Comparison of Quantitative Sensory-Thresh old Measures for Their Association With Foot Ulceration in Diabetic Patients
We compared the accuracy of cutaneous pressure perception-threshold measurements with that of other sensory-threshold measurements for detecting diabetic foot ulcer patients. Three hundred fourteen non-insulindependent diabetic patients were studied, of whom 91 had either a current foot ulcer or a history of foot ulceration. Foot ulcer patients had much higher pressure perception thresholds at the hallux than those without foot ulcers (mean ± SE 4.63 ± 0.05 vs. 3.54 ± 0.04 U, P < 0.001). The magnitude of association was higher than that for vibration thresholds and markedly greater than those for cool and warm thresholds. Pressure thresholds were highly accurate for identifying foot ulcer patients. At a threshold level of 4.21 U, the sensitivity was 0.84, with a specificity of 0.96. At similar sensitivities for vibration and thermal thresholds, specificities were lower. Foot ulceration and cutaneous pressure perception threshold are strongly associated. Pressure-threshold measurements are extremely accurate and perform at least as well as other quantitative sensory tests in identifying foot ulcer patients. Assessment of the foot pressure threshold may have promise as a simple and inexpensive method for detecting diabetic patients at risk for foot ulcers. Diabetes Care 13:1057-61, 1990
iabetes mellitus is associated with an extremely high risk of lower-extremity amputation (1,2), and foot ulceration often contributes to this complication. Although both peripheral ischemia and neuropathy have been considered causal factors for foot ulcers, some data suggest that most may be the result of sensory neuropathy (3). Hypoesthesia associated with sensory neuropathy apparently leads to the development of excessive foot pressures and resultant ulceration (4). Thus, foot ulceration can probably
D
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
lay M. Sosenko, MD, MS Marta Kato, MD Ramon Soto, MD Diane E. Bild, MD, MPH
be prevented by identifying and educating hypoesthetic patients about proper foot care. Assessments of hypoesthesia have been enhanced by the development of quantitative sensory testing for various sensory modalities (5-8). Cutaneous pressure sensitivity testing with the Semmes-Weinstein monofilament pressure esthesiometer (9) may have particular promise for screening diabetic patients at risk for foot ulceration. This inexpensive device consists of a series of nylon filaments of differing calibers. The pressure applied varies with the caliber of the monofilament when it is pressed against a surface until it bends. In recent years, these monofilaments have been used to evaluate patients with sensory abnormalities resulting from leprosy and nerve compression (1014). Although there is less information concerning their use in diabetic patients, in one study, diabetic foot ulcer patients were observed to have less pressure sensation than diabetic patients without foot ulcers (15). We conducted a study in which the accuracy of pressure-sensation measurements was compared with that of other quantitative sensory indices for identifying diabetic foot ulcer patients. In addition, we examined which levels of insensitivity identify patients with foot ulcers.
From the Department of Medicine, University of Miami School of Medicine, Miami, Florida; and the Division of Diabetes Translation, Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, Atlanta, Georgia. Address correspondence and reprint requests to Jay M. Sosenko, MD, Department of Medicine, R-103, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. Received for publication 12 January 1990 and accepted in revised form 4 April 1990.
1057
SENSORY THRESHOLDS AND DIABETIC FOOT ULCERS
RESEARCH DESIGN AND METHODS The study included 314 non-insulin-dependent diabetic patients who attended clinics at Jackson Memorial Hospital and a satellite clinic in Miami (Family Health Center). All patients were >25 yr of age, and none had diabetes diagnosed before that age. Individuals with other etiologic factors that could cause neuropathy were excluded, as were those who could not adequately perform the testing procedures. Foot ulcer patients consisted of those with a history of foot ulcers and/or a current foot ulcer. Most of the foot ulcer patients were derived from the foot ulcer clinic at Jackson Memorial Hospital. All subjects signed informed consent forms approved by the Subcommittee for the Protection of Human Subjects of the University of Miami before their participation. During the visit, patients were asked about numbness, and a history was obtained on the number and site(s) of foot ulcers. (Medical record documentation was obtained for all subjects who claimed previous ulcers but had no current ulcers.) Height was measured with a height rod after the removal of footwear. Subjects were then tested for their ability to sense cotton wisp and pinprick applications at the plantar surface of the right hallux. Patients underwent sensory testing with the monofilament pressure esthesiometer (Research Designs, Houston, TX) along with a battery of other quantitative sensory tests. After sensory testing, a venipuncture was performed for the measurement of HbA1c (cation-exchange chromatography). One observer performed all measurements. Testing with the monofilament pressure esthesiometer was performed at the plantar surface of the right hallux and at the 1st, 2nd, and 5th metatarsal heads, whereas the other quantitative sensory tests were performed at the right hallux (9). Monofilaments were applied until there was bowing. Starting with the highest pressure, a forced-choice algorithm was used. At each level (17 potential levels) of pressure (range 1.65-6.16 U), the monofilament was applied at either time A or time B and patients stated at which time they thought that the monofilament was placed. Units are defined as log10 (force in mg x 10). With each correct response, the next lowest pressure was applied. When subjects were unable to detect the applied pressure, they were tested again at the same level, and the applied pressure was not decreased until there were correct responses on two consecutive trials. For levels below 3.00 U, tests were repeated twice at the same level before the pressure was decreased. Testing was concluded when a total of three errors were made. The cutaneous pressure perception threshold was the mean of the levels of the last three correct responses and the levels of the last three errors excluding the highest and lowest values. The one patient who responded correctly to all trials was considered to have a threshold of 1.65 U. The monofilaments were periodically tested with a balance for potential changes
1058
in the pressure applied. There was essentially no change throughout the study. Warm and cool thresholds were assessed with the thermal sensitivity tester (Sensortek, Clifton, NJ) by testing the ability of patients to discriminate temperature differences from 25°C. For measurement of warm sensitivity, one plate was set at 25°C, and the other plate was set at a higher temperature. The two plates were changed according to a standard algorithm. The right hallux was placed on each of the two plates for not >2 s, and subjects were asked which plate was warmer. Subjects were first asked to discriminate a temperature difference of 20°C. If there was an incorrect response, they were tested again at the same level, and the difference was not lowered until there were two correct responses in a row. With a correct response, the temperature difference between the two plates was lowered by 10% decrements until a difference of 1.0°C was reached. At that point, the difference was gradually lowered by 0.1 °C for the remainder of the test. For temperature differences of 2 s. The vibrating probe was alternated according to an algorithm, and subjects were asked to identify that probe. The amplitude of vibration was initially set at 20 U and gradually decreased in the same manner as that for thermal sensitivity testing until there were five incorrect responses. The threshold for vibration perception was calculated identically to that for thermal perception. Data analysis. The t tests for the comparison of independent means were used to examine differences between patients with and without foot ulcers. Simple associations between discrete variables were assessed with the x2-test. Diagnostic testing indices have been described previously (16). Because the proportion of foot ulcer patients in our study was not representative of the true prevalence of foot ulcers, positive predictive values were estimated on the basis of a foot ulcer prevalence of 0.13 (17). Multiple logistic regression analyses were performed to examine associations of foot ulceration with patient characteristics. P values were two sided. Calculations were performed with the Systat statistical package.
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
J.M. SOSENKO AND ASSOCIATES
TABLE 2 Quantitative sensory-threshold values of diabetic patients
RESULTS
Of the 314 subjects who entered the study, 91 had a current foot ulcer (n = 33) and/or a history of foot ulceration (n = 79). Seventy-two percent of the patients without foot ulcers were women, and 61 % were White. Sixty-five percent of the foot ulcer patients were women, and 59% were White. Other characteristics of the study subjects are shown in Table 1. The foot ulcer patients were taller (P = 0.002) and had a longer duration of diabetes (P < 0.001). When the most recently occurring foot ulcer in each patient was considered, 45% were located at the toes, 12% at the metatarsal heads, and 20% at the midfoot plantar surface. To determine whether there was heterogeneity in quantitative sensory testing among the foot ulcer patients, we compared the 12 patients who had current foot ulcers and no previous foot ulcers with the 58 patients who had previous foot ulcers and no current foot ulcers. Values for all of the quantitative sensory measurements were almost identical for the two groups (P > 0.05 for all comparisons). Sensory-threshold values are shown for patients with and without foot ulcers in Table 2. There were highly significant differences between groups for all modalities (P < 0.001). Differences between groups for the pressure sensitivities at the 1st, 2nd, and 5th metatarsals were similar to the difference at the hallux. We examined associations among threshold measures at the hallux, and the correlation coefficients were all appreciable (r = 0.61-0.90). Table 3 shows sensitivities, specificities, and estimated positive predictive values for the identification of foot ulcer patients through measurements of pressure (at hallux), vibration, and thermal thresholds. Potential cutoff values are not shown if sensitivities were ^0.80 or specificities were ^0.50. Pressure testing performed at least as well as vibration testing and better than thermal testing for the detection of foot ulcer patients. At a pressure threshold of 4.21 U, the sensitivity was 0.84, specificity was 0.96, and the estimated positive predictive value was 0.76. Table 4 shows sensitivities, specificities, and estimated positive predictive values when the pressure threshold (at hallux) was considered the level at which TABLE 1 Characteristics of study subjects No foot ulcers n Age (yr) Diabetes duration (yr) HbAlc (%) Body mass index (kg/m2) Height (m)
Foot ulcers
± ± ± ± ±
0.6 0.6 0.14 0.4 0.01
57.5 15.1 7.22 30.3 1.65
Values are means ± SE.
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
± ± ± ± ±
0.9 0.9 0.21 0.7 0.01
Pressure (U) Hallux 1st metatarsal 2nd metatarsal 5th metatarsal Vibration (U)t Cool (°C)t Warm (°C)t
No foo t ulcers (n = 223)
3.54 3.81 3.74 3.64 3.89 1.98 2.47
± dt dt dt dt it nt
0.04
0.04 0.04 0.04 0.11 0.06 0.08
Foot ulcers (n = 91)
4.63 4.89 4.83 4.75 7.17 3.51 4.34
± ± ± ± ± ± ±
0.05 0.04 0.04 0.05 0.19 0.18 0.18
t
17.3 16.7 16.7 16.1 15.7 11.0 10.1
Values are means ± SE. P < 0.001 between groups for all comparisons. *See algorithms in text. tMeasurements at hallux.
the first, second, or third error was made (see RESEARCH DESIGN AND METHODS). The sensitivity, specificity, and estimated positive predictive value for a threshold at the level of the third error were comparable with those for the more complex algorithm (Table 3). There was no association between foot ulceration and the presence of hypoesthesia by history (P > 0.10), and 68% of the foot ulcer patients denied having hypoesthesia. Although there were highly significant associations of foot ulceration with both the absence of cotton wisp (P < 0.001) and pinprick (P < 0.001) sensations, 47% of foot ulcer patients were capable of sensing the cotton wisp, whereas 67% were capable of sensing the pinprick. In multiple logistic regression analyses, foot ulceration was associated with both diabetes duration (P < 0.01) and height (P < 0.05). However, when pressure thresholds were added to the model, the associations became nonsignificant. There were no significant associations with ethanol, smoking, sex, or HbAlc either before or after the addition of pressure thresholds to the model.
DISCUSSION
I
91
223
58.1 10.8 7.01 30.5 1.62
P
Sensory modality*
NS
We compared the accuracy of cutaneous pressure perception-threshold measurements with that of other sensory-threshold measurements for detecting diabetic foot ulcer patients. Three hundred fourteen non-insulindependent diabetic patients were studied, of whom 91 had either a current foot ulcer or a history of foot ulceration. Foot ulcer patients had much higher pressure perception thresholds at the hallux than those without foot ulcers (mean ± SE 4.63 ± 0.05 vs. 3.54 ± 0.04 U, P < 0.001). The magnitude of association was higher than that for vibration thresholds and markedly greater than those for cool and warm thresholds. Pressure thresholds were highly accurate for identifying foot ulcer patients. At a threshold level of 4.21 U, the sensitivity was 0.84, with a specificity of 0.96. At similar sensitivities for vibration and thermal thresholds, specificities were lower. Foot ulceration and cutaneous pressure perception threshold are strongly associated. Pressure-threshold measurements are extremely accurate and perform at least as well as other quantitative sensory tests in identifying foot ulcer patients. Assessment of the foot pressure threshold may have promise as a simple and inexpensive method for detecting diabetic patients at risk for foot ulcers. Diabetes Care 13:1057-61, 1990
iabetes mellitus is associated with an extremely high risk of lower-extremity amputation (1,2), and foot ulceration often contributes to this complication. Although both peripheral ischemia and neuropathy have been considered causal factors for foot ulcers, some data suggest that most may be the result of sensory neuropathy (3). Hypoesthesia associated with sensory neuropathy apparently leads to the development of excessive foot pressures and resultant ulceration (4). Thus, foot ulceration can probably
D
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
lay M. Sosenko, MD, MS Marta Kato, MD Ramon Soto, MD Diane E. Bild, MD, MPH
be prevented by identifying and educating hypoesthetic patients about proper foot care. Assessments of hypoesthesia have been enhanced by the development of quantitative sensory testing for various sensory modalities (5-8). Cutaneous pressure sensitivity testing with the Semmes-Weinstein monofilament pressure esthesiometer (9) may have particular promise for screening diabetic patients at risk for foot ulceration. This inexpensive device consists of a series of nylon filaments of differing calibers. The pressure applied varies with the caliber of the monofilament when it is pressed against a surface until it bends. In recent years, these monofilaments have been used to evaluate patients with sensory abnormalities resulting from leprosy and nerve compression (1014). Although there is less information concerning their use in diabetic patients, in one study, diabetic foot ulcer patients were observed to have less pressure sensation than diabetic patients without foot ulcers (15). We conducted a study in which the accuracy of pressure-sensation measurements was compared with that of other quantitative sensory indices for identifying diabetic foot ulcer patients. In addition, we examined which levels of insensitivity identify patients with foot ulcers.
From the Department of Medicine, University of Miami School of Medicine, Miami, Florida; and the Division of Diabetes Translation, Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, Atlanta, Georgia. Address correspondence and reprint requests to Jay M. Sosenko, MD, Department of Medicine, R-103, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101. Received for publication 12 January 1990 and accepted in revised form 4 April 1990.
1057
SENSORY THRESHOLDS AND DIABETIC FOOT ULCERS
RESEARCH DESIGN AND METHODS The study included 314 non-insulin-dependent diabetic patients who attended clinics at Jackson Memorial Hospital and a satellite clinic in Miami (Family Health Center). All patients were >25 yr of age, and none had diabetes diagnosed before that age. Individuals with other etiologic factors that could cause neuropathy were excluded, as were those who could not adequately perform the testing procedures. Foot ulcer patients consisted of those with a history of foot ulcers and/or a current foot ulcer. Most of the foot ulcer patients were derived from the foot ulcer clinic at Jackson Memorial Hospital. All subjects signed informed consent forms approved by the Subcommittee for the Protection of Human Subjects of the University of Miami before their participation. During the visit, patients were asked about numbness, and a history was obtained on the number and site(s) of foot ulcers. (Medical record documentation was obtained for all subjects who claimed previous ulcers but had no current ulcers.) Height was measured with a height rod after the removal of footwear. Subjects were then tested for their ability to sense cotton wisp and pinprick applications at the plantar surface of the right hallux. Patients underwent sensory testing with the monofilament pressure esthesiometer (Research Designs, Houston, TX) along with a battery of other quantitative sensory tests. After sensory testing, a venipuncture was performed for the measurement of HbA1c (cation-exchange chromatography). One observer performed all measurements. Testing with the monofilament pressure esthesiometer was performed at the plantar surface of the right hallux and at the 1st, 2nd, and 5th metatarsal heads, whereas the other quantitative sensory tests were performed at the right hallux (9). Monofilaments were applied until there was bowing. Starting with the highest pressure, a forced-choice algorithm was used. At each level (17 potential levels) of pressure (range 1.65-6.16 U), the monofilament was applied at either time A or time B and patients stated at which time they thought that the monofilament was placed. Units are defined as log10 (force in mg x 10). With each correct response, the next lowest pressure was applied. When subjects were unable to detect the applied pressure, they were tested again at the same level, and the applied pressure was not decreased until there were correct responses on two consecutive trials. For levels below 3.00 U, tests were repeated twice at the same level before the pressure was decreased. Testing was concluded when a total of three errors were made. The cutaneous pressure perception threshold was the mean of the levels of the last three correct responses and the levels of the last three errors excluding the highest and lowest values. The one patient who responded correctly to all trials was considered to have a threshold of 1.65 U. The monofilaments were periodically tested with a balance for potential changes
1058
in the pressure applied. There was essentially no change throughout the study. Warm and cool thresholds were assessed with the thermal sensitivity tester (Sensortek, Clifton, NJ) by testing the ability of patients to discriminate temperature differences from 25°C. For measurement of warm sensitivity, one plate was set at 25°C, and the other plate was set at a higher temperature. The two plates were changed according to a standard algorithm. The right hallux was placed on each of the two plates for not >2 s, and subjects were asked which plate was warmer. Subjects were first asked to discriminate a temperature difference of 20°C. If there was an incorrect response, they were tested again at the same level, and the difference was not lowered until there were two correct responses in a row. With a correct response, the temperature difference between the two plates was lowered by 10% decrements until a difference of 1.0°C was reached. At that point, the difference was gradually lowered by 0.1 °C for the remainder of the test. For temperature differences of 2 s. The vibrating probe was alternated according to an algorithm, and subjects were asked to identify that probe. The amplitude of vibration was initially set at 20 U and gradually decreased in the same manner as that for thermal sensitivity testing until there were five incorrect responses. The threshold for vibration perception was calculated identically to that for thermal perception. Data analysis. The t tests for the comparison of independent means were used to examine differences between patients with and without foot ulcers. Simple associations between discrete variables were assessed with the x2-test. Diagnostic testing indices have been described previously (16). Because the proportion of foot ulcer patients in our study was not representative of the true prevalence of foot ulcers, positive predictive values were estimated on the basis of a foot ulcer prevalence of 0.13 (17). Multiple logistic regression analyses were performed to examine associations of foot ulceration with patient characteristics. P values were two sided. Calculations were performed with the Systat statistical package.
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
J.M. SOSENKO AND ASSOCIATES
TABLE 2 Quantitative sensory-threshold values of diabetic patients
RESULTS
Of the 314 subjects who entered the study, 91 had a current foot ulcer (n = 33) and/or a history of foot ulceration (n = 79). Seventy-two percent of the patients without foot ulcers were women, and 61 % were White. Sixty-five percent of the foot ulcer patients were women, and 59% were White. Other characteristics of the study subjects are shown in Table 1. The foot ulcer patients were taller (P = 0.002) and had a longer duration of diabetes (P < 0.001). When the most recently occurring foot ulcer in each patient was considered, 45% were located at the toes, 12% at the metatarsal heads, and 20% at the midfoot plantar surface. To determine whether there was heterogeneity in quantitative sensory testing among the foot ulcer patients, we compared the 12 patients who had current foot ulcers and no previous foot ulcers with the 58 patients who had previous foot ulcers and no current foot ulcers. Values for all of the quantitative sensory measurements were almost identical for the two groups (P > 0.05 for all comparisons). Sensory-threshold values are shown for patients with and without foot ulcers in Table 2. There were highly significant differences between groups for all modalities (P < 0.001). Differences between groups for the pressure sensitivities at the 1st, 2nd, and 5th metatarsals were similar to the difference at the hallux. We examined associations among threshold measures at the hallux, and the correlation coefficients were all appreciable (r = 0.61-0.90). Table 3 shows sensitivities, specificities, and estimated positive predictive values for the identification of foot ulcer patients through measurements of pressure (at hallux), vibration, and thermal thresholds. Potential cutoff values are not shown if sensitivities were ^0.80 or specificities were ^0.50. Pressure testing performed at least as well as vibration testing and better than thermal testing for the detection of foot ulcer patients. At a pressure threshold of 4.21 U, the sensitivity was 0.84, specificity was 0.96, and the estimated positive predictive value was 0.76. Table 4 shows sensitivities, specificities, and estimated positive predictive values when the pressure threshold (at hallux) was considered the level at which TABLE 1 Characteristics of study subjects No foot ulcers n Age (yr) Diabetes duration (yr) HbAlc (%) Body mass index (kg/m2) Height (m)
Foot ulcers
± ± ± ± ±
0.6 0.6 0.14 0.4 0.01
57.5 15.1 7.22 30.3 1.65
Values are means ± SE.
DIABETES CARE, VOL. 13, NO. 10, OCTOBER 1990
± ± ± ± ±
0.9 0.9 0.21 0.7 0.01
Pressure (U) Hallux 1st metatarsal 2nd metatarsal 5th metatarsal Vibration (U)t Cool (°C)t Warm (°C)t
No foo t ulcers (n = 223)
3.54 3.81 3.74 3.64 3.89 1.98 2.47
± dt dt dt dt it nt
0.04
0.04 0.04 0.04 0.11 0.06 0.08
Foot ulcers (n = 91)
4.63 4.89 4.83 4.75 7.17 3.51 4.34
± ± ± ± ± ± ±
0.05 0.04 0.04 0.05 0.19 0.18 0.18
t
17.3 16.7 16.7 16.1 15.7 11.0 10.1
Values are means ± SE. P < 0.001 between groups for all comparisons. *See algorithms in text. tMeasurements at hallux.
the first, second, or third error was made (see RESEARCH DESIGN AND METHODS). The sensitivity, specificity, and estimated positive predictive value for a threshold at the level of the third error were comparable with those for the more complex algorithm (Table 3). There was no association between foot ulceration and the presence of hypoesthesia by history (P > 0.10), and 68% of the foot ulcer patients denied having hypoesthesia. Although there were highly significant associations of foot ulceration with both the absence of cotton wisp (P < 0.001) and pinprick (P < 0.001) sensations, 47% of foot ulcer patients were capable of sensing the cotton wisp, whereas 67% were capable of sensing the pinprick. In multiple logistic regression analyses, foot ulceration was associated with both diabetes duration (P < 0.01) and height (P < 0.05). However, when pressure thresholds were added to the model, the associations became nonsignificant. There were no significant associations with ethanol, smoking, sex, or HbAlc either before or after the addition of pressure thresholds to the model.
DISCUSSION
I
91
223
58.1 10.8 7.01 30.5 1.62
P
Sensory modality*
NS
