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Hardness of Plantar Skin in Diabetic Neuropathic Feet
Hardness of Plantar Skin in Diabetic Neuropathic Feet Alberto Piaggesi, Marco Romanelli, Elena Schipani, Fabrizio Campi, Antonio Magliaro, Fabio Baccetti, and Renzo Navalesi
ABSTRACT To evaluate if skin hardness in diabetic neuropathic feet was increased and if its eventual modifications could be correlated to the severity of neuropathy, we studied a group of diabetic outpatients with and without neuropathy. Patients, selected among those who were attending their routine screening for diabetic neuropathy at our diabetologic clinic, were divided into two groups according to the presence (ND1) or absence (ND2) of diabetic neuropathy with the criteria of the S. Antonio Consensus Conference on Diabetic Neuropathy. Patients then underwent an evaluation of vibration perception threshold (VPT) by means of a biotesiometer, measurement of skin hardness (DMT) by means of a durometer, and transcutaneous oxygen tension (TcPO2) determination. VPT was determined at allux (VPTA) and external malleolus (VPT-M), DMT was measured at heel (DMT-H), at medial (DMT-M) and lateral (DMT-L) midfoot, and at posterior midcalf (DTM-C) as a control site; TcPO2 was evaluated at dorsum (TcPO2-D) and at medial midfoot (TcPO2-M), respectively. All measurements were performed on the nondominant side with the patients supine.
Patients were compared with age and gendermatched healthy volunteers (Controls), who underwent the same evaluations in the same order. ND1 patients showed higher values of VPT than ND2 and Controls, both at first toe and at malleolus analysis of variance (ANOVA) p , 0.01), as well of DMT in all the three sites explored (ANOVA, p , 0.01). Moreover, ND1 showed no difference in DMT among the sites, while both in ND2 and in controls DMT-M was significantly (p , 0.05) lower than DMTH and DMT-L. No difference among the three groups were observed in TcPO2 measurements, and no difference in DMT-C was observed either. A significant correlation was observed between DMTH and VPT-M (r2 5 0.516) and between DMT-M and VPT-A (r2 5 0.624) in ND1 patients. Skin hardness was diffusely increased in ND1 patients, and this increase strongly correlates with the severity of neuropathy. Simple, noninvasive determination of skin hardness could identify patient at potential risk to develop neuropathic foot ulcers. (Journal of Diabetes and Its Complications 13; 3: 129–134, 1999.) 1999 Elsevier Science Inc.
INTRODUCTION
autonomic component of peripheral nerves.1 One of the key events in the pathogenetic pathway to neuropathic ulceration is hyperkeratosis, which develops in areas of increased pressure. Although orthostatic stress has been claimed to be the major responsible of hyperkeratosis, other factors, such as nonenzymatic glycation and autonomic dysidrosis are suspected of being involved in the pathogenesis of skin hardening.2 Recently, a new and easy method to assess skin hardness, durometry, was developed and applied to various skin pathologies, such as hypertrophic scars, dermatosclerosis, lymphedema, with interesting results.3
P
eripheral polyneuropathy is one of the major risk factors of foot ulcers in diabetic patients, through a multifactorial pathogenetic sequence that involves motor, sensitive, and
Department of Metabolic Diseases (A.P., E.S., F.C., F.B., R.N.), and Department of Dermatology (M.R., A.M.), University of Pisa, Pisa, Italy Reprint requests to be sent to: Dr. Alberto Piaggesi, U.O. Malattie del Ricambio e Diabetologia, Azienda Ospedaliera Pisana, Cisanello, Via Paradisa 2, 56100 Pisa, Italy. Journal of Diabetes and Its Complications 1999; 13:129–134 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
1056-8727/99/$–see front matter PII S1056-8727(98)00022-1
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The Durometer (Rex Gauge Co., Inc., Glenview, IL) is the international standard for hardness measurement of various nonmetallic materials, from rubber to plastic, wood etc. Model 0, as used in this study, is suitable for soft material such as animal tissues, in which there is a minimal amount of creep.4 The durometer shows the relative degree of tissue hardness on a linear calibrated gauge as the result of a spring-loaded interior that senses hardness by applying an indentation load on the specimen. Determination of skin hardness by this instrument has been proven to be accurate and reproducible, both in normal and pathological conditions.4,5 The purpose of this study was to measure skin hardness in diabetic neuropathic feet, in order to check if neuropathy-associated modifications of skin elasticity may be found before the occurrence of ulcerations. METHODS We studied a selected group of outpatients attending our diabetic clinic, chosen among those who were attending a routine periodic control scheduled between June and December 1996. Patients were selected according to the following inclusion criteria: diagnosis of type I or type II diabetes mellitus from more than 5 years, age range between 18 and 60 years, presence of peripheral polyneuropathy as ascertained by the bilateral absence of Achilles tendon reflexes, Michigan Neuropathy Screening Instrument [MNSI, normal range <26] score of greater than 7 and/or Autonomic Score [AS, an integrated index that takes into account the results of a battery of five different autonomic cardiovascular tests, normal range <27] score of greater than 3. Excluding criteria were having or having had in the past foot ulcerations, presence of clinically evident peripheral vascular disease (PVD) or absence of peripheral pulses, prolipherative retinopathy, serum creatinine greater than 2 mg/dL, scleroderma or other reumatologic diseases, other causes of polyneuropathy than diabetes mellitus, lymphedema, body-mass index [BMI 5 weight (kg) height (m)2 (normal range <25)] of 30 or greater. Patients, who were recruited after having performed their routine screening for diabetic chronic complications, were divided in two groups, ND1 and ND2 according to the presence or not of diabetic polyneuropathy following the criteria of the San Antonio Consensus Conference on Diabetic Neuropathy and compared to a group of gender- and age-matched healthy volunteers (Controls) chosen among the relatives of patients who agreed to participate. All participants were informed about the aims and methodology of the study, and informed consent was elicited before any evaluation was performed. The Study had previously obtained the approval of local ethic committee.
FIGURE 1 Evaluation of skin hardness was by applying the Durometert on the surface of heel, only held by gravity. Figure shows the upper side of the instrument, on which the graduated scale is visible.
Vibration Perception Threshold (VPT). Once recruited, patients underwent a second-level neuropathy assessment through the determination of VPT [normal range , 25 volts8] at first toe and external malleolus with a biothesiometer (Ohio Instruments), both in the nondominant leg, according to the recommendations of the American Diabetes Association for the diagnosis of diabetic neuropathy.9 The biothesiometer is an electric device provided with a vibrating probe, which can be applied on measurement site, held by gravity, and to which an increasing vibrating intensity is applied. The lowest of three intensity of vibration defines the VPT. VPT is a sensitive and reproducible method to determine the presence of peripheral neuropathy and quantify the extent of neural damage in diabetic patients; it shows a close correlation both with electrophysiology and with autonomic testing.10
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TABLE 1. CLINICAL AND DEMOGRAPHIC FEATURES OF PATIENTS AND CONTROLS Item n (IDDM/NIDDM) Age (years) Duration of disease (years) BMI (kg/m2) HbA1c (%) MNSI (score) AS (score)
ND1
ND2
Controls
36 (8/28) 51.48 6 12.03 17.34 6 08.52 28.84 6 06.12 8.7 6 2.6 12.22 6 2.41** 5.05 6 1.35**
36 (6/30) 53.22 6 08.96 15.66 6 04.44 29.54 6 09.23 9.1 6 1.8 2.13 6 1.89 1.0 6 0.5
36 54.98 6 09.11 — 28.17 6 08.81 4.6 6 0.9* 2.06 6 1.14 1.0 6 1.0
* Controls vs ND1 and ND2: ANOVA p , 0.01. ** ND1 versus ND2 and Controls; ANOVA p , 0.001. IDDM, insulin-dependent diabetes mellitus; NIDDM, non–insulin-dependent diabetes mellitus; BMI, body-mass index; HbA1c, glycosylated hemoglobin; MNSI, Michigan Neuropathy Screening Instrument; AS, autonomic Score; ND1, neuropathic diabetic patients; ND2, non-neuropathic diabetic patients; ANOVA, analysis of variance.
Skin Hardness Evaluation — DMT. After a rest in supine position for about 20 min at a room temperature of 258C with the shoes off, patients had their skin hardness measured with the Durometer [Rex Gauge, Glenview, IL] at the heel (DMT-H), median [the midpoint of the line connecting the center of the heel with the base of the first toe (DMT-M)], and lateral [the midpoint of the line connecting the center of the heel with the base of the fifth toe (DMT-L)] midfoot on the foot of nondominant side; measurements were performed also on posterior midcalf on the same side (DMT-C), which served as a control site. Areas with bony prominences were avoided. Any localized hyperkeratotic area was avoided as well, as any area reckonable by inspection or by light touch as hyperkeratotic. In no case, anyhow, hyperkeratosis was found to be present at sites of measurement, while in 16/36 (44%) ND1 patients, in 10/36 (28%) ND2, and in 11/36 (30%) controls hyperkeratosis was found under metatarsal heads and/or first toe. Durometer was positioned directly on the site of measurement with an angle of 90 degrees, held by gravity only (Figure 1); four measurements were repeated at all sites, and mean values were considered for analysis.4 Transcutaneous Oxygen Tension — TcPO2. TcPO2 was then measured at dorsum of feet (TcPO2-D) and on plantar side at median midfoot (TcPO2-M) with a TCM3 Oxymeter (Radiometer, Copenhagen, Denmark), according to a previously described methodology.11 The Probe was placed on the skin in the selected sites and the measurements were taken after at least 20 min, once the system had reached the steady state, and lasted for 5 consecutive min. The VPT, DMT, and TcPO2 evaluations were performed with patients lying in supine position (with the exception of plantar measurements, which were all performed in a prone position, with the leg flexed at 90 de-
grees), at standard room temperature: room temperature 258C 6 28C and humidity 45% 6 5%. Skin temperature ranged between 328C and 348C: if skin temperature, measured with a contact thermometer, was lower than 328C, infrared heating was activated, before the beginning of determinations. Patients were compared to a group of non-neuropathic diabetic patients superimposable for age, duration of diabetes, and absence of exclusion criteria (ND2), and with a group of gender- and age-matched healthy volunteers (C). Data, which are expressed as mean 6 standard deviation (SD), were analyzed with analysis of variance (ANOVA) and linear regression test with a commercially available software (Statview 512TM, running on a Macintosh SE computer). RESULTS Fifty-five patients fulfilled all inclusion criteria for entering the study, but only 36 were actually enrolled in the study; clinical and demographic characteristics of ND1, ND2, and controls are shown in Table 1. As expected, ND1 patients had significantly higher values of MNSI and AS than ND2 ones and controls, whereas no differences were found between ND2 and controls for these items (Table 1). VPT was significantly more enhanced in ND1 than in ND2 and controls both at first toe (39.25 6 9.13 versus 18.17 6 7.92 and 16.97 6 4.03 volts, respectively; ANOVA p , 0.01) and at malleolus (42.56 6 8.99 versus 17.35 6 6.21 and 19.24 6 8.45 volts, respectively; ANOVA p , 0.01), thus confirming the presence of and quantifying peripheral neuropathy (Figure 2). Skin hardness, as measured with DMT, was more pronounced in ND1 patients than in ND2 and in controls in the three sites explored, while ND2 skin showed no difference in comparison to controls at the three sites. At control sites, DMT-C showed no differences between the three groups. Both in ND2 and in
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FIGURE 2 Vibration perception threshold at allux (VPT-A) and external malleoulus (VPT-M) of neuropathic (ND1) and non neuropathic (ND2) diabetic patients and Controls.
controls, but not in ND1, DMT-M was significantly lower than DMT-H and DMT-L (Table 2 ). Among ND1 patients, those with metatarsal hyperkeratosis had significantly higher DMT-H (56.81 6 2.97 versus 46.75 6 3.61 UI; p , 0.001) and DMT-L (55.25 6 2.79 versus 44.9 6 2.86 UI; p , 0.001) compared to those without hyperkeratosis. No differences in TcPO2 was found in ND1 compared to ND2 and controls, neither at dorsum (TcPO2D, 60.56 6 9.15 versus 59.37 6 8.89 and 61.44 6 12.04, mm Hg, respectively) nor on plantar (TcPO2-M, 57.62 6 7.71 versus 58.12 6 9.44 and 58.91 6 6.76, mm Hg, respectively) side of the feet. No significant differences were elicited between dorsum and plantar determinations in any group as well. A significant positive correlation was evidentiated between DMT-H and VPTM (r2 5 0.516) and between DMT-M and VPT-A (r2 5 0.624) in ND1 patients, as shown in Figures 3 and 4, respectively. CONCLUSIONS Peripheral polyneuropathy has been claimed to be the major factor responsible for diabetic foot ulcerations: more than 65% of ulcers in diabetic feet have an underlying neuropathic etiology.12,13 Other factors may play a role in determining the ulcerations, like malformations and hyperkeratosis, which have been demonstrated to
FIGURE 3 Correlation between vibration perception threshold at malleolus (VPT-M) and skin hardness measurement at heel (DMT-H) in neuropathic diabetic patients.
be associated with an increased risk for foot ulcerations.14,15 Our study demonstrated a higher degree of skin hardness in neuropathic feet compared to non-neuropathic and controls, before any ulceration was present. The hypothesis is that an increase of plantar pressures in hyposensitive neuropathic feet can lead to an increase of skin hardness as a reactive phenomenon. An indirect confirmation of this hypothesis is the higher level of skin hardness found in ND1 patients with hyperkeratosis compared to those without it. Nevertheless, the increase in hardness is present both in areas which are exposed to orthostatic stress, like the heel or the lateral midfoot, and in areas usually not exposed to this load, like medial midfoot. This observation, in a neuropathic foot still free from ulceration, can be explained in two different ways, the first independent, and the second dependent from the presence and severity of neuropathy. Delbridge et al.16 demonstrated an increased glycation of keratin from the stratum corneum of the skin of diabetic feet, and many studies had previously evidentiated a different structure in collagen chains from diabetic connective tissue, which is dehydrated and much more cross-linked than in non diabetic subjects.17,18 This could account for the increase of skin
TABLE 2. SKIN HARDNESS EVALUATED WITH DUROMETER AT HEEL (DMT-H), LATERAL MIDFOOT (DMT-L) AND MEDIAL MIDFOOT (DMT-M), IN NEUROPATHIC (ND1) AND NON-NEUROPATHIC (ND2) DIABETIC PATIENTS AND CONTROLS, RESPECTIVELY ND1 DMT-H (IU) DMT-L (UI) DMT-M (UI) DMT-C (UI)
51.18 51.16 49.51 42.12
6 6 6 6
6.19* 4.54* 3.42* 4.06
* (ANOVA) p , 0.01 [ND1 versus ND2 and Controls]. ** ANOVA p , 0.05 [DMT-M versus DMT-L and DMT-H].
ND2 44.53 43.78 39.02 41.07
6 6 6 6
5.33 4.11 8.27** 3.31
Controls 43.18 42.13 37.42 44.61
6 6 6 6
3.26 4.87 2.29** 2.97
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fuse increase of skin hardness in neuropathic diabetic patients compared both to non-neuropathic patients and healthy controls. Such modifications are detectable by simple, non-invasive measurements, and are strongly correlated with the severity of neuropathy. Skin hardening in diabetic feet can thus be considered as a feature of peripheral neuropathy an a potential determinant for the development of neuropathic ulcerations. ACKNOWLEDGMENT FIGURE 4 Correlation between vibration perception threshold at allux (VPT-A) and skin hardness measurement at medial midfoot (DMT-M) in neuropathic diabetic patients.
hardness independently from the pressure distribution and explain the finding of increased hardness also in the medial midfoot. Alternatively, the loss of control of the ankle joint in neuropathic patients which has recently been extensively documented by Simoneau et al.,19 by Uccioli et al.,20 and by Boucher et al.,21 could lead to an abnormal distribution of pressure also in the areas that are normally preserved from this stress. It has been shown how, in these conditions, the hyperpronation of feet while walking is a common adaptive mechanism to try to enhance the surface of contact between the foot and the ground.20 The exposition of the skin of plantar arch to the pressure stresses could stimulate the keratinocytes to replicate and increase the amount of keratin, which would account for the increased hardness. Although we have no direct tool to choose one of these alternative interpretations, the strong positive correlation between VPT, probably the most sensitive index of peripheral neuropathy in diabetes, and DMT, strengthens the pathogenetic role of neuropathy. On the other hand, the lack of differences observed in TcPO2 among the groups complicates the scene: one would expect a decrease of TcPO2 in ND1 related to the lower diffusibility of hardened skin compared to normal tissues, as an indirect confirmation of their structural changes. Actually, in diabetic peripheral neuropathy, an altered microvasomotility has been documented as a consequence of the loss of sympathetic efferent fibers, that leads to a fixed opening of arteriolar–venular precapillary shunts of lower extremities, with the consequence of a hyperoxygenation of venous blood and an increased TcPO2.22 The presence of altered tissues between the electrode and the micro-circulatory vessels can decrease the TcPO2 detected from the probe, and this can explain why no differences can be detected with this noninvasive technique between ND1 and control groups. In conclusion, our study provides evidence of a dif-
We are grateful to Dr. Luca Benzi for reviewing the manuscript and to Dr. Paola Bargagna for supervising the English translation.
REFERENCES 1. Boulton AJM: End-stage complications of diabetic neuropathy: Foot ulceration. Can J Neurol Sci 21:s18–s22, 1994. 2. Murray HJ, Boulton AJM: The pathophysiology of diabetic foot ulceration. Clin Podiatr Med Surg 12:1–17, 1995. 3. Romanelli M, Falanga V: Use of a durometer to measure the degree of skin induration in lipodermatosclerosis. J Am Acad Dermatol 32:188–191, 1995. 4. Falanga V, Bucalo B: Use of a durometer to assess skin hardness. J Am Acad Dermatol 29:47–51, 1993. 5. Aghassi D, Monoson T, Braverman I: Reproducible measurements to quantify cutaneous involvement in scleroderma. Arch Dermatol 13:1160–1166, 1995. 6. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA: A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17:1281–1289, 1994. 7. Bellavere F, Bosello G, Fedele D, Cardone C, Ferri M: Diagnosis and management of diabetic autonomic neuropathy [Letter]. Br Med J 287:61, 1983. 8. Goldberg JM, Ludblom U: Standardized method of determining vibratory perception threshold for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatry 42:739–743, 1979. 9. American Diabetes Association: Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes 37:1000–1004, 1988. 10. Piaggesi A, Castro Lopez E, Bini L, Giampietro O, Benzi L, Schipani E, Navalesi R: Measurable deficit of sensory and autonomic nerve function in asymptomatic diabetic patients. J Diabet Complications 6:157–162, 1992. 11. Eickoff JH, Engell HC: Transcutaneous oxygen tension (TcPO2) measurement on foot in normal subjects and in patients with peripheral arterial disease admitted for vascular surgery. Scand J Clin Lab Invest 41:743–748, 1981. 12. Boulton AJM: Clinical presentation and management of diabetic neuropathy and foot ulceration. Diabetic Med 8:552–557, 1991. 13. Veves A, Murray AH, Young MJ, Boulton AJM: The risk of foot ulceration in diabetic patients with high foot
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pressure: A prospective study. Diabetologia 35:660–663, 1992.
18. Kohn RR, Schnider SL: Glycosylation of human collagen. Diabetes 31 (suppl 3): 47, 1982.
14. Boulton AJM, Betts RP, Franks CI, Ward JD, Duckworth T: The natural history of foot pressure abnormalities in neuropathic diabetic subjects. Diabetes Res 5:73–77, 1987.
19. Simoneau GC, Ulbrecht JS, Derr JA, Becker MB, Cavanagh PR: Postural instability in patients with diabetic sensory neuropathy. Diabetes Care 17:1411–1421, 1994.
15. Young MJ, Cavanagh PR, Thomas G, Johnson MM, Boulton AJM: The effect of callus removal on dynamic plantar pressures in diabetic patients. Diabetic Med 9:55– 57, 1992.
20. Uccioli L, Giacomini PG, Monticone G, Magrini A, Durola L, Bruno E, Parisi L, Di Girolamo S, Menzinger G: Body sway in diabetic neuropathy. Diabetes Care 18:339– 344; 1995.
16. Delbridge L, Ellis CS, Robertson K, Lequesne LP: Nonenzymatic glycosylation of keratin from the stratum corneum of the diabetic foot. Br J Dermatol 112:547–554, 1985. 17. Burton JL: Thick skin and stiff joints in insulin-dependent diabetes mellitus. Br J Dermatol 106:369–374, 1982.
21. Boucher P, Teasdale N, Courtemenche R, Bard C, Fleury M: Postural stability in diabetic polyneuropathy. Diabetes Care 18:638–645, 1995. 22. Tooke JE: Microvascular haemodynamics in diabetes mellitus. Clin Sci 70:119–125, 1986.
ABSTRACT To evaluate if skin hardness in diabetic neuropathic feet was increased and if its eventual modifications could be correlated to the severity of neuropathy, we studied a group of diabetic outpatients with and without neuropathy. Patients, selected among those who were attending their routine screening for diabetic neuropathy at our diabetologic clinic, were divided into two groups according to the presence (ND1) or absence (ND2) of diabetic neuropathy with the criteria of the S. Antonio Consensus Conference on Diabetic Neuropathy. Patients then underwent an evaluation of vibration perception threshold (VPT) by means of a biotesiometer, measurement of skin hardness (DMT) by means of a durometer, and transcutaneous oxygen tension (TcPO2) determination. VPT was determined at allux (VPTA) and external malleolus (VPT-M), DMT was measured at heel (DMT-H), at medial (DMT-M) and lateral (DMT-L) midfoot, and at posterior midcalf (DTM-C) as a control site; TcPO2 was evaluated at dorsum (TcPO2-D) and at medial midfoot (TcPO2-M), respectively. All measurements were performed on the nondominant side with the patients supine.
Patients were compared with age and gendermatched healthy volunteers (Controls), who underwent the same evaluations in the same order. ND1 patients showed higher values of VPT than ND2 and Controls, both at first toe and at malleolus analysis of variance (ANOVA) p , 0.01), as well of DMT in all the three sites explored (ANOVA, p , 0.01). Moreover, ND1 showed no difference in DMT among the sites, while both in ND2 and in controls DMT-M was significantly (p , 0.05) lower than DMTH and DMT-L. No difference among the three groups were observed in TcPO2 measurements, and no difference in DMT-C was observed either. A significant correlation was observed between DMTH and VPT-M (r2 5 0.516) and between DMT-M and VPT-A (r2 5 0.624) in ND1 patients. Skin hardness was diffusely increased in ND1 patients, and this increase strongly correlates with the severity of neuropathy. Simple, noninvasive determination of skin hardness could identify patient at potential risk to develop neuropathic foot ulcers. (Journal of Diabetes and Its Complications 13; 3: 129–134, 1999.) 1999 Elsevier Science Inc.
INTRODUCTION
autonomic component of peripheral nerves.1 One of the key events in the pathogenetic pathway to neuropathic ulceration is hyperkeratosis, which develops in areas of increased pressure. Although orthostatic stress has been claimed to be the major responsible of hyperkeratosis, other factors, such as nonenzymatic glycation and autonomic dysidrosis are suspected of being involved in the pathogenesis of skin hardening.2 Recently, a new and easy method to assess skin hardness, durometry, was developed and applied to various skin pathologies, such as hypertrophic scars, dermatosclerosis, lymphedema, with interesting results.3
P
eripheral polyneuropathy is one of the major risk factors of foot ulcers in diabetic patients, through a multifactorial pathogenetic sequence that involves motor, sensitive, and
Department of Metabolic Diseases (A.P., E.S., F.C., F.B., R.N.), and Department of Dermatology (M.R., A.M.), University of Pisa, Pisa, Italy Reprint requests to be sent to: Dr. Alberto Piaggesi, U.O. Malattie del Ricambio e Diabetologia, Azienda Ospedaliera Pisana, Cisanello, Via Paradisa 2, 56100 Pisa, Italy. Journal of Diabetes and Its Complications 1999; 13:129–134 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
1056-8727/99/$–see front matter PII S1056-8727(98)00022-1
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The Durometer (Rex Gauge Co., Inc., Glenview, IL) is the international standard for hardness measurement of various nonmetallic materials, from rubber to plastic, wood etc. Model 0, as used in this study, is suitable for soft material such as animal tissues, in which there is a minimal amount of creep.4 The durometer shows the relative degree of tissue hardness on a linear calibrated gauge as the result of a spring-loaded interior that senses hardness by applying an indentation load on the specimen. Determination of skin hardness by this instrument has been proven to be accurate and reproducible, both in normal and pathological conditions.4,5 The purpose of this study was to measure skin hardness in diabetic neuropathic feet, in order to check if neuropathy-associated modifications of skin elasticity may be found before the occurrence of ulcerations. METHODS We studied a selected group of outpatients attending our diabetic clinic, chosen among those who were attending a routine periodic control scheduled between June and December 1996. Patients were selected according to the following inclusion criteria: diagnosis of type I or type II diabetes mellitus from more than 5 years, age range between 18 and 60 years, presence of peripheral polyneuropathy as ascertained by the bilateral absence of Achilles tendon reflexes, Michigan Neuropathy Screening Instrument [MNSI, normal range <26] score of greater than 7 and/or Autonomic Score [AS, an integrated index that takes into account the results of a battery of five different autonomic cardiovascular tests, normal range <27] score of greater than 3. Excluding criteria were having or having had in the past foot ulcerations, presence of clinically evident peripheral vascular disease (PVD) or absence of peripheral pulses, prolipherative retinopathy, serum creatinine greater than 2 mg/dL, scleroderma or other reumatologic diseases, other causes of polyneuropathy than diabetes mellitus, lymphedema, body-mass index [BMI 5 weight (kg) height (m)2 (normal range <25)] of 30 or greater. Patients, who were recruited after having performed their routine screening for diabetic chronic complications, were divided in two groups, ND1 and ND2 according to the presence or not of diabetic polyneuropathy following the criteria of the San Antonio Consensus Conference on Diabetic Neuropathy and compared to a group of gender- and age-matched healthy volunteers (Controls) chosen among the relatives of patients who agreed to participate. All participants were informed about the aims and methodology of the study, and informed consent was elicited before any evaluation was performed. The Study had previously obtained the approval of local ethic committee.
FIGURE 1 Evaluation of skin hardness was by applying the Durometert on the surface of heel, only held by gravity. Figure shows the upper side of the instrument, on which the graduated scale is visible.
Vibration Perception Threshold (VPT). Once recruited, patients underwent a second-level neuropathy assessment through the determination of VPT [normal range , 25 volts8] at first toe and external malleolus with a biothesiometer (Ohio Instruments), both in the nondominant leg, according to the recommendations of the American Diabetes Association for the diagnosis of diabetic neuropathy.9 The biothesiometer is an electric device provided with a vibrating probe, which can be applied on measurement site, held by gravity, and to which an increasing vibrating intensity is applied. The lowest of three intensity of vibration defines the VPT. VPT is a sensitive and reproducible method to determine the presence of peripheral neuropathy and quantify the extent of neural damage in diabetic patients; it shows a close correlation both with electrophysiology and with autonomic testing.10
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TABLE 1. CLINICAL AND DEMOGRAPHIC FEATURES OF PATIENTS AND CONTROLS Item n (IDDM/NIDDM) Age (years) Duration of disease (years) BMI (kg/m2) HbA1c (%) MNSI (score) AS (score)
ND1
ND2
Controls
36 (8/28) 51.48 6 12.03 17.34 6 08.52 28.84 6 06.12 8.7 6 2.6 12.22 6 2.41** 5.05 6 1.35**
36 (6/30) 53.22 6 08.96 15.66 6 04.44 29.54 6 09.23 9.1 6 1.8 2.13 6 1.89 1.0 6 0.5
36 54.98 6 09.11 — 28.17 6 08.81 4.6 6 0.9* 2.06 6 1.14 1.0 6 1.0
* Controls vs ND1 and ND2: ANOVA p , 0.01. ** ND1 versus ND2 and Controls; ANOVA p , 0.001. IDDM, insulin-dependent diabetes mellitus; NIDDM, non–insulin-dependent diabetes mellitus; BMI, body-mass index; HbA1c, glycosylated hemoglobin; MNSI, Michigan Neuropathy Screening Instrument; AS, autonomic Score; ND1, neuropathic diabetic patients; ND2, non-neuropathic diabetic patients; ANOVA, analysis of variance.
Skin Hardness Evaluation — DMT. After a rest in supine position for about 20 min at a room temperature of 258C with the shoes off, patients had their skin hardness measured with the Durometer [Rex Gauge, Glenview, IL] at the heel (DMT-H), median [the midpoint of the line connecting the center of the heel with the base of the first toe (DMT-M)], and lateral [the midpoint of the line connecting the center of the heel with the base of the fifth toe (DMT-L)] midfoot on the foot of nondominant side; measurements were performed also on posterior midcalf on the same side (DMT-C), which served as a control site. Areas with bony prominences were avoided. Any localized hyperkeratotic area was avoided as well, as any area reckonable by inspection or by light touch as hyperkeratotic. In no case, anyhow, hyperkeratosis was found to be present at sites of measurement, while in 16/36 (44%) ND1 patients, in 10/36 (28%) ND2, and in 11/36 (30%) controls hyperkeratosis was found under metatarsal heads and/or first toe. Durometer was positioned directly on the site of measurement with an angle of 90 degrees, held by gravity only (Figure 1); four measurements were repeated at all sites, and mean values were considered for analysis.4 Transcutaneous Oxygen Tension — TcPO2. TcPO2 was then measured at dorsum of feet (TcPO2-D) and on plantar side at median midfoot (TcPO2-M) with a TCM3 Oxymeter (Radiometer, Copenhagen, Denmark), according to a previously described methodology.11 The Probe was placed on the skin in the selected sites and the measurements were taken after at least 20 min, once the system had reached the steady state, and lasted for 5 consecutive min. The VPT, DMT, and TcPO2 evaluations were performed with patients lying in supine position (with the exception of plantar measurements, which were all performed in a prone position, with the leg flexed at 90 de-
grees), at standard room temperature: room temperature 258C 6 28C and humidity 45% 6 5%. Skin temperature ranged between 328C and 348C: if skin temperature, measured with a contact thermometer, was lower than 328C, infrared heating was activated, before the beginning of determinations. Patients were compared to a group of non-neuropathic diabetic patients superimposable for age, duration of diabetes, and absence of exclusion criteria (ND2), and with a group of gender- and age-matched healthy volunteers (C). Data, which are expressed as mean 6 standard deviation (SD), were analyzed with analysis of variance (ANOVA) and linear regression test with a commercially available software (Statview 512TM, running on a Macintosh SE computer). RESULTS Fifty-five patients fulfilled all inclusion criteria for entering the study, but only 36 were actually enrolled in the study; clinical and demographic characteristics of ND1, ND2, and controls are shown in Table 1. As expected, ND1 patients had significantly higher values of MNSI and AS than ND2 ones and controls, whereas no differences were found between ND2 and controls for these items (Table 1). VPT was significantly more enhanced in ND1 than in ND2 and controls both at first toe (39.25 6 9.13 versus 18.17 6 7.92 and 16.97 6 4.03 volts, respectively; ANOVA p , 0.01) and at malleolus (42.56 6 8.99 versus 17.35 6 6.21 and 19.24 6 8.45 volts, respectively; ANOVA p , 0.01), thus confirming the presence of and quantifying peripheral neuropathy (Figure 2). Skin hardness, as measured with DMT, was more pronounced in ND1 patients than in ND2 and in controls in the three sites explored, while ND2 skin showed no difference in comparison to controls at the three sites. At control sites, DMT-C showed no differences between the three groups. Both in ND2 and in
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FIGURE 2 Vibration perception threshold at allux (VPT-A) and external malleoulus (VPT-M) of neuropathic (ND1) and non neuropathic (ND2) diabetic patients and Controls.
controls, but not in ND1, DMT-M was significantly lower than DMT-H and DMT-L (Table 2 ). Among ND1 patients, those with metatarsal hyperkeratosis had significantly higher DMT-H (56.81 6 2.97 versus 46.75 6 3.61 UI; p , 0.001) and DMT-L (55.25 6 2.79 versus 44.9 6 2.86 UI; p , 0.001) compared to those without hyperkeratosis. No differences in TcPO2 was found in ND1 compared to ND2 and controls, neither at dorsum (TcPO2D, 60.56 6 9.15 versus 59.37 6 8.89 and 61.44 6 12.04, mm Hg, respectively) nor on plantar (TcPO2-M, 57.62 6 7.71 versus 58.12 6 9.44 and 58.91 6 6.76, mm Hg, respectively) side of the feet. No significant differences were elicited between dorsum and plantar determinations in any group as well. A significant positive correlation was evidentiated between DMT-H and VPTM (r2 5 0.516) and between DMT-M and VPT-A (r2 5 0.624) in ND1 patients, as shown in Figures 3 and 4, respectively. CONCLUSIONS Peripheral polyneuropathy has been claimed to be the major factor responsible for diabetic foot ulcerations: more than 65% of ulcers in diabetic feet have an underlying neuropathic etiology.12,13 Other factors may play a role in determining the ulcerations, like malformations and hyperkeratosis, which have been demonstrated to
FIGURE 3 Correlation between vibration perception threshold at malleolus (VPT-M) and skin hardness measurement at heel (DMT-H) in neuropathic diabetic patients.
be associated with an increased risk for foot ulcerations.14,15 Our study demonstrated a higher degree of skin hardness in neuropathic feet compared to non-neuropathic and controls, before any ulceration was present. The hypothesis is that an increase of plantar pressures in hyposensitive neuropathic feet can lead to an increase of skin hardness as a reactive phenomenon. An indirect confirmation of this hypothesis is the higher level of skin hardness found in ND1 patients with hyperkeratosis compared to those without it. Nevertheless, the increase in hardness is present both in areas which are exposed to orthostatic stress, like the heel or the lateral midfoot, and in areas usually not exposed to this load, like medial midfoot. This observation, in a neuropathic foot still free from ulceration, can be explained in two different ways, the first independent, and the second dependent from the presence and severity of neuropathy. Delbridge et al.16 demonstrated an increased glycation of keratin from the stratum corneum of the skin of diabetic feet, and many studies had previously evidentiated a different structure in collagen chains from diabetic connective tissue, which is dehydrated and much more cross-linked than in non diabetic subjects.17,18 This could account for the increase of skin
TABLE 2. SKIN HARDNESS EVALUATED WITH DUROMETER AT HEEL (DMT-H), LATERAL MIDFOOT (DMT-L) AND MEDIAL MIDFOOT (DMT-M), IN NEUROPATHIC (ND1) AND NON-NEUROPATHIC (ND2) DIABETIC PATIENTS AND CONTROLS, RESPECTIVELY ND1 DMT-H (IU) DMT-L (UI) DMT-M (UI) DMT-C (UI)
51.18 51.16 49.51 42.12
6 6 6 6
6.19* 4.54* 3.42* 4.06
* (ANOVA) p , 0.01 [ND1 versus ND2 and Controls]. ** ANOVA p , 0.05 [DMT-M versus DMT-L and DMT-H].
ND2 44.53 43.78 39.02 41.07
6 6 6 6
5.33 4.11 8.27** 3.31
Controls 43.18 42.13 37.42 44.61
6 6 6 6
3.26 4.87 2.29** 2.97
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fuse increase of skin hardness in neuropathic diabetic patients compared both to non-neuropathic patients and healthy controls. Such modifications are detectable by simple, non-invasive measurements, and are strongly correlated with the severity of neuropathy. Skin hardening in diabetic feet can thus be considered as a feature of peripheral neuropathy an a potential determinant for the development of neuropathic ulcerations. ACKNOWLEDGMENT FIGURE 4 Correlation between vibration perception threshold at allux (VPT-A) and skin hardness measurement at medial midfoot (DMT-M) in neuropathic diabetic patients.
hardness independently from the pressure distribution and explain the finding of increased hardness also in the medial midfoot. Alternatively, the loss of control of the ankle joint in neuropathic patients which has recently been extensively documented by Simoneau et al.,19 by Uccioli et al.,20 and by Boucher et al.,21 could lead to an abnormal distribution of pressure also in the areas that are normally preserved from this stress. It has been shown how, in these conditions, the hyperpronation of feet while walking is a common adaptive mechanism to try to enhance the surface of contact between the foot and the ground.20 The exposition of the skin of plantar arch to the pressure stresses could stimulate the keratinocytes to replicate and increase the amount of keratin, which would account for the increased hardness. Although we have no direct tool to choose one of these alternative interpretations, the strong positive correlation between VPT, probably the most sensitive index of peripheral neuropathy in diabetes, and DMT, strengthens the pathogenetic role of neuropathy. On the other hand, the lack of differences observed in TcPO2 among the groups complicates the scene: one would expect a decrease of TcPO2 in ND1 related to the lower diffusibility of hardened skin compared to normal tissues, as an indirect confirmation of their structural changes. Actually, in diabetic peripheral neuropathy, an altered microvasomotility has been documented as a consequence of the loss of sympathetic efferent fibers, that leads to a fixed opening of arteriolar–venular precapillary shunts of lower extremities, with the consequence of a hyperoxygenation of venous blood and an increased TcPO2.22 The presence of altered tissues between the electrode and the micro-circulatory vessels can decrease the TcPO2 detected from the probe, and this can explain why no differences can be detected with this noninvasive technique between ND1 and control groups. In conclusion, our study provides evidence of a dif-
We are grateful to Dr. Luca Benzi for reviewing the manuscript and to Dr. Paola Bargagna for supervising the English translation.
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