Clinical Diagnosis of Diabetic.pdf

7/30/2019 Clinical Diagnosis of Diabetic.pdf

1/5

Clinical Diagnosis of DiabeticPolyneuropathy With the DiabeticNeuropathy Symptom and DiabeticNeuropathy Examination Scores JAN-W ILLEM G. M EIJER , MD, PHD 1,2

EELKE BOSMA , MD 3

JOHAN D. L EFRANDT , MD 3

THERA P. L INKS , MD, PHD 4

ANDRIES J. S MIT , MD, PHD 3

ROY E. STEWART 2

JOHANNES H. VAN DER HOEVEN , MD, PHD 5

K LAAS HOOGENBERG , MD, PHD 6

OBJECTIVE To evaluate the discriminative power of the Diabetic Neuropathy Symptom(DNS) and Diabetic Neuropathy Examination (DNE) scores for diagnosing diabetic polyneu-ropathy (PNP), as well as their relation with cardiovascular autonomic function testing (cAFT)and electro-diagnostic studies (EDS).

RESEARCH DESIGN AND METHODS Three groups (matched for age and sex)were selected: 24 diabetic patients with neuropathic foot ulcers (DU), 24 diabetic patientswithout clinical neuropathy or ulcers (DC), and 21 control subjects without diabetes (C). In allparticipants, the DNS and DNE scores were assessed and cAFT (heart rate variability [HRV],baroreex sensitivity [BRS]), and EDS were performed (Nerve Conduction Sum [NCS] score;muscle ber conduction velocity: fastest/slowest ratio [F/S ratio]).

RESULTS Both theDNSand theDNE scoresdiscriminated between theDU andDC groupssignicantly (P 0.001). The DNE score even discriminated between DC and C (P 0.05).Spearmans correlation coefcients between both DNS and DNE scores and cAFT (HRV 0.42and 0.44; BRS 0.30 and 0.29, respectively) and EDS (NCS 0.51 and 0.62; F/S ratio 0.44and 0.62, respectively) were high. Odds ratios were calculated for both DNS and DNE scoreswith cAFT (HRV 4.4 and 5.7; BRS 20.7 and 14.2, respectively) and EDS (NCS 5.6 and 16.8; F/Sratio 7.2 and 18.8, respectively).

CONCLUSIONS TheDNS andDNEscores areable to discriminatebetween patients withand without PNP and are strongly related to cAFT and EDS. This further conrms the strengthof the DNS and DNE scores in diagnosing diabetic PNP in daily clinical practice.

Diabetes Care 26:697701, 2003

O ne of the major risk factors for thedevelopment of diabetic foot com-plications is distal symmetric sen-sorimotor polyneuropathy (PNP) (1,2).

For diagnosing PNP, no gold standard isavailable. The San Antonio consensuspanel has recommended that at least onemeasurement shouldbe performedin ve

different diagnostic categories (3). Theseare symptom scoring, physical examina-tion scoring, quantitative sensory testing(QST), cardiovascular autonomic func-tion testing (cAFT), and electro-diagnos-tic studies (EDS).

Because none of the existing symp-tom and physical examination scores fordiabetic PNP completely fullled meth-odological criteria for diagnostic tests, theDiabetic Neuropathy Symptom (DNS)and Diabetic Neuropathy Examination(DNE) scoreswere developed(4,5). (DNSguidelines can be found in an online ap-pendix at http://care.diabetesjournals.org.) Theconstruct validity of these scoreswas studied in relation to Semmes Wein-stein monolaments and vibration per-ception threshold testing (both forms of QST) because of their predictive value tothe development of diabetic foot compli-cations (6 9).

cAFT has an important prognosticvalue for the prediction of diabetic footcomplications (8,10,11) and mortalitydue to cardiovascular problems (12,13).The prognostic value of EDS is less clear,although EDSaresupposedto be themostsensitive diagnostic tool for diabetic PNP(14). The relation between the DNS andDNE scores and cAFT and EDS, respec-tively, has not been studied.

The objective of this study was to as-sess the discriminative power of the DNSand DNE scores for diagnosing diabeticPNP, as well as their relation with cAFTand EDS, respectively.

RESEARCH DESIGN ANDMETHODS

Patients All participants were recruited from theDiabetes Outpatient Clinic (UniversityHospital Groningen) and the Rehabilita-tion Center Beatrixoord Haren after in-formed consent was obtained. To studythe discriminative power of the DNS andDNEscores, three groupsof subjects werestudied. Patient records were consecu-

From the 1 RehabilitationCenter, Tolbrug/Jeroen BoschHospital,Den Bosch, the Netherlands; the 2 Northern

Center for Health Care Research, Groningen, the Netherlands; the3

Department of Internal Medicine,University Hospital Groningen, Groningen, the Netherlands; the 4 Department of Endocrinology, UniversityHospital Groningen, Groningen, the Netherlands; the 5 Department of Neurology, University Hospital Gro-ningen, Groningen, the Netherlands; and the 6 Department of Internal Medicine, Martini Hospital, Gro-ningen, the Netherlands.

Address correspondence and reprint requests to Jan-Willem G. Meijer, MD, PhD, Rehabilitation CenterTolbrug, PO Box 90153, 5200 ME Den Bosch, The Netherlands. E-mail: [email protected].

Received for publication 3 June 2002 and accepted in revised form 26 November 2002. Addit ion al informat ion for thi s art icl e can be fou nd in an online app end ix at htt p:/ /ca re.

diabetesjournals.org.Abbreviations: BRS, baroreex sensitivity; cAFT, cardiovascular autonomic function testing; DNE, Di-

abetic Neuropathy Examination; DNS, Diabetic Neuropathy Symptom; EDS, electro-diagnostic studies; F/Sratio, fastest/slowest ratio; HRV, heart rate variability; MFCV, muscle ber conduction velocity; NCS, NerveConduction Sum; PNP, polyneuropathy; QST, quantitative sensory testing; RV, reference value.

A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversionfactors for many substances.

E p i d e m i o l o g y / H e a l t h S e r v i c e s / P s y c h o s o c i a l R e s e a r c hO R I G I N A L A R T I C L E

D IABETES C ARE , VOLUME 26, NUMBER 3, M ARCH 2003 697


2/5

tively screened during our outpatientclinics for patients with previous neuro-pathicfoot ulceration in whom peripheralvascular disease was not considered tohave contributed to the foot ulcers. Afterthis screening, they were recruited in a

randomized order. The rst group con-sisted of 24 diabetic patients known tohave had neuropathic foot ulcers (DUgroup). These ulcers were purely neuro-pathic by origin, as conrmed by theirlocalization (plantar surface of the foot athigh-pressure points) and the absence of peripheral arterial disease, as describedbelow. In the second group, 24 diabeticpatients without clinical neuropathy orfoot ulcers (DC group) were included. Toconrm this, the 10-g Semmes Weinsteinmonolament was tested on the plantarsurface of the hallux and central at theheel. The ability to correctly sense themonolament in six trials on both loca-tions was dened as normal, whereas theinability to sense the mono lament cor-rectly in one or more trials was dened asdisturbed. The third group consisted of 21 control subjects with normal glucosetolerance (C group). All groups werematched for sex and age (within 5 years),and the diabetic groups were alsomatched for duration and type of diabetes(type 1/type 2 diabetes; type 1 diabeteswas considered on clinical grounds when

the onset of the disease was a ketoacidosisor before the age of 40 years). Subjectswith a history of or clinically apparentcardiacdisease, withelectrocardiographicabnormalities, or who used -blockers orcalcium antagonists were excluded. Pe-ripheral arterial disease was excluded bynormal ankle-arm indexes ( 0.90) , toe-arm indexes ( 0.70), and normal pleth-ysmography (crest time 0.22 s) in allgroups. Normal glucose tolerance of thecontrol subjects was demonstrated by afasting capillary blood glucose 6.1

mmol/l and a blood glucose 7.8 mmol/l2 h after a 75-g oral glucose tolerance test.Details of the clinical characteristics of each group are given in Table 1.

Methods

The DNS and DNE scores (E.B.), cAFT(J.L.), and EDS (J.v.d.H.) were performedby different researchers who wereblindedto participant group. The researcherswere acting independently, and no infor-mation about the results was exchangedduring the study. An overall NeuropathySum score, according to the San Antonioconsensus, was composed.

DNS scoreBoth the DNS and DNE scores have beendescribed in detail elsewhere (4,5). Inshort, the DNS score is a four-item vali-dated symptom score, with high predic-tive value to screen for PNP in diabetes(4). Symptoms of unsteadiness in walk-ing, neuropathic pain, paraesthesia, andnumbness are elicited. The presence of one symptom is scored as 1 point; themaximum score is4 points. A score of 1 orhigher is dened as positive for PNP.

DNE scoreTheDNEscore is a sensitiveandvalidatedhierarchical scoring system (5). The scorecontains two items concerning muscle

strength, one concerning re exes, andve concerning sensation (eight totalitems). Each item is scored from 0 to 2 (0is normal and 2 severely disturbed). Themaximum score is 16 points. A score of 3 points is dened as positive for PNP.

cAFTCardiovascular autonomic function wasassessed by analysis of heart rate variabil-ity (HRV) and baroreex sensitivity(BRS). Allparticipants were studied in themorning. All measurements took place in

a quiet room with the temperature keptconstant at 22 C. Blood pressure wasmonitored by a Finapres (Ohmeda 2300;Ohmeda, Inglewood, CO) and heart rateby an electrocardiogram monitor (Hewlett-Packard 78351T; Hewlett-Packard, Palo Alto, CA). After 30 min of supine rest, theFinapres and electrocardiogram signalswere sampled at 100 Hz and stored on apersonal computer during 15 min. Off-line, 300 s of each recording were ana-lyzed by the CARSPAN program (IECProGamma; IEC, Groningen, the Nether-lands), as previously described (15,16). After artifact correction and stationaritycheck, discrete Fourier transformation of systolic blood pressure and R-R intervallength measurement were performed.HRV analysis was performed in accor-dance with the guidelines of the Task

Force of the European Society of Cardiol-ogy and the North American Society of Pacing and Electrophysiology (17). Thetotal power frequency band of HRV wasdened as 0.02 0.40 Hz. Because no ref-erence values (RVs) of HRV are available,the medianof the control group was used,9.2 ln(ms 2 ). BRS was determined by thetransfer function method and de ned asthemeanmodulus between systolic bloodpressure and HRV in the 0.07- to 0.14-Hzfrequency band with at least 0.5 coher-ence, expressed in ms/mmHg (15,16,18). A BRS 3 ms/mmHg has shown highmortalityrates in chronic heart failure andafter myocardial infarction, but in diabe-tes, the prognostic value of the BRS is un-known (19,20). Therefore, in this study, aBRS 3 ms/mmHg was considered indic-ative for cardiovascular autonomic neu-ropathy.

Electro-diagnostic testing (EDS)Nerve conduction studies were per-formed with standard surface stimulationand recording techniques using an elec-tromyograph type Nicolet Viking IIe and

IV with standard lter settings. All mea-surements were performed after warmingin hot water (38 C) of forearm and lowerleg during at least 15 min. Peak-peak am-plitudes were used. RVs from our ownlaboratory were used, with abnormal val-ues dened as 2 SD of normal meanvalues.

Motor nerve conduction velocity(RVs) were measured in the left median(thenar) (RV 58.5 4.6 m/s [means SD]) and peroneal nerves (tibialis ante-rior) (RV 57.8 7.1 m/s). Sensory nerve

Table 1 Patient characteristics

DU DC C

n 24 24 21Mean 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 1/type 2 diabetes 5/19 8/16Mean HbA1c (%) 8.3 1.1* 7.5 0.8Data are means SD. C, control subjects; DC, diabetic patients without neuropathy; DU, diabetic patientswith neuropathic ulcer. * P 0.01.

Diagnosis of PNP: the DNS and DNE scores

698 D IABETES C ARE , VOLUME 26, NUMBER 3, M ARCH 2003


3/5

conduction velocities and amplitudeswere measured antidromically with ringelectrodes placed around the middle n-ger (median nerve) (RV 45.6 3.7 m/s)

andstimulation lateral of theAchilles ten-don(suralnerve) (RV47.4 3.6 m/s).Anoverall Nerve Conduction Sum (NCS)score was dened as the number of thesefour nerves with an abnormal conductionvelocity, ranging from 0 (all normal) to 4(all abnormal).

Invasive muscle ber conduction ve-locity (MFCV) measurements were per-formed in the tibialis anterior muscle atrest by means of needle electrodesadapted from a previously describedmethod (21). In short, muscle bers weredirectly stimulated in thedistalpart of thetibial anterior muscle by a small monopo-larneedleelectrode (cathode) using a sur-face electrode as anode ( lter settings 500Hz10 kHz, stimulation0.2ms,1 2 mA).The resulting muscle ber action poten-tials were detected at a known distance(50 60 mm)by a small concentric needleelectrode. With this technique, action po-tentials supposed to represent individualmuscle bers were identi ed and the re-sulting conduction velocities were calcu-lated. As parameters, the mean invasiveMFCV and the fastest/slowest ratio (F/S

ratio) representing the scatter of conduc-tion velocities were used and comparedwith normative values from our own lab-oratory (3.17 0.40; F/S ratio 1.47

0.19, slowest 2.59 0.40, fastest 3.78 0.49).

Neuropathy Sum scoreFor this study, an overall score was com-posed of the DNS score (symptom score),DNE score (examination score), BRS(cAFT), andNCS(EDS).Because Semmes Weinstein mono lament testing wasusedin patient selection, these data, represent-ing QST as the fth category of the San Antonio consensus (3), were also avail-able. These ve tests together formed theNeuropathy Sum score. For each abnor-mal test result, 1 point was given; themaximum score was 5 points.

StatisticsThe statistical package SPSS-PC 10.0 wasused to compute thedescriptive statistics: ANOVA, 2 tests, independent samples ttest, Spearman s correlation coef cient,and odds ratios. Unless otherwise indi-cated, means SD are given. AP value 0.05 was considered statistically signif-icant.

RESULTS Table 1 shows the patientcharacteristics. There were no signi cantdifferences between the groups for meanage(P 0.15) and sex ( P 0.77) and, forthe DU and DC groups, duration ( P 0.23) and typeof diabetes ( P 0.33). Themean HbA1c of the DC group was signif-icantly lower (P 0.01) than that of theDU group.

Results of DNS and DNE scores forthe three groupsFor the DNS score, the scores ( SD) of the DU, DC, and C groups were 2.29

1.23, 0.44 0.84, and 0.38 0.74, re-spectively. Differences between DU andboth DC and C were signicant, P 0.001 in both cases, but not between DCand C. For the DNE score, the scores( SD) of the DU, DC, and C groups were8.90 1.98, 1.46 2.02, and 0.43 0.81, respectively. Signi cant differenceswere found in allcomparisons of thethreegroups, between DU and both DC and Cgroups, P 0.001 in both cases, and be-tween DC and C (P 0.05).

There were no signicant differencesfor DNS and DNE scores for type 1 andtype 2 diabetic patients. There was a sig-nicant correlation between the DNS andDNE scores and HbA1c (0.35, P 0.01;0.57, P 0.001, respectively), as well asbetween the DNS and DNE scores andduration of diabetes (0.41, P 0.01;

0.56, P 0.001, respectively). There wasno signicant correlation between bothscores and subject age.

Results of the PNP testsTable 2 shows the percentage of patientsin the three groups who scored abnormalon the individual diagnostic tests and onthe Neuropathy Sum score. The DNS andDNE scores correctly identied the DUgroup in 96 and 100%, respectively, andthe healthy control subjects in 76 and100%, respectively. Almost one-half (47%) of the patients of the DC group and40% of the C group scoredat least 1 pointon the Neuropathy Sum score, whichmeans that they scored abnormal on atleast one diagnostic category of the San Antonio consensus. Table 3 shows thespecied results on the Neuropathy Sumscore.

Relation of the DNS and DNE scores with cAFT and EDSIn Table 4, the correlation between theDNS and DNE scores and cAFT (BRS andHRV) and EDS (NCSand invasive MFCV)

is shown. The odds ratios for these testsare also shown.

CONCLUSIONS This study showsthat the DNS and DNE scores are able todifferentiate between subjects with andwithout neuropathy in diabetes. Previ-ously,the constructvalidityof both scoreswas studied in relation to Semmes Wein-stein mono laments and vibration per-ception threshold testing (4,5) twoquantitative sensory tests known to bestrong predictors for the development of

Table 2 Results of the tests for PNP for the three groups

DU DC C

n 24 24 21DNS (% 1 point abnormal) 96% 26% 24%DNE (% 3 points abnormal) 100% 13% 0%NCS (% 1 point abnormal) 85% 32% 15%F/S ratio (% 1.9 abnormal) 91% 33% 10%BRS (% 3 ms/mmHG) 52% 0% 11%HRVtp (% median) 95% 57% 50%Neuropathy Sum score (% 1 point) 100% 47% 40%Data are means SD. C, control subjects; DC, diabetic patients without neuropathy; DU, diabetic patientswith neuropathic ulcer. HRVtp, total power of HRV(abnormalde ned aslessthan the medianof the controlgroup).

Table 3 The number of patients with nor-mal (0) or abnormal scores (15) on the Neu-ropathy Sum (NS) score for the three groups

NS score 0 1 2 3 4 5

DU (22) 1 12 6 3DC (23) 12 7 3 1C (20) 12 6 2C, control subjects; DC, diabetic patients withoutneuropathy; DU, diabetic patients with neuropathiculcer.

Meijer and Associates



4/5

diabetic foot complications. In this re-port, the DNS and DNE scores are furthervalidatedwith theEDS andcAFT.There isa strong relation between the DNS andDNE scores and EDS in both nerve andmuscle ber conductionstudies. Further-more, the relation of the DNS and DNE

scores with cAFT is signicant, althoughthis is stronger for HRV than for BRS forboth scores. These results further con rmthe strength of the DNS and DNE scoresin diagnosing diabetic PNP.

HRV and BRS are advanced measuresthat are able to detect early abnormalitiesin cAFT (1013). The relation of HRVwith the parameters for PNP (DNS andDNE scores, NCS, and F/S ratio of MFCV)is stronger than for BRS. While HRV mea-sures the efferent part of the barore exarc, i.e., vagal and sympathetic nerve mediated modulation of heart rate, BRSmeasures the relation between input(blood pressure sensed at the carotid ar-teries and aorta baroreceptors) and theoutput (modulations of heart rate, myo-cardial contractility, and peripheral arte-rial resistance) of thebarore ex.Thus, thedifferences in HRV and BRS in relation todiabetic PNP may be due to the fact thatBRS assesses different aspects of cardio-vascular reex function than HRV. Inter-estingly, it has also been proposed thatPNP and cAFT are distinct entities with adifferent pathogenesis (22), thereby ex-

plaining the previously noticed variablerelation between cAFT and PNP.The odds ratios for the DNS and DNE

scores with NCS, MFCV (F/S ratio), HRV,and BRS are high, which means that theDNS and DNE scores are able to predictthe results of these other diagnostic tests.By assessing the DNS and DNE scores atthe outpatient clinic, a good indication isgiven for performing these more labori-ous and expensive and less patient-friendly laboratory tests. However, in ouropinion, the necessity of complementary

performance of cAFT and EDS with theDNS and DNE scores, as proposed in theSan Antonio consensus, is debatable inclinical practice. No specic therapeuticinterventions are available for neuropathyexcept strict glycemic control, symptom-atic treatment of, for example, neuro-

pathic pain, prevention, and instruction.For screening, prevention, and instruc-tion, the performance of the DNS andDNE scores, eventually in combinationwith QST, may be suf cient.

As expected, performance of thesevarious tests for diabetic PNP shows ahigh number of abnormalities among thegroupof patientswithneuropathic ulcers. Although the percentage with abnormalBRS is rather low compared with the per-centages of the other tests, these patientsare expected to have a very poor progno-sis due to their high risk of cardiovascularcomplications (19,20). In their treatment,hospitalization, and rehabilitation pro-gram, this should be taken into account.Strikingly, 48% of this group with obvi-ous neuropathy has a BRS 3 ms/mmHg.This supports the hypothesis that cAFTmight develop differently from PNP as anindependent complication of diabetes.

In both the diabetic group withoutneuropathy andthecontrol group,abnor-mal test results were found for most tests.This might be caused by lack of speci cityof the tests, as shown in the control group,

although it also shows that after carefuland sensitive screening, more abnormali-ties can be found (also in diabetic patientsnot known to have neuropathy), as ex-pected after checking the records. The re-sults of the DNS and Neuropathy Sumscores are most striking. In our previousDNS score validation, we chose a cutoff value of 1 to dene a sensitive measurefor diabetic PNP. Our present valuesshow that almost one-quarter of our con-trol group scores were abnormal. Thesame problem will exist for other symp-

tom scores, such as for the NeuropathySymptom Score (NSS) (14,23), becausethese scores also score these four items of the DNS score. The Neuropathy Sumscore, based on the ve diagnosticcatego-ries as advised by the San Antonio con-sensus (3), also shows high percentagesof

participants, even in the control group,with abnormal test results. Therefore, oneshould consider the risk of overdiagnosisby using all ve the diagnostic categoriesof the San Antonio consensus. Further re-search should be done to characterize anoptimal set of diagnostic categories for di-abetic PNP.

In conclusion, this report shows thatthe DNS and DNE scores allow discrimi-nation between patients with and withoutdiabetic PNP. Both scores are strongly re-lated to EDS and cAFT. These results, to-gether with the previously publishedresults of the validation of both scores,further con rm the strength of the DNSand DNE scores in diagnosing diabeticPNP in clinical practice.

References

1. Boulton AJM: The pathogenesis of dia-betic foot problems: an overview. DiabetMed13:S12S16, 1996

2. Mayeld JA, Reiber GE, Sanders LJ, Janisse DJ, Pogach LM: Preventive footcare inpeoplewithdiabetes. DiabetesCare21:2161 2177, 1998

3. AmericanDiabetes Association, American Academy of Neurology: Report andrecommendations of the San AntonioConference on Diabetic Neuropathy (Con-sensus Statement). Diabetes Care11:592 597, 1988

4. Meijer JWG, Smit AJ, van Sonderen E,Groothoff JW, Eisma WH, Links TP:Symptom scoring systems to diagnosedistal polyneuropathy in diabetes: the Di-abetic Neuropathy Symptom score. Dia-bet Med19:962 965, 2002

5. Meijer JWG, van Sonderen E, Blaauw-wiekel EE, Smit AJ, Groothoff JW, Eisma

Table 4 Correlation (Spearmans rho) and odds ratios (95% CI) of DNS score and DNE scores with EDS and cAFT, respectively

DNS score DNE score NCS F/S BRS HRVtp

DNS score 42.7 (8.4215) 5.6 (1.7 18.2) 7.2 (2.3 22.3) 20.7 (2.5 172) 4.4 (1.5 12.8)DNE score 0.67* 16.8 (3.8 74) 18.8 (5.0 71) 14.2 (2.8 74) 5.7 (1.8 17.8)NCS 0.51* 0.62* 13.9 (3.6 53) 4.0 (0.7 24.4) 4.4 (1.3 14.7)F/S ratio 0.44* 0.62* 0.60* 3.0 (0.7 11.7) 4.6 (1.5 14.2)BRS 0.30 0.29 0.22 0.12 22.4 (2.7 186)HRVtp 0.42* 0.44* 0.37* 0.32 0.69**P 0.001; P 0.05; not signicant. HRVtp, total power of HRV.

Diagnosis of PNP: the DNS and DNE scores

700 D IABETES C ARE , VOLUME 26, NUMBER 3, M ARCH 2003


5/5

WH, Links TP: Diabetic Neuropathy Ex-amination: a hierarchical scoring systemto diagnose distal polyneuropathy in dia-betes. Diabetes Care23:750 753, 2000

6. Young MJ, Breddy L, Veves A, Boulton AJM: The prediction of diabetic neuro-pathic foot ulceration using vibratoryper-

ception thresholds. DiabetesCare17:557 560, 19947. Armstrong DG, Lavery LA, Vela SA,

Quebedeaux TL, Fleischli JG: Choosing apractical screening instrument to identifypatients at risk for diabetic foot ulcer-ation. Arch Int Med158:289 292, 1998

8. Boyko EJ, Ahroni JH, Stensel V, ForsbergRC, Davignon DR, Smith DG: A prospec-tive study of risk factors for diabetic footulcer. Diabetes Care22:1036 1042, 1999

9. Pham H, Armsytrong DG, Harvey C, Har-kless LB, Giurini JM, Veves A: Screeningtechniques to identify people at high riskfor diabetic foot ulceration. Diabetes Care

23:606 611, 200010. McFadden JP, Corrall RJM, OBrien IAD: Autonomic and sensory nerve function indiabetic foot ulceration. Clin and Exp Der-matology16:193 196, 1991

11. Aso Y, Fujiwara Y, Inukai T, Takemura Y:Power spectral analysis of heart rate vari-ation in diabetic patients with neuro-pathic foot ulceration. Diabetes Care 21:1173 1177, 1998

12. Ewing DJ, Campbell IW, Clarke BF: Mor-tality in diabetic autonomic neuropathy.Lancet1:601 603, 1976

13. Weston PJ, Panerai RB, McCullough A,McNally PG, James MA, Potter JF, Thur-ston H, Swales JD: Assessment of barore-ceptor-cardiac reex sensitivity using

time domain analysis in patients withIDDM and the relation to left ventricularmass index. Diabetologia39:1385 1391,1996

14. Dyck PJ: Detection, characterization andstaging of polyneuropathy: assessed in di-abetics. Muscle Nerve11:21 32, 1988

15. Robbe HW, Mulder LJ, Ruddel H, Lange-witz WA, Veldman JB, Mulder G: Assess-ment of baroreceptor re ex sensitivity bymeans of spectral analysis. Hypertension10:538 543, 1987

16. Boer de RW, Karemaker JM, Strackee J:Hemodynamic uctuations and barore-ex sensitivity in humans: a beat-to-beat

model. Am J Physiol253:H680 H689,198717. Lefrandt JD, Hoogenberg K, van Roon

AM, Dullaart RP, Gans RO, Smit AJ:Baroreex sensitivity is depressed in mi-croalbuminuric type I diabetic patients atrest and during sympathetic manoeuvres.Diabetologia42:1345 1349, 1999

18. Task Force of the European Society of Cardiology and the North American Soci-

ety of Pacing and Electrophysiology:Heart rate variability: standards of mea-surement, physiological interpretationand clinical use. Circulation 93:1043 1065, 1996

19. Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasch

C, Tavazzi L: Arterial baroreex modula-tion of heart rate in chronic heart failure.Circulation96:3450 3458, 1997

20. La Rovere MT, Bigger JT, Marcus FI,Mortara A, Schwartz PJ: Baroreex sensi-tivity and heart-rate variability in predic-tion of total cardiac mortality after myo-cardial infarction. Lancet 351:478 484,1998

21. van der Hoeven JH, van Weerden TW,Zwarts MJ: Long-lasting supernormalconduction velocity after sustained maxi-mal isometric contraction in human mus-cle. Muscle Nerve16:312 320, 1993

22. TentolourisN, Pagoni S, TzonouA, Katsi-

lambros N: Peripheral neuropathy doesnot invariably coexist with autonomicneuropathy in diabetes mellitus. Eur J In-tern Med12:20 27, 2001

23. Dyck PJ, Sherman WR, Hallcher LM, Ser-vice FJ, OBrien PC, Grina LA, PalumboPJ, Swanson CJ: Human diabetic endo-neurial sorbitol, fructose and myo-inosi-tol related to sural nerve morphometry. Ann Neurol6:590 596, 1980

Meijer and Associates


Documents

Clinical Diagnosis of Diabetic.pdf