilitation medicine has specificknowledge of foot disorders and underlying causes, its treatment andconsequences on activities, participation and quality of life. He or she has acentral role in the multidisciplinary diabetic foot clinic and be available asconsultant at the various in- and outpatient departments of the hospital.The primary responsibility of the physician for rehabilitation medicine isassessment of impairments and their influence on daily activities,participation in society and quality of life. Also the prescription of adequatefootwear, total contact casting and the development and co-ordination of amodule to optimise patient mobility are essential contributions of thephysician for rehabilitation medicine. Participation in the development of118 - The diabetic foot syndrome
  • 125. prevention and education programmes and contacting relevant localparamedics and orthopaedic technicians about foot care and orthosis is alsothe field of the physician for rehabilitation medicine. Diabetes regulation andevaluation of other risk factors has to be co-ordinated by the diabetologists,endocrinologists, internists and general practitioners.Shoe-prescriptionIn the Netherlands, orthopaedic surgeons and physicians for rehabilitationcan prescribe therapeutic footwear. This prescription is mostly experiencebased 58. At this moment two different rehabilitation medicine researchgroups are working on consensus reports about shoe prescription in diabetes.In Amsterdam, van der Wilden and Dahmen are working on a consensusabout an algorithm of foot impairments and shoe characteristics for theneuropathic foot. In Enschede, de Vries and Grady are developing guidelinesfor the prescription of shoes for the diabetic foot.Even more important than the prescription, is the control of the prescribedshoes after delivery to the patient and its follow up, next to prevention andeducation in general, and evaluation of the need for walking aids or specifictraining. The prescription of shoes in diabetes asks for an attitude to feelresponsible for the entire process and to look further than only the shoes andfeet.In diabetic foot care, co-operation between orthopaedic surgeon andphysician for rehabilitation medicine is important. Regular co-operation willimprove patient care, because it enhances the interdisciplinary knowledgeabout (contra)indications for surgery, the possibility of alternative treatmentoptions and the attunement of care during this entire process. In clinicalpractice this can be achieved by regular combined consults. The orthopaedicsurgeon and physician for rehabilitation medicine have a commonresponsibility for restoring foot stability and optimising biomechanics todecrease disability of the patient with the diabetic foot syndrome.In orthopaedic surgery, progress has been made in the operative treatment torestore anatomical alignment and improve function in diabetic patients withCharcot deformities 59. Before prescribing footwear these options should betaken more into account.The organisation of prescription of therapeutic footwear in the Netherlandshas to become revised. The increasing amount of diabetic patients at risk forfoot disorders will cause major capacity problems. The number of availablephysicians for rehabilitation medicine, and of other medical specialistsinvolved, is insufficient to take care for all these patients. Paramedics ornurse practitioners can evaluate the feet of diabetic patients by a protocol Chapter 9: Discussion and conclusions - 119
  • 126. under supervision of a physician for rehabilitation medicine, continued by astandardised prescription and follow up 60. The patients at risk, with presenceof neuropathy without other problems as foot deformity, ulcers etc, can beprovided with prevention shoes, also known as thematic shoes for diabeticpatients in the Netherlands. Delivery of these shoes is fast, standardpreventive characteristics are present. The prescription of thematic shoes willspare time of physicians and orthopaedic shoe technicians for more complexproblems. Unfortunately, the insurance companies in the Netherlands do notsupply thematic shoes.An alternative treatment option is Total Contact Casting (TCC). In theNetherlands, TCC might be used more often in treating diabetic neuropathicfoot disorders. The results of TCC, when performed by an experienced team,are good 61,62. The patient stays mobile, the cast serves as an optimal wounddressing, and application can be performed immediately. TCC seems to be agood tool to bridge the waiting time for the shoes, which can vary from 2 to16 weeks.Mobility in patients with diabetic foot disordersDiabetic foot disorders cause physical limitations, secondary enhanced bytreatment and prevention advices about minimising loading to spare the feet,which has consequences for mobility and social functioning of the patients. Amodular rehabilitation programme with objectives as described in Table 2can improve this limitation.Table 2: modular rehabilitation programme Mobility• The patient has an optimal general cardiovascular and locomotor condition (muscle strength, joint mobility, etc).• The patient knows his load-bearing capacity and ergonomic principles.• The patient is optimal supported in standing and walking by adequate foot wear, walking devices etc and knows how to deal with these.• The patient has an alternative for standing and walking/walking the stairs, in case of vulnerability of the feet to compensate load bearing.120 - The diabetic foot syndrome
  • 127. 9.3 Conclusions: answers to the questions1 How many patients from the diabetes outpatient clinic, unknown withdiabetic foot complications, are at risk to develop these complications andwhat is their actual state of prevention?Sixty percent of the patients were at risk for developing diabetic footcomplications. The preventive measures were low in these patients, patientknowledge was insufficient and behaviour even worse.2 What is the influence of having a present or former foot ulcer on the qualityof life of patients with diabetes mellitus?Presence or history of diabetic foot ulcers has a large impact on quality of lifeof the patients, especially on physical role, physical functioning and mobility.Quality of life was mainly influenced by physical impairments.3 Is it possible to modify the Neuropathy Symptom Score (NSS) and theNeurological Disability Score (NDS) into valid, easily managed, graded andaccurate scoring systems for diagnosing distal symmetric polyneuropathy?The DNS- and DNE-score, modified from the NSS and NDS respectively,are sensitive and well-validated scoring systems for distal symmetricpolyneuropathy, and fast and easy to perform in clinical practice.4 Is polyneuropathy present in patients with DM before any sign of micro- ormacroangiopathy is detectable? Does sensory polyneuropathy occurpreliminary to motor neuropathy or do they occur simultaneously?Early sensory and motor axonal loss is present in patients without micro- ormacro-angiopathy. This supports a primary metabolic causal pathway inpathophysiology of diabetic neuropathy, instead of a vascular hypothesis.Sensory and motor neuropathy occur simultaneously in patients with DM. Apresumed preliminary presence of sensory neuropathy is based on sensitivityof diagnostic methods used and compensating mechanisms.5 Do cardiovascular autonomic neuropathy tests reflect diabeticpolyneuropathy or diabetic vasculopathy?After correction for age, cardiovascular autonomic neuropathy (CAN) testsare weakly related to quantitative sensory testing (Monofilaments andVibration Perception Threshold testing) and to the examination score forpolyneuropathy (DNE-score) in diabetes. The relation to the symptom scorefor polyneuropathy (DNS-score) is more limited. There was a significantrelation of some of the CAN tests with microcirculatory parameters. Thus,CAN tests might be both a reflection of microvascular angiopathy anddiabetic polyneuropathy. Chapter 9: Discussion and conclusions - 121
  • 128. 9.4 References1 Syllabus Richtlijnen diabetische retinopathie, diabetische nephropathie, diabetische voet en hart en vaat ziekten bij diabetes mellitus. Richtlijnen NDF/CBO september 1998. Banda Heerenveen BV, the Netherlands.2 Shaw JE, Boulton AJM. The pathogenesis of diabetic foot problems. Diabetes 1997; 46 (2): s58-61.3 Cavanagh PR, Ulbrecht JS, Caputo GM. Biomechanical aspects of diabetic foot disease: aetiology, treatment, and prevention. Diabet Med 1996; 13: s17-22.4 McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, Pecoraro RE. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. Diabetes Care 1995; 18 (2), 216-19.5 Harwell TS, Helgerson SD, Gohdes D, McInerney MJ, Roumagoux LP, Smilie JG. Foot care pratices, services and perceptions of risk among medicare beneficiaries with diabetes at high and low risk for future foot complications. Foot Ankle Int 2001; 22(9): 734-8.6 Coleman WC. Footwear in a management programme for injury prevention. In: The Diabetic Foot / 5th edition/ edited by Levin ME, ONeal LW, Bowker JH. St Louis: Mosby Yearbook, p 533-36.7 The DCCT Research Group. Factors in development of diabetic neuropathy. Diabetes 1988; 37: 476-81.8 Veves A, Uccioli L, Manes C, Van Acker K, Komninou H, Philippides P, de Leeuw I, Menzinger G, Boulton AJM. Comparison of risk factors for foot problems in diabetic patients attending teaching hospital outpatient clinics in four different European states. Diabet Med 1994; 11: 709-711.9 Reenders K, de Nobel E, van den Hoogen HJM, Rutten GEHM, van Weel C. Diabetes and its long term complications in general practice: a survey in a well defined population. Family Practice 1993; 10: 169-72.10 Houtum van WH, Lavery LA. Regional variation in the incidence of diabetes-related amputations in the Netherlands. Diabetes Res and Clin Practice 1996; 31: 125-32.11 Brown MJ, Asbury AK. Diabetic neuropathy. Ann Neurol 1984; 15: 2- 12.12 Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. NEJM 1994; 331 (13): 854-60.13 Greene DA, Feldman EL, Stevens M. Neuropathy in the diabetic foot: new concepts in etiology and treatment. In: the diabetic foot. Levin ME, ONeal LW, Bowker JH eds. St Louis, Mosby Yearbook,1993.122 - The diabetic foot syndrome
  • 129. 14 Cameron NE, Cotter MA. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 1997; 46: s31-37.15 The DCCT trial research group. The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med 1993; 329: 977-986.16 Hendriksen PH. Neurophysiological aspects of neuropathy in human diabetes and in experimental models. Thesis, Addis Wijk bij Duurstede, 1992, p. 47.17 Dyck PJ, Gianini C. Pathologic alterations in the diabetic neuropathies of humans: a review. J Neuropathol Exp Neurol 1996; 55: 1181-93.18 Airey M, Bennett C, Nicolucci A, Williams R. Aldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathy. Cochrane Database Syst Review 2000; 2: cd002182.19 Ward JD. Biochemical and vascular factors in the pathogenesis of diabetic neuropathy. Clin Invest Med 1995; 18 (4): 267-74.20 Tomlinson DR. Future prevention and treatment of diabetic neuropathy. Diabetes Metab 1998; 24, supl 3: 79-83.21 Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44 (11): 1973-88.22 American Diabetes Association, American Academy of Neurology; Report and recommendations of the San Antonio Conference on Diabetic Neuropathy (Consensus Statement). Diabetes Care 1988; 11: 592-97.23 Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998; 21: 2161-77.24 Valk GD, Grootenhuis PA, Bouter LM, Bertelsman 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: 29-34.25 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: 105-10.26 Valk GD, Nauta JJP, Strijers RLM, Bertelsman FW. Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy. Diabet Med 1992; 9: 716-21.27 Dyck PJ, Karnes JL, Daube J, OBrien P, Service JF. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: 861-80.28 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 1988; 11: 21-32. Chapter 9: Discussion and conclusions - 123
  • 130. 29 Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23(5): 606-11.30 Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJM. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998; 21(7): 1071- 75.31 Schaper NC, Kitselaar PJEHM, Nieuwenhuijzen Kruseman AC. Tekortschietende gezondheidszorg voor diabetespatienten met voetproblemen. NTvG 1994; 138 (11): 548-50.32 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 Intern Med 1998; 158: 289-292.33 Young MJ, Breddy JL, Veves A, Boulton AJM. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. Diabetes Care 1994: 17 (6): 557-560.34 Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJM. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998; 21 (7): 1071- 75.35 Tack CJJ, Netten PM, Scheepers MH, Meijer JWG, Smits P, Lutterman JA. Comparison of clinical examination, current and vibratory perception threshold in diabetic polyneuropathy. Netherlands J of Medicine 1994; 44: 41-49.36 McGill M, Molyneaux L, Spencer R, Fan Heng L, Yue DK. Possible sources of discrepancies in the use of the Semmes-Weinstein Monofilament. Diabetes Care 1999; 22 (4): 598-602.37 Bertelsman FW, Heimans JJ, van Rooy JCGM, Heine RJ, van der Veen EA. Reproducibility of vibratory perception thresholds in patients with diabetic neuropathy. Diabetes Research 1986; 3: 463-66.38 Williams G, Gill JS, Aber V, Mather HM. Variability in vibration perception threshold among sites: a potential source of error in biothesiometry. BMJ 1988; 296: 233-35.39 Neeling de JN, Beks PJ, Bertelsmann FW, Heine RJ, Bouter LM. Sensory thresholds in older adults: reproducibility and reference values. Muscle and Nerve 1994: 17: 454-61.40 Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol, Neurosurg and Psych 1979; 42: 793-803.124 - The diabetic foot syndrome
  • 131. 41 Davis EA, Jones TW, Walsh P, Byrne GC. The use of biothesiometry to detect neuropathy in children and adolescents with IDDM. Diabetes Care 1997; 20(9): 1448-53.42 Quantitative Sensory Testing: a consensus report from the Peripheral Nerve Association. Neurology 1993; 43: 1050-52.43 Ijff GA, Bertelsmann FW, Nauta JJ, Heimans JJ. Cold and warm cutaneous sensation in diabetic patients. Diabet Med 1991; 8: s71-73.44 Jensen TS, Bach FW, Kastrup J, Dejgaard A, Brennum J. Vibratory and thermal thresholds in diabetics with and without clinical neuropathy. Acta Neurol Scand 1991; 84(4): 326-33.45 Tobin K, Giuliani MJ, Lacomis D. Comparison of different modalities for detection of small fiber neuropathy. Clin Neurophysiol 1999; 110(11): 1909-12.46 Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8(5): 491-98.47 Frattola A, Parati G, Gamba P, Paleari F, Mauri G, DiRienzo M, Castiglioni P, Mancia G. Time and frequency domain etsimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia 1997; 40: 1470-75.48 Mancia G. Early diagnosis of diabetic autonomic neuropathy: present and future approaches. Diabetologia 1997; 40(4): 482-84.49 Aso Y, Fujiwara Y, Inukai T, Takemura Y. Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration. Diabetes Care 1998; 21: 1173-77.50 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): 1036-42.51 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: 1385-91.52 Lefrandt JD, Hoogenberg K, van Roon AM, Dullaart RPF, Gans ROB, Smit AJ. Baroreflex sensitivity is depressed in microalbuminuric type 1 diabetic patients at rest and during sympathic manoeuvres. Diabetologia 1999; 42: 1345-49.53 American Diabetes Association. Standardized measures in diabetic neuropathy. Diabetes Care 1992; 16: 82-112.54 Ragnarson-Tennvall G, Apelqvist J. Cost-effective management of diabetic foot ulcers, a review. Pharmacoeconomics 1997; 12 (1): 42- 53. Chapter 9: Discussion and conclusions - 125
  • 132. 55 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: 602-13.56 Bakker K, Dooren J. Een gespecialiseerde voetenpolikliniek voor diabetespatienten vermindert het aantal amputaties en is kostenbesparend. NTvG 1994; 138(11): 565-69.57 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): 763-71.58 Meijer JWG. De schoenvoorziening van de diabetische voet. In: Dekker R, Geertzen JHB, Rietman JS (eds). De orthopaedische schoen. Groningen, Huisdrukkerij AZG 2000, p. 91-98.59 Pinzur MS, Shields N, Trepman E, Dawson P, Evans A. Current practice patterns in the treatment of Charcot foot. Foot Ankle Int 2000; 21 (11): 916-20.60 Pinzur MS, Kernan-Schroeder D, Emanuele NV, Emanuel M. Development of a nurse-provided health system strategy for diabetic foot care. Foot Ankle Int 2001; 22(9): 744-6.61 Spencer S. Pressure relieving interventions for preventing and treating diabetic foot ulcers. Cochrane Database Syst Rev 2000.62 Armstrong DG, Nguyen HC, Lavery LA, van Schie CHM, Boulton AJM, Harkless LB. Off-loading the diabetic foot wound. Diabetes Care 2001; 24: 1019-1022.126 - The diabetic foot syndrome
  • 133. SummaryThe diabetic foot syndrome is a disabling and frequent long-termcomplication of diabetes mellitus (DM). It can be defined as an array of footabnormalities, resulting from the presence of both peripheral neuropathy andmacro-angiopathy, but also from other consequences of metabolicdisturbances. A clinical important manifestation of the diabetic footsyndrome is the diabetic foot ulcer, which can be followed by an amputation.The number of patients with DM in the Netherlands was estimated to be450.000 in 1994, of which about fifty percent were undiagnosed. An ulcerwill affect fifteen to twenty-five percent of all individuals with diabetes atleast once in their lifetime. The relative risk of a lower limb amputation is 20for the entire Dutch diabetic population, whereas in the province ofGroningen this relative risk is 45. This illustrates that diabetic foot disordersare common in our society.The diabetic foot syndrome leads to a major burden, both on the patient andthe health care system. The risk of amputation is a life long threat to thediabetic patient, and the costs due to diabetic ulcers and amputation are high.Early detection, strict diabetes regulation, patient education about foot care,and appropriate footwear can reduce the occurrence of ulcers andamputations.The high number of amputations in patients with DM in the province ofGroningen shows that there is an urgent need to evaluate the care for thediabetic foot in this region. The results of this evaluation are condensed inthis thesis and are a stimulus for the multidisciplinary approach of thediabetic foot in the University Hospital.In this thesis the extent of the problem of the diabetic foot syndrome (1) andthe consequences of this syndrome on quality of life (2) are addressed. Also,the development of diagnostic tests for diabetic neuropathy (3) and therelation between neuropathy and angiopathy in diabetes (4) are discussed.(1) The extent of the problem: evaluation of a screening and preventionprogramme for diabetic foot complications (Chapter 2).Foot complications in diabetes can be decreased by preventive measures. Toinvestigate the local situation, the presence of risk factors and theperformance of preventive measures was studied in a sample taken from thediabetes outpatient clinic of the University Hospital Groningen. Fifty diabeticpatients, not known to have foot ulcers, were selected at random. Risk factorsand preventive measures were investigated with the Coleman risk- Summary - 127
  • 134. categorisation system and the Preventive Measures Scale, respectively. Ofthese patients, sixty percent were at risk in developing diabetic footcomplications. Few preventive measures were taken by this sixty percent atrisk. Patient knowledge was insufficient and their behaviour was even worse.Standard preventive shoe adaptations were absent in most patients at risk.(2) Consequences of diabetic foot ulcers on quality of life (Chapter 3).The influence of a diabetic foot ulcer on the Quality of Life (QoL) has beenstudied by the comparison of diabetic patients with and without foot ulcers.Fourteen patients with previous or current, but clinically stable diabetic footulcers (DFUs) were compared with a matched diabetic control group of 24patients without DFUs. The diabetic foot risk score of the Dutch consensusreport was assessed. QoL was scored with the RAND-36, the Barthel Scoreand the Walking and Walking Stairs Questionnaire (WSQ). Between the twogroups, marked and significant differences were found in physicalfunctioning, social functioning, physical role and health experience with theRAND-36 and with the four sub-scales of the WSQ. On all these scales, QoLwas significantly poorer in patients with previous or current (stable) ulcers. Amarked correlation was found between the risk score and QoL (physicalfunctioning and physical role). Consequently, the presence or history ofDFUs has a large impact on physical role, physical functioning and mobility.Physical impairments especially influenced QoL. QoL can be improved byproviding advice about adaptations and special equipment.(3) Diagnosis of neuropathy.(A) Symptom and physical examination scoring systems.Distal polyneuropathy (PNP) is the major risk factor for the diabetic footsyndrome. Several symptom and physical examination scoring systems forPNP are available. The generally accepted Neuropathy Symptom Score(NSS) (17 items) and Neurological Disability Score (NDS) (35 items) areboth valid and accepted. However, these scores are extensive, because theyassess on neuropathy in general and not specifically on distal symmetricPNP. The availability of valid, easily managed and predictive scores isnecessary in clinical practice, because large groups have to be screened on aregular base for presence of PNP. For use in daily clinical practice, simplescores for symptoms and examination have been developed: the DiabeticNeuropathy Symptom (DNS) score and the Diabetic NeuropathyExamination (DNE) score.128 - The diabetic foot syndrome
  • 135. The DNS-score (Chapter 4).The score characteristics of the NSS and the DNS-score were compared inseventy-three patients. The construct validity, predictive value andreproducibility were assessed with the DNE-score, monofilaments andVibration Perception Threshold (clinical standards) to validate the DNS-scorefor diagnosing distal diabetic PNP. The correlation between NSS and DNS-score was high. The correlation of the NSS and DNS-score, respectively,with the clinical standards was good. Both scores had a comparablepredictive value. Reproducibility of the DNS-score was good. In conclusion,the DNS-score has been shown to be a validated symptom score, with highpredictive value for screening PNP in diabetes. It is fast and easy to performin clinical practice and favoured for daily clinical use above the NSS.The DNE-score (Chapter 5).The NDS is a score for neuropathy in general. Seventy-three diabetic patientswere studied with monofilaments and biothesiometry, as clinical standardsfor PNP, and subsequently with the NDS. Items of the NDS were selected onclinical relevance (positive score in > 3 patients). The resulting 8-item DNE-score could accurately predict the results of the clinical standards and wasfound to be strongly hierarchic. Sensitivity and specificity of the DNE-scoreat a cut-off level of 3-4 was high for both abnormal monofilament and VPTscores. Reproducibility, as assessed by inter- and intrarater agreement, wasgood. In conclusion, the DNE-score is a sensitive and well-validatedhierarchic scoring system that is fast and easy to perform in clinical practice.(B) The relation of the DNS- and DNE-score with cardiovascular AutonomicFunction Testing and Electro Diagnostic Studies (Chapter 6).The discriminative power of the DNS- and DNE-score for presence of PNP,and their relation with cardiovascular Autonomic Function Testing (cAFT)and Electro Diagnostic Studies (EDS) has been evaluated. Three matchedgroups were studied: 24 diabetic patients with neuropathic foot ulcers(diabetic ulcer group), 24 diabetic patients without clinical neuropathy orulcers (diabetic control group) and 21 controls without diabetes (controls). Inall participants the DNS- and DNE-score were assessed, cAFT wasperformed (Heart Rate Variability (HRV) and Baro Reflex Sensitivity (BRS))and EDS were performed (Nerve Conduction Sum (NCS) score; muscle fiberconduction velocity: fastest/slowest ratio (F/S ratio)). Both the DNS- and theDNE-score discriminated between the diabetic ulcer and diabetic controlgroup significantly. The DNE-score even discriminated between the diabeticcontrol group and the controls without DM. For cAFT, the correlationbetween both DNS- and DNE-score was higher with HRV than with BRS,respectively. A high correlation of DNS- and DNE-score, respectively, wasfound with EDS, for both I-MFCV and NCS. High Odds ratios were found Summary - 129
  • 136. for both DNS- and DNE-score with HRV, BRS, I-MFCV and NCS. Theseresults further confirm the strength of the DNS- and DNE-score indiagnosing diabetic PNP in daily clinical practice. Both scores are capable todiscriminate between patients with and without PNP and are strongly relatedto cAFT and EDS.(4) The relation between neuropathy and angiopathy in diabetes mellitus.(A) Sensory and motor disturbances preceding microangiopathy (Chapter 7).Diabetic PNP is supposed to be primary a disorder of sensory nerves.Hypoxic neuropathy has been held as an important pathogenetic factor. Thefollowing hypothesis was studied: (1) PNP starts before any sign of micro- ormacroangiopathy is detectable, and (2) sensory and motor dysfunction in DMoccurs concurrently and not sequentially. Twelve male patients withoutclinical manifestations of micro- or macroangiopathy, were studied byclinical and neurophysiological testing including invasive muscle fiberconduction velocity (I-MFCV) estimation. Sensory nerve conduction velocity(SNCV) was abnormal in six subjects. I-MFCV showed abnormal results insix subjects (five had also low SNCV). In summary, half of the subjectsshowed a combination of sensory and I-MFCV abnormalities, suggestingconcurrent and not sequential motor and sensory involvement in earlydiabetic PNP, before micro- or macroangiopathy is detectable.(B) Are Cardiovascular Autonomic Neuropathy scores a reflection ofmicroangiopathy or of diabetic polyneuropathy (Chapter 8)?The autonomic function tests by Ewing (Ewing battery), short-term heart ratevariability (HRV) and baroreflex sensitivity (BRS) are tests forCardiovascular Autonomic Neuropathy (CAN), one of the recommendeddiagnostic categories for diabetic PNP. However, CAN tests may be more areflection of cardiovascular abnormalities than of PNP in diabetes. Therelation between CAN tests and other neuropathy and vascular categories hasbeen evaluated in a random sample of fourty-five diabetic patients. In thesepatients, CAN tests were related with diabetic neuropathy physicalexamination (DNE-score) and symptom (DNS-score) scores and withmonofilaments and vibration perception threshold (VPT). CAN tests werealso related to ankle and toe-brachial index (A/TBI) to assessmacroangiopathy and to laser Dopplerflow (LDF) measures (Tmax) at thefoot to measure microangiopathy.A weak relation of the Ewing test score to monofilament scores and VPT wasnot significant after age correction, while no association was evident withDNE- and DNS-scores. For HRV (HFnu) the relation remained significantafter age correction with DNE-score, monofilament scores and VPT. BRS130 - The diabetic foot syndrome
  • 137. was not associated to peripheral neuropathy scores. CAN tests were notrelated to A/TBI. HRV (HFnu) was significantly associated to LDF-Tmax.CAN tests are both related to microcirculatory abnormalities and to clinicalstandards for diabetic PNP (monofilaments, VPT and DNE-score) and evenless to neuropathy symptom scores. CAN scores might both reflect commonmicroangiopathy and specific diabetic PNP.Discussion.The development of the validated DNS- and DNE-score has helped toprovide more manageable instruments to reliably diagnose diabetic PNP. Thescores can be used for discriminative, predictive and evaluative purposes ingeneral practice, and in diabetes and neurology clinics. The use of the scoresis not restricted for use by neurologists or other physicians, they can beexecuted by nurses and paramedics too, as standardised items are scored in astructured fashion.It is still an unresolved question how extensively a set of diagnosticprocedures should be performed to establish a diagnosis of diabetic PNP. In1988, the San Antonio consensus proposed that five diagnostic categoriesshould all be represented. There is no evidence whether a limited set ofprocedures is justified. One should even consider the risk of overdiagnosiswhen many diagnostic procedures with low cut-off values are used. This itemhas also been addressed in the discussion in Chapter 6. Further researchshould be performed to characterise an optimal set of diagnostic categoriesfor diabetic PNP.In the multidisciplinary care for the diabetic foot, the physician forrehabilitation medicine has an important and complementary role.Particularly the specific knowledge of foot disorders and underlying causes,the adaptation to foot disorders and the consequences on daily activities,participation in society and quality of life is the field of expertise ofrehabilitation medicine. The increase in number of patients with DM andsecondary foot complications necessitates organisation of screening andprevention programmes, and revised foot prescription procedures.The diabetic foot syndrome is an important challenge for all of us! The scoresfor PNP as have been developed in this thesis can contribute to tracingpatients at risk. Patient care can be improved by transmural multidisciplinaryattunement and by offering attention to consequences of the diabetic footsyndrome on daily functioning and quality of life of the patients involved. Summary - 131
  • 138. 132 - The diabetic foot syndrome
  • 139. SamenvattingHet diabetische voet syndroom is een invaliderende en frequentvoorkomende lange termijn complicatie van diabetes mellitus (DM). Hetbetreft een verscheidenheid aan afwijkingen van de voeten die ontstaan tengevolge van een combinatie van perifere neuropathie, macro-angiopathie enandere gevolgen van metabole stoornissen. Een klinisch belangrijkemanifestatie van het diabetische voet syndroom is het diabetische voetulcus,dat kan leiden tot een amputatie.De prevalentie van DM in Nederland werd in 1994 geschat op 450.000.Aangezien de ziekte vaak pas laat wordt herkend, is bij ongeveer vijftigprocent van deze patiënten de ziekte niet als zodanig vastgesteld. Vijftien totvijfentwintig procent van alle diabetes patiënten krijgt eens in zijn/haar levente maken met een voetulcus. Het relatief risico op het ondergaan van eenbeenamputatie bedraagt voor de Nederlandse diabetes populatie 20. Voor dediabetes patiënten in de provincie Groningen bedraagt het relatief risico zelfs45. Diabetische voet problemen komen dus veel voor in onze samenleving.Het diabetisch voet syndroom vormt een grote belasting voor zowel depatiënt als voor de gezondheidszorg. Door vroege opsporing, strikte diabetesregulatie, voorlichting betreffende voetverzorging en adequaat schoeisel kanhet aantal ulcera en amputaties worden gereduceerd.Het hoge aantal amputaties bij patiënten met DM in de provincie Groningenillustreert de noodzaak om de zorg voor de diabetische voet in deze regionader te evalueren. De resultaten van deze evaluatie zijn samengevat in ditproefschrift en vormen een stimulans voor de multidisciplinaire aanpak vande diabetische voet in het Academisch Ziekenhuis. Deze dissertatie richt zichop (1) de omvang van het probleem van het diabetische voet syndroom in hetAcademisch Ziekenhuis Groningen, (2) de consequenties op de kwaliteit vanleven, (3) de ontwikkeling van diagnostische tests voor diabetischeneuropathie en (4) de relatie tussen neuropathie en angiopathie bij DM.(1) De omvang van het probleem: de evaluatie van een screening enpreventie programma voor diabetische voet complicaties (hoofdstuk 2).Het optreden van voetcomplicaties ten gevolge van DM kan wordenverminderd door goede preventie. Om een indruk te krijgen van deaanwezigheid van risicofactoren en het toepassen van preventievemaatregelen werd een steekproef genomen van patiënten van de diabetespolikliniek van het Academisch Ziekenhuis Groningen. Vijftig patiënten, nietbekend met voetcomplicaties, werden at random geselecteerd. Deaanwezigheid van risico factoren werd onderzocht met het risico classificatiesysteem van Coleman, de preventieve maatregelen met de Preventieve Samenvatting - 133
  • 140. Maatregelen Schaal. Zestig procent van de patiënten had een verhoogd risicoop het ontwikkelen van een diabetisch voet ulcus. Preventieve maatregelenwerden slechts beperkt toegepast door de patiënten met een verhoogd risico.De kennis van patiënten met betrekking tot preventie was onvoldoende, descore op het gebied van de uitvoering van de preventieve maatregelen in depraktijk was nog slechter dan de score op het gebied van de kennis. Hetschoeisel van de meeste risico patiënten voldeed niet aan de algemenebasisvoorwaarden.(2) De consequenties van de aanwezigheid van diabetische voet ulcera op dekwaliteit van leven (hoofdstuk 3).De invloed van een diabetisch voetulcus op de kwaliteit van leven werdbestudeerd door diabetes patiënten met en zonder ulcera te vergelijken.Veertien patiënten met een klinisch stabiel ulcus of een ulcus in devoorgeschiedenis werden vergeleken met een controle groep van 24 diabetespatiënten zonder ulcera. Het risico profiel werd beoordeeld met behulp vande Nederlandse Diabetische Voet consensus. De kwaliteit van leven werdgescoord met de RAND-36, de Barthel score (ADL) en de vragenlijstLoopvaardigheid. Significante verschillen tussen de 2 groepen werdengevonden op het gebied van het risicoprofiel, op fysiek en sociaalfunctioneren, fysieke rol en ervaren gezondheid met de RAND-36 en met de4 subschalen van de vragenlijst Loopvaardigheid. Op al deze schalen was dekwaliteit van leven significant slechter in de groep met voetulcera. Er werdeen significante correlatie gevonden tussen het risico profiel en de kwaliteitvan leven, met name op het gebied van het fysiek functioneren en de fysiekerol van de RAND-36 en de vragenlijst Loopvaardigheid. De aanwezigheidvan een klinisch stabiel ulcus of een ulcus in de voorgeschiedenis heeft duseen grote invloed op de fysieke rol, het fysiek functioneren en op deloopvaardigheid. Met name fysieke stoornissen beïnvloeden de kwaliteit vanleven. De kwaliteit van leven kan worden verbeterd door advies te geven overmogelijke voorzieningen en aanpassingen om dit te compenseren.(3) De diagnostiek van neuropathie.(A) anamnese- en onderzoeksschalen.Distale polyneuropathie (PNP) is de belangrijkste risico factor voor hetdiabetische voet syndroom. Er bestaan diverse anamnese- enonderzoeksschalen voor PNP. De algemeen geaccepteerde NeuropathySymptom Score (NSS) (17 items) en de Neurological Disability Score (NDS)(35 items) zijn beide gevalideerd. Deze schalen zijn echter omvangrijk,omdat ze bedoeld zijn voor diagnostiek van neuropathie in het algemeen enniet specifiek voor distale symmetrische PNP. Aangezien grote aantallenpatiënten regelmatig gescreend moeten worden op aanwezigheid van PNP, ishet van belang om valide, eenvoudig toepasbare en goed voorspellende134 - The diabetic foot syndrome
  • 141. schalen te hebben in de praktijk. Daarom werden een eenvoudige anamnese-en onderzoeksschaal ontwikkeld: de Diabetic Neuropathy Symptom (DNS)score en de Diabetic Neuropathy Examination (DNE) score.De Diabetic Neuropathy Symptom (DNS) score (hoofdstuk 4).In een groep van drieënzeventig diabetes patiënten werden dekarakteristieken van de NSS en de DNS-score vergeleken. Om de DNS-scorete valideren voor de diagnostiek van distale diabetische PNP, werden deconstruct validiteit, voorspellende waarde en de reproduceerbaarheidonderzocht met de DNE-score, monofilamenten en de vibratiezin(Biothesiometer) als klinische standaarden. De correlatie tussen de NSS en deDNS-score was hoog. De correlatie van respectievelijk de NSS en de DNS-score, met de klinische standaarden was goed. Beide scores hadden eenvergelijkbare voorspellende waarde. De reproduceerbaarheid van de DNS-score was goed. De DNS-score blijkt een valide en betrouwbare anamneseschaal te zijn voor diabetische PNP. Bovendien is de DNS-score snel eneenvoudig uit te voeren in de praktijk. Daarom heeft de DNS-score voordagelijks gebruik de voorkeur boven de uitgebreide NSS score.De Diabetic Neuropathy Examination (DNE) score (hoofdstuk 5).De NDS is ontwikkeld voor het vaststellen van neuropathie in het algemeen.Drieënzeventig diabetes patiënten werden onderzocht met monofilamentenen vibratiezin (Biothesiometer) als klinische standaarden voor PNP. Tevenswerd de NDS uitgevoerd. Items van de NDS werden geselecteerd opklinische relevantie (positief gescoord in > 3 patiënten). Zo ontstond deDNE-score met 8 items. De DNE- score voorspelde de resultaten van deklinische standaarden adequaat en bleek sterk hiërarchisch te zijn. Bij eenafkappunt van 3 versus 4 waren de sensitiviteit en specificiteit van de DNE-score hoog voor abnormale monofilament scores en voor de vibratiezin. Dereproduceerbaarheid, zowel inter- als intraobserver, was goed. De DNE-scoreis een sensitieve en gevalideerde hiërarchische onderzoeksschaal voor PNPdie snel en eenvoudig uitvoerbaar is in de dagelijkse praktijk.(B) De relatie tussen de DNS- en DNE-score en cardiovasculaire AutonomeFunctie Tests en Electro Diagnostische Studies (hoofdstuk 6).Het differentiërend vermogen van de DNS- en DNE-score voor deaanwezigheid van PNP en de relatie van deze scores met respectievelijkcardiovasculaire Autonome Functie Tests (cAFT) en Electro DiagnostischeStudies (EDS) werd geëvalueerd met drie vergelijkbare groepen: 24 diabetespatiënten met neuropathische voetulcera (diabetes ulcus groep), 24 diabetespatiënten zonder neuropathie of ulcera (diabetes controle groep) en 21controle personen zonder DM. Bij alle deelnemers werd de DNS- en DNE-score afgenomen, evenals cAFT (Heart Rate Variability (HRV) en Baro Samenvatting - 135
  • 142. Reflex Sensitivity (BRS)) en EDS (nerve conduction sum (NCS) score enmuscle fiber conduction velocity (MFCV): fastest/slowest ratio (F/S ratio)).De resultaten bevestigden de kracht van de DNS- en DNE-score in dediagnostiek van diabetische PNP in de praktijk. Beide scores waren in staatom te differentiëren tussen patiënten met en zonder PNP en waren sterkgecorreleerd aan cAFT en EDS, als harde parameters voor neuropathie.Zowel de DNS- als de DNE-score konden significant onderscheid makentussen de diabetes ulcus en de diabetes controle groep, de DNE-score liet ookeen duidelijk verschil zien tussen de diabetes controle groep en de controlegroep zonder diabetes. De correlatie van de DNS- en de DNE-score washoger met HRV dan met de BRS met betrekking tot cAFT. Een hogecorrelatie voor DNS- en DNE score werd gevonden met EDS, voor zowel deMFCV als de NCS. Hoge Odds ratios werden gevonden voor zowel de DNS-als de DNE-score met HRV, BRS, MFCV en NCS.(4) De relatie tussen neuropathie en angiopathie bij diabetes mellitus.(A) Gaat diabetische PNP vooraf aan aanwezigheid van microangiopathie(hoofdstuk 7)?Diabetische PNP wordt verondersteld primair een probleem van desensorische zenuwen te zijn. Microangiopathie wordt gezien als debelangrijkste pathogenetische factor voor het ontstaan van PNP. De volgendehypothesen werden bestudeerd: (1) PNP is aanwezig voordat micro- ofmacroangiopathie aantoonbaar is, en (2) sensorische en motorischestoornissen treden gelijktijdig op bij patiënten met DM. Twaalf mannelijkepatiënten zonder aanwijzingen voor micro- of macroangiopathie werdenbestudeerd met de DNS- en DNE-score, dynamometrie en zenuw- enspiervezelgeleidingsonderzoek. De sensibele zenuwgeleiding van de n.suralis was afwijkend bij zes patiënten. De spiervezelgeleidingssnelheid vande m. tibialis anterior was gestoord bij zes patiënten, vijf van deze zespatiënten hadden ook een afwijkende sensibele zenuwgeleiding.De helft van de proefpersonen had een combinatie van sensibele enmotorische afwijkingen. Dit steunt de hypothese dat sensibele en motorischeafwijkingen aan de zenuwen bij vroege diabetische PNP gelijktijdig ontstaanen niet na elkaar, voordat op andere wijze klinische micro- ofmacroangiopathie waarneembaar is.(B) Vormen Cardiovasculaire Autonome Neuropathie scores een afspiegelingvan microangiopathie of van diabetische PNP (Hoofdstuk 8)?De autonome functie tests volgens Ewing (Ewing batterij), korte termijn hartfrequentie variabiliteit (heart rate variability HRV) en baroreflexgevoeligheid (baroreflex sensitivity BRS) zijn vormen van testen voorCardiovasculaire Autonome Neuropathie (CAN). CAN testen wordenaanbevolen als een van de diagnostische categorieën voor diabetische PNP.136 - The diabetic foot syndrome
  • 143. Toch rijst de vraag of deze testen wel PNP vaststellen. Bij vijfenveertigdiabetes patiënten werden de CAN testen vergeleken met testen voor (1)PNP: de DNS- en DNE-score, monofilamenten en vibratiezin, (2)macroangiopathie: enkel en teen/arm index en (3) microangiopathie: laserdopplerflow (LDF) metingen aan de voet. Een zwakke relatie werd gevondentussen de Ewing tests en monofilamenten en vibratiezin, deze relatie bleekechter na correctie voor de leeftijd niet significant. Er werd geen significanterelatie tussen de Ewing tests en de DNS- en DNE-scores gevonden. Decorrelatie tussen HRV en respectievelijk de DNE-score, monofilamenten envibratiezin was significant, ook na leeftijdscorrectie. De BRS was nietgerelateerd aan testen voor PNP. Er werd geen correlatie gevonden tussen deCAN tests en de testen voor macroangiopathie. Er was wel een significanterelatie aanwezig tussen HRV en de LDF, als maat voor microangiopathie.CAN testen blijken dus gerelateerd te zijn aan microcirculatoire stoornissenen aan klinische testen voor PNP (monofilamenten, vibratiezin en DNE-score) en nog minder aan de DNS-score. De CAN testen lijken hiermeezowel een uiting te zijn van algemene microangiopathie als van specifiekediabetische PNP.Discussie.Door ontwikkeling van de gevalideerde DNS- en DNE-score zijn eenvoudiguitvoerbare, betrouwbare instrumenten beschikbaar gekomen voor dediagnostiek van diabetische PNP in de dagelijkse praktijk. De scores kunnenworden gebruikt voor screening en evaluatie, zowel in de 1e lijn, als indiabetes en neurologische (poli)klinieken. De scores kunnen zowel doormedici, als door verpleegkundigen en paramedici worden afgenomen. Deuitvoering is gestandaardiseerd.Er is nog steeds onduidelijkheid over de meest betrouwbare combinatie voorde diagnostiek van diabetische PNP. In 1988 werd in de San Antonioconsensus voorgesteld om 5 verschillende diagnostische categorieëncomplementair te gebruiken. Tot nu toe zijn er geen harde bewijzen dat eenbeperktere combinatie van onderzoeken gerechtvaardigd is. Indien te veellage afkappunten gebruikt worden, bestaat echter het risico datoverdiagnostiek plaats vindt. Dit onderwerp wordt bediscussieerd inhoofdstuk 6. Toekomstig onderzoek dient zich te richten op de ontwikkelingvan een optimale set van diagnostische tests voor diabetische PNP.In de multidisciplinaire zorg voor de diabetische voet heeft de revalidatieartseen belangrijke rol. De revalidatiearts heeft specifieke kennis vanvoetafwijkingen en de daaraan ten grondslag liggende problematiek. Metname ook de aanpassing bij voetafwijkingen en de consequenties opdagelijkse activiteiten, maatschappelijke participatie en kwaliteit van levenbehoren tot de specifieke expertise van de revalidatiearts. Samenvatting - 137
  • 144. De toename van het aantal mensen met DM en secundaire voetcomplicatiesvraagt aanpassing van de organisatie van screening en preventie programmasen herziening van procedures voor bijvoorbeeld het voorschrijven vanschoenen.Preventie van het diabetische voet syndroom vormt een belangrijke uitdagingvoor ons allen! De in dit proefschrift ontwikkelde schalen voor PNP kunneneen bijdrage leveren aan de opsporing van patiënten met een verhoogd risico.De zorg kan verder verbeterd worden door multidisciplinaire samenwerkingen bundeling van krachten in een transmuraal netwerk en door aandacht tebesteden aan de gevolgen van het diabetische voet syndroom op het dagelijksfunctioneren en de kwaliteit van leven.138 - The diabetic foot syndrome
  • 145. Northern Centre for Healthcare Research (NCH) and previousdissertations The Northern Centre for Healthcare Research (NCH) was founded in1986 as a research institute of the University of Groningen (RUG), TheNetherlands. Researchers from both the Medical and Social Faculty, withvarious professional backgrounds, are members of the NCH. These includemedical sociologists, medical doctors, psychologists and human movementscientists. Research of the NCH is aimed at optimising quality of life ofpatients and quality of healthcare, and focuses on (a) determinants of healthand illness, (b) consequences of illness, (c) the effects of medical treatmentand decision making, and (d) the evaluation of health services and varioustypes of interventions. At the time that this thesis is published, the NCHcomprises five research programmes. Until 1998, the NCH covered two research programmes, i.e.Determinants of Health and Medical Decision Making and Evaluation ofHealthcare. The first programme was reformulated in 1996 and wascontinued as Disorder, Disability and Quality of Life (DDQ). Hence,previous dissertations in this area are listed as part of the present DDQ-programme. The second programme was subdivided in 1998 into two newprogrammes, i.e. Public Health and Public Health Services Research andRational Drug Use. Dissertations published earlier within the second programme are listedretrospectively under these new headings. In 1998, two new programmes,The Outcome and Evaluation of Interventions in Patients with MotorProblems and Process and Effects of Movement Programs, were formulatedand officially integrated in the NCH in January 1999. The accomplisheddissertations since the start of the programmes in 1998 are included in the list.In 2000 the Department of General Practice joined the NCH and togetherwith the Rational Drug Use group initiated a new research programme, i.e.Implementation of Evidence Based Medicine in the Medical Practice. More information regarding the institute and its research can beobtained from our internet site: http://www.med.rug.nl/nchDisorder, Disability and Quality of LifeSchroevers MJ (2002) Short- and long-term adaptation to cancer; a comparison of patients with the general population. PROMOTOR: prof dr R SandermanHoekstra-Weebers JEHM (2000) Parental adaptation to pediatric cancer. PROMOTORES: prof dr EC Klip, prof dr WA Kamps. REFERENT: dr JPC JaspersDoeglas DM (2000) Functional ability, social support and quality of life: a longitudinal study in patients with early rheumatoid arthritis. PROMOTORES: prof dr WJA van den Heuvel, prof dr R Sanderman. CO-PROMOTOR: dr ThPBM Suurmeijer 139
  • 146. Nijboer C (2000) Caregiving to patients with colorectal cancer: a longitudinal study on caregiving by partners. PROMOTORES: prof dr GAM van den Bos, prof dr R Sanderman CO-PROMOTOR: dr AHM TriemstraTiesinga LJ (1999) Fatigue and Exertion Fatigue: from description through validation to application of the Dutch Fatigue Scale (DUFS) and the Dutch Exertion Fatigue Scale (DEFS). PROMOTORES: prof dr WJA van den Heuvel, prof dr ThWN Dassen. CO-PROMOTOR: dr RJG HalfensJong GM de (1999) Stress, stress management and issues regarding implementation. PROMOTORES: prof dr PMG Emmelkamp, prof dr JL Peschar. REFERENT: dr R SandermanAlberts JF (1998) The professionalized patient: sociocultural determinants of health services utilization. PROMOTOR: prof dr WJA van den Heuvel. REFERENT: dr R SandermanEijk LM van (1997) Activity and well-being in the elderly. PROMOTORES: prof dr WJA van den Heuvel, prof dr SM Lindenberg. REFERENT: dr GIJM KempenNieboer AP (1997) Life-events and well-being: a prospective study on changes in well- being of elderly people due to a serious illness event or death of the spouse. PROMOTORES: prof dr SM Lindenberg, prof dr J OrmelScaf-Klomp W (1997) Screening for breast cancer: attendance and psychological consequences. PROMOTOR: prof dr WJA van den Heuvel. REFERENT: dr R SandermanZwanikken CP (1997) Multiple sclerose: epidemiologie en kwaliteit van leven. PROMOTOR: prof dr J Minderhoud. CO-PROMOTORES: dr JW Groothoff, dr ThPBM SuurmeijerKooiker SE (1996) Illness in everyday life: a health diary study of common symptoms and theirconsequences. PROMOTORES: prof dr WJA van den Heuvel, prof dr J van der ZeeKrol B (1996) Quality of life in rheumatoid arthritis patients: the relation between personality, social support and depression. PROMOTOR: prof dr WJA van den Heuvel. REFERENTEN: dr R Sanderman, dr ThPBM SuurmeijerRuiter JH de (1995) Sociale ondersteuning en kwaliteit van leven bij patiënten met kanker. PROMOTORES: prof dr WJA van den Heuvel, prof dr H Schraffordt Koops. REFERENTEN: dr FLP van Sonderen, dr R SandermanSteverink N (1995) Zo lang mogelijk zelfstandig: naar een verklaring van verschillen ten aanzien van opname in een verzorgingstehuis onder fysiek kwetsbare ouderen. PROMOTORES: prof dr WJA van den Heuvel, prof dr TAB Snijders, prof dr J OrmelUitenbroek DG (1995) Exercise behaviour. PROMOTOR: prof dr WJA van den HeuvelLinden-van den Heuvell GFEC van (1994) Voorbereiding op medische ingrepen. PROMOTOR: prof dr EC KlipLinschoten CP van (1994) Gezondheidsbeleving van ouderen: een Iongitudinale studie. PROMOTOR: prof dr WJA van den Heuvel. CO-PROMOTOR: dr J Ormel140
  • 147. Oosterhuis A (1994) De gedragstherapeutische behandeling van slaapklachten. PROMOTOR: prof dr EC KlipRanchor AV (1994) Social class, psychosocial factors and disease: from description towards explanation. PROMOTORES: prof dr WJA van den Heuvel, prof dr AP Buunk. REFERENTEN: dr R Sanderman, dr J BoumaReitsma B (1994) The end of the line? Evaluation of a multidisciplinary team approach to chronic pain. PROMOTORES: prof dr EC Klip, prof dr JWF Beks, prof dr JP HennisGerritsen JC (1993) Onafhankelijkheid van ouderen: mogelijkheden en voorwaarden. PROMOTOR: prof dr WJA van den HeuvelHeyink JW (1992) Levertransplantatie: psycho-sociale aspecten. PROMOTORES: prof dr WJA van den Heuvel, prof dr MJH Slooff. REFERENT: dr Tj TijmstraSonderen FLP van (1991) Het meten van sociale steun. PROMOTORES: prof dr WJA van den Heuvel, prof dr FN Stokman. REFERENT: dr J OrmelKempen GIJM (1990) Thuiszorg voor ouderen: een onderzoek naar de individuele determinanten van het gebruik van wijkverpleging en/of gezinsverzorging op verzorgend en huishoudelijk gebied. PROMOTORES: prof dr WJA van den Heuvel, prof dr W Molenaar. REFERENT: dr ThPBM SuurmeijerSanderman R (1988) Life events, mediating variables and psychological distress: a longitudinal study. PROMOTORES: prof dr WJA van den Heuvel, prof dr PE Boeke, prof dr PMG Emmelkamp. REFERENT: dr J OrmelPublic Health and Public Health Services ResearchHoekstra EJ (2002) Arbeidsbemiddeling met behulp van Supported Employment als interventie bij de reïntegratie van chronisch zieken; de rol van de arbeidsbemiddelaar, chronisch zieke en werkgever. PROMOTORES: prof dr JW Groothoff, prof dr K Sanders, prof dr WJA van den Heuvel, prof dr D PostEnk, JG van (2002) Determinants of use of healthcare services in childhood. PROMOTORES: prof dr D Post, prof dr AJP Veerman, prof dr WJA van den HeuvelLege W de (2002) Medische consumptie in de huisartspraktijk op Urk PROMOTORES: prof dr D Post, prof dr JW GroothoffGecková A (2002) Inequality in health among Slovak adolescents. PROMOTORES: prof dr D Post, prof dr JW GroothoffDijk JP van (2001) Gemeentelijk gezondheidsbeleid; omvang en doelgerichtheid. PROMOTORES: prof dr D Post, prof dr M Herweijer, prof dr JW GroothoffMiddel LJ (2001) Assessment of change in clinical evaluation PROMOTOR: prof dr WJA van den Heuvel. REFERENT: dr MJL de JongsteBijsterveld HJ (2001) Het ouderenperspectief op thuiszorg; wensen en behoeften van ouderen ten aanzien van de thuis(zorg)situatie in Friesland PROMOTORES: prof dr D Post, prof dr B Meyboom-de Jong. REFERENT: dr J Greidanus 141
  • 148. Dijkstra GJ (2001) De indicatiestelling voor verzorgingshuizen en verpleeghuizen. PROMOTORES: prof dr D Post, prof dr JW GroothoffBeltman H (2001) Buigen of barsten? Hoofdstukken uit de geschiedenis van de zorg aan mensen met een verstandelijke handicap in Nederland 1945-2000. PROMOTORES: prof dr D Post, prof dr AThG van GennepDalen IV van (2001) Second opinions in orhopaedic surgery: extent, motives, and consequences. PROMOTORES: prof dr JR van Horn, prof dr PP Groenewegen, prof dr JW GroothoffPal TM (2001) Humidifiers disease in synthetic fiber plants: an occupational health study. PROMOTORES: prof dr JGR de Monchy, prof dr D Post, prof dr JW GroothoffGoossen WTF (2000) Towards strategic use of nursing information in the Netherlands. PROMOTORES: prof dr WJA van den Heuvel, prof dr ThWN Dassen, prof dr ir A HasmanHospers JJ (1999) Allergy and airway hyperresponsiveness: risk factors for mortality. PROMOTORES: prof dr D Post, prof dr DS Postma, prof dr ST WeissWijk P van der (1999) Economics: Charon of Medicine? PROMOTORES: prof dr WJA van den Heuvel, prof dr L Koopmans, prof dr FFH Rutten. REFERENT: dr J BoumaDijkstra A (1998) Care dependency: an assessment instrument for use in long-term care facilities. PROMOTORES: prof dr WJA van den Heuvel, prof dr ThWN DassenTuinstra J (1998) Health in adolescence: an empirical study of social inequality in health, health risk behaviour and decision making styles. PROMOTORES: prof dr D Post, prof dr WJA van den Heuvel. CO-PROMOTOR: dr JW GroothoffMink van der Molen AB (1997) Carpale letsels: onderzoek naar de verzuimaspecten ten gevolge van carpale letsels in Nederland 1990-1993. PROMOTORES: prof dr PH Robinson, prof WH Eisma. CO-PROMOTOR: dr JW Groothoff. REFERENT: dr GJP VisserMulder HC (1996) Het medisch kunnen: technieken, keuze en zeggenschap in de moderne geneeskunde. PROMOTOR: prof dr WJA van den HeuvelDekker GF (1995) Rugklachten-management-programma bij de Nederlandse Aardolie Maatschappij B.V.: ontwerp, uitvoering en evaluatie. PROMOTORES: prof dr D Post, prof WH Eisma. CO-PROMOTOR: dr JW GroothoffPuttiger PHJ (1994) De medische keuring bij gebruik van persluchtmaskers. PROMOTORES: prof dr D Post,prof dr WJA Goedhard. CO-PROMOTOR: dr JW GroothoffEngelsman C & Geertsma A (1994) De kwaliteit van verwijzingen. PROMOTORES: prof dr WJA van den Heuvel, prof dr FM Haaijer-Ruskamp, prof dr B Meyboom-de JongLucht F van der (1992) Sociale ongelijkheid en gezondheid bij kinderen. PROMOTOR: prof dr WJA van den Heuvel. REFERENT: dr JW Groothoff142
  • 149. Implementation of Evidence Based Medicine in the Medical PracticePont LG (2002) Assessing the quality of prscribing in general practice. PROMOTORES: prof dr FM Haaijer-Ruskamp, prof dr WH van Gilst, prof dr T van der MolenBemelmans WJE (2001) Prevention of coronary heart disease by nutritional interventions. Impact of nutritional education in groups and supplementation with alpha-linolenic acid. PROMOTOR: prof dr B Meyboom-de Jong. CO-PROMOTOR: dr JF May REFERENTEN: dr J Broer, dr EJM Feskens, dr FW Siero, dr AJ SmitVeninga CCM (2000) Improving prescribing in general practice. PROMOTOR: prof dr FM Haaijer-Ruskamp.REFERENT: dr P DenigVeehof LJG (1999) Polypharmacy in the elderly. PROMOTORES: prof dr B Meyboom-de Jong, prof dr FM Haaijer-RuskampVries SO de (1998) Management strategies for intermittent claudication. PROMOTOR: prof dr MGM Hunink. REFERENT: dr JB WongBosch JL (1997) Outcome assessment of the percutaneous treatment of lilac artery occlusive disease. PROMOTORES: prof dr MGM Hunink, prof dr WPThM Mall, prof dr L KoopmansDijkers FW (1997) Repeat prescriptions: a study in general practice in the Netherlands. PROMOTORES: prof dr B Meyboom-de Jong, prof dr FM Haaijer-Ruskamp, prof dr AF CasparieTrigt AM van (1995) Making news about medicines. PROMOTORES: prof dr TFJ Tromp, prof dr FM Haaijer-RuskampBoerkamp E (1995) Assessing professional services quality: an application in health care. PROMOTORES: prof dr JC Reuijl, prof dr FM Haaijer-RuskampDenig P (1994) Drug choice in medical practice: rationals, routines, and remedies. PROMOTORES: prof dr FM Haaijer-Ruskamp, prof dr H WesselingJong-van den Berg LTW de (1992) Drug utilization studies in pregnancy: what can they contribute to safety assessment? PROMOTORES: prof dr MNG Dukes, prof dr H Wesseling. REFERENT: dr FM Haaijer-RuskampZijlstra IF (1991) De regionaal klinisch farmacoloog. PROMOTORES: prof dr H Wesseling, prof dr FWJ Gribnau, prof dr C van Weel. REFERENTEN: dr FM Haaijer-Ruskamp, dr H WollersheimThe Outcome and Evaluation of Interventions in Patients with MotorProblems (from 1998 onwards)Rommers GM (2000) The elderly amputee: rehabilitation and functional outcome. PROMOTOR: prof WH Eisma. CO-PROMOTOR: dr JW GroothoffHalbertsma JPK (1999) Short hamstrings & stretching: a study of muscle elasticity. PROMOTORES: prof WH Eisma, prof dr LNH Göeken. CO-PROMOTOR: dr JW Groothoff. REFERENT: dr ir AL HofGeertzen JHB (1998) Reflex sympathetic dystrophy: a study in the perspective of rehabilitation medicine. PROMOTORES: prof WH Eisma, prof dr HJ ten Duis. CO-PROMOTOR: dr JW Groothoff. REFERENT: dr PU Dijkstra 143
  • 150. Sluis CK van der (1998) Outcomes of major trauma. PROMOTORES: prof dr HJ ten Duis, prof WH EismaProcess and Effects of Movement Programs (from 1998 onwards)Kamsma YPT (2002) Functional Reorganisation of basic motor actions in Parkinson’s disease. Problem analysis, development and evaluation of a compensatory strategy training. PROMOTORES: prof dr P Rispens, prof dr WH BrouwerStevens M (2001) Groningen Active Living Model (GALM): development and initial validation. PROMOTOR: prof dr P Rispens. REFERENTEN: dr KAPM Lemmink, dr MHG de GreefLettinga AT (2000) Diversity in neurological physiotherapy: a comparative analysis of clinical and scientific practices. PROMOTORES: prof dr P Rispens, prof dr PJM Helders, prof dr A MolHeuvelen MJG van (1999) Physical activity, physical fitness and disability in older persons. PROMOTOR: prof dr P Rispens. CO-PROMOTORES: dr WH Brouwer, dr GIJM Kempen. REFERENT: dr MHG de GreefBerkhuysen MA (1999) Toward tailor-made cardiac rehabilitation: getting at the heart of the matters. PROMOTORES: prof dr AP Buunk, prof dr P Rispens. REFERENT: dr R Sanderman144
  • 151. Dankwoord
  • 152. 146
  • 153. Stap voor stap heb ik de voetproblemen bij diabetes mellitus onderzocht,zoals mooi weergegeven op de omslag door Roeland. Negen jaar lang heefthet geduurd en ik ben blij dat het karwei geklaard is.Door stap voor stap dit enorme project aan te pakken bleef het overzichtelijken leuk. Het begon als onderzoek in het kader van mijn opleiding totrevalidatiearts. Na enkele omzwervingen kwam ik terug op het onderwerpvan mijn wetenschappelijke stage voor het artsexamen, uitgevoerd op deAfdeling Interne Geneeskunde van het UMC St. Radboud. Onder begeleidingvan Dr. C.J.J. Tack en Prof. dr. J.A. Lutterman onderzocht ik detoepasbaarheid van de Neurometer in de diagnostiek van diabetischeneuropathie. De complexe voetproblematiek bij diabetes mellitus met deernstige gevolgen voor de betrokken patiënt intrigeerde mij. Ik besloot meverder te verdiepen in de diagnostiek en de consequenties van de diabetischevoet.Het verrichten van een promotie onderzoek is een omvangrijke klus. Depromovendus is de spin in het web die alle lijntjes strak houdt, de contactenlegt en coördineert, daarbij ondersteund door zijn achterban. Veel mensenzijn bij mijn onderzoek betrokken geweest. Alle patiënten, collegas, vriendenen familieleden die hun medewerking hebben verleend wil ik bedanken voorhun bijdrage.Professor Eisma, beste Willem, jij bent als mijn opleider en eerste promotorvanaf het begin betrokken geweest bij dit onderzoek. Ik waardeer je inzet enstimulans voor opleiding en onderzoek. Mede dankzij de familiaire sfeer dieer op jouw afdeling heerste, kijk ik met veel plezier terug op mijnopleidingstijd en de periode daarna. Willem, mijn hartelijke dank!Nadat de keuze voor onderzoek naar de diabetische voet was gemaaktwerden via Prof. dr. W.D. Reitsma afspraken gemaakt met Dr. T.P. Links enDr. A.J. Smit.Prof. dr. H.J.G.H. Oosterhuis werd gevraagd mee te denken in de eersteopzet. Helaas heeft Professor Oosterhuis de afronding van ditpromotieonderzoek niet meer mee mogen maken, ik ben hem veel dankverschuldigd voor de uiterst kritische beoordeling van het protocol voor deontwikkeling van een diagnostische test voor diabetische polyneuropathie.Zonder mijn co-promotores Dr. T.P. Links en Dr. A.J. Smit was dit projectzeker nooit afgerond. Telkens weer slaagden zij erin mij te stimuleren enenthousiast te maken. Vele versies gingen er door hun handen, keer op keerontving ik razendsnel zeer waardevol commentaar en nieuwe stof tot 147
  • 154. nadenken. Het proefschrift heeft hierdoor extra kwaliteit en diepganggekregen.Dr. T.P. Links, beste Thera, heel hartelijk dank voor al je hulp. Hoe druk jehet ook had, ik vond altijd een luisterend oor. Dankzij de goede contacten dieje hebt met je patiënten, wist je ze altijd weer te motiveren tot deelname ineen van onze projecten. Ik bewonder je enorme energie en inzet. Het was heelinspirerend om met je samen te werken.Dr. A.J. Smit, beste Andries. Tijdens de discussies van Thera en mij zat jijrustig na te denken. Gaandeweg leerde ik dat van jou kennen en wist ik datwe op een gegeven moment even stil moesten zijn. En dan kwam jouwbriljante idee. Meestal waren we dan in een keer klaar en kon ik het verderuitwerken. Andries, bedankt voor alle hulp en ondersteuning.Mijn tweede promotor is Prof. Dr. J.W. Groothoff. Beste Johan, ik ben jeerkentelijk voor de methodologische ondersteuning, het bewaken van de rodedraad en het inperken van het project. Als er weer eens iemand enthousiastaan tafel riep "dat kunnen we ook wel leuk even meenemen" was jij degenedie mij, soms tegen mezelf, in bescherming nam door af te perken wat wewilden.Leden van de begeleidingsgroep, Thera, Willem, Johan en Andries, ik zal deafspraken missen die we elk kwartaal hadden. Onder het genot van gebak, tercompensatie van de stapels rondgezonden leeswerk, hadden we het, naast dezeer vruchtbare discussies, ook heel gezellig samen.Het personeel van de Diabetes Polikliniek, het Vaatlab van de afdelingInterne Geneeskunde en de afdeling Klinische Neurofysiologie van hetAcademisch Ziekenhuis Groningen bedank ik voor de medewerking.Het team en de teamleiding van het Diabetes team Beatrixoord bedank ikvoor de genoten gastvrijheid en het enthousiasme.Bij de uitvoering van de reproduceerbaarheidsstudie werd ik geholpen doorE.E.E. Blauwwiekel. Beste Eddie, mijn hartelijk dank.J. Trip en Dr. S.M.H.J. Scholten-Jaegers, beste Jeroen en Sonja, bedankt voorjullie hulp bij de studie naar de kwaliteit van leven.J.D. Lefrandt en Dr. A.K.L. Oei-Reinders, Joop en An, bedankt voor julliehulp bij het verrichten en bewerken van de autonome functie tests.F. Lange en Dr. J.H. van der Hoeven, Fiete en Han, ik ben jullie veel dankverschuldigd voor de adviezen en de uitvoering van de neurofysiologischemetingen.E. Bosma en Dr. K. Hoogenberg, beste Eelke en Klaas, hartelijk bedanktvoor de samenwerking en de toepassing van de door ons ontwikkelde scoresin jullie onderzoek.148
  • 155. Het Noordelijk Centrum voor Gezondheidsvraagstukken bood mijmethodologische en statistische ondersteuning. Ik wil hier met nameR.E. Stewart en Dr. E. van Sonderen bedanken voor de tijd en het geduld omde data toch maar weer net even anders te bewerken en steeds weer opnieuwuitleg te geven over de gebruikte technieken. Roy en Eric, bedankt!De agios en stafleden van het Circuit voor Revalidatie, locaties A.Z.G. enBeatrixoord, wil ik hartelijk bedanken voor de collegialiteit. Op allerleimanieren heb ik met jullie samen gewerkt, eerst als agio, later als collegastaflid en supervisor in Beatrixoord. De gezellige contacten en gezamenlijkeuitstapjes, cursussen en congressen hebben de Groningse tijd voor dezezuiderling onvergetelijk gemaakt. Met name Dineke Mulder, Rita SchiphorstPreuper, Marleen Schönherr, Mitzy Reinders en Luc Vos wil ik persoonlijkbedanken voor de waarneming van mijn afdeling op de studiedagen.De leden van het CVA-team van Beatrixoord, waar ik 4.5 jaar met heel veelplezier heb gewerkt, dank ik voor de fantastische tijd. Ik heb veel van julliegeleerd. B. Feringa en M. Franssen, Betty en Marjan, heel hartelijk dank voorde samenwerking en steun die ik mocht ervaren.Prof. dr. J.H. Arendzen, beste Hans, hartelijk dank dat je deel hebt uit willenmaken van de Beoordelingscommissie. Bedankt voor je vertrouwen en voorhet faciliteren van het onderzoek in de periode dat ik staflid was inBeatrixoord. Ik heb veel van je geleerd.Prof. Dr. R.O.B. Gans en Prof. Dr. J.A. Lutterman, hartelijk dank voor devlotte beoordeling van het manuscript.De vakgroep Revalidatiegeneeskunde, het management en het personeel vanhet Revalidatiecentrum Tolbrug dank ik hartelijk voor de gebodenondersteuning bij de afronding van het proefschrift. We zullen ons nu gaanwijden aan het opzetten van nieuwe projecten, in samenwerking met deNijmeegse collegas.H.R. Schiphorst Preuper en F. de Laat, beste Rita en Fred, ik ben heel blij datjullie mijn paranimfen willen zijn. Rita, ik kijk met veel plezier terug op onzesamenwerking in Beatrixoord. Bedankt voor de gezelligheid en collegialiteit.En nu verder in Den Bosch, hè Fred.Veel dank en waardering gaat uit naar de vele bereidwillige patiënten die deelhebben genomen aan de verschillende projecten. Belangeloos waren zijbereid om nog eens extra naar het ziekenhuis te komen, zodat wij onzemetingen konden verrichten. Bedankt! 149
  • 156. Een speciaal woord van dank wil ik hier plaatsen voor mijn ouders. Bedanktvoor alle steun en interesse en voor het bieden van de mogelijkheid om tedoen wat ik graag wilde.Lieve Roeland, Christiaan en Miriam, jullie zijn het belangrijkste in mijnleven. Ondanks dat papa naast dokter nu ook nog schrijver was geworden(volgens Roeland), genieten we gelukkig veel van en met elkaar.Roeland en Christiaan, jullie liefde, enthousiasme en fantasie vormen voormij de beste ontspanning. Bedankt voor de mooie tekeningen voor de omslag,ons volgende gezamenlijke boek zal wel over ridders en piraten gaan denk ik.Lieve Miriam, hartelijk dank voor de onvoorwaardelijke steun. Bij alle drukteen veranderingen hield jij het hoofd koel en vormde de stabiele basis voor jedrie mannen. Bedankt voor alles.En dan begin ik nu aan de periode "na het boekje" …150
  • 157. Curriculum vitaeJan-Willem Meijer werd geboren op 21 januari 1966 te Hulst. In 1984behaalde hij aan het Rivendell College te Uden zijn eindexamen V.W.O. enving hij aan met de studie Geneeskunde aan de Katholieke UniversiteitNijmegen. Als wetenschappelijk keuzeproject werd op de afdeling InterneGeneeskunde van het UMC St. Radboud onderzoek verricht getiteld "deNeurometer: een aanwinst voor de diagnostiek van diabetische neuropathie?".Het artsexamen behaalde hij op 3 mei 1991.Op 1 mei 1991 startte hij als AGNIO reumatologie in het ZiekenhuisRijnstate te Arnhem. Vervolgens was hij vanaf 1 mei 1992 werkzaam alsAGNIO neurologie en cardiologie in het Ziekenhuis Gelderse Vallei te Ede.Van 1 mei 1993 tot 1 mei 1997 volgde hij zijn opleiding tot revalidatiearts inhet Opleidingscircuit Groningen (opleider Prof. drs. W.H. Eisma). In dezeperiode is het in dit proefschrift gebundelde onderzoek naar het diabetischevoet syndroom gestart en was hij betrokken bij de oprichting van deDiabetische Voet werkgroep in het Academisch Ziekenhuis Groningen.Na zijn opleiding was hij gedurende 4½ werkzaam als revalidatiearts in hetRevalidatiecentrum Beatrixoord. Sinds 1 november 2001 werkt hij in hetRevalidatiecentrum Tolbrug, onderdeel van het Jeroen Bosch Ziekenhuis tes-Hertogenbosch. Zijn interessegebieden vormen de neurorevalidatie en deproblematiek van de voet.Hij is getrouwd met Miriam van Kalmthout. Zij hebben twee zonen,Roeland en Christiaan. 151

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