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The prevalence of symptoms of sensorimotor and autonomic neuropathy in Type 1 and Type 2 diabetic subjects
Journal of Diabetes and Its Complications 18 (2004) 27 – 31
The prevalence of symptoms of sensorimotor and autonomic neuropathy in Type 1 and Type 2 diabetic subjects Thomas Ka¨stenbauer a,*, Paul Irsigler b, Susanna Sauseng a, Angelika Grimm a, Rudolf Prager a,c a
L. Boltzman Institute of Metabolic Diseases and Nutrition, Hospital Lainz, Wolkersbergenstrasse 1, 1130 Vienna, Austria b Hanusch Hospital, Vienna, Austria c 3rd Medical Department of Metabolic Diseases and Nephrology, Hospital Lainz, Vienna, Austria Received in revised form 24 April 2003; accepted 13 May 2003
Abstract The aim of this study was to analyze the prevalence and severity of sensorimotor and autonomic neuropathic symptoms within an outpatients diabetic population. A total of 350 consecutive Type 1 (26.9%) and Type 2 diabetic subjects were investigated using the Michigan Neuropathy Screening Instrument (MNSI). The original questionnaire was extended with questions on autonomic neuropathy and to include a six-point scale to rate the severity of symptoms, which were recorded accurately in order to avoid overrating. More than one half of Type 2 and nearly a third of Type 1 diabetic subjects suffer from at least one neuropathic symptom; the former suffered significantly more often from paresthesia ( P < .05) and burning pain ( P = .05). Less than 10% of the study population had autonomic symptoms. The prevalence of symptomatic polyneuropathy (PNP), diagnosed by an abnormal MNSI together with the presence of any symptom, was 16.0% in Type 1 and 37.5% ( P < .001) in Type 2 diabetic subjects. Subjects with an abnormal ankle reflex (54.6%) had in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor plus autonomic symptoms. The corresponding percentages for subjects with an abnormal vibration perception threshold (VPT; 28.9%) were 59.4%, 46.5%, and 34.7%, respectively. An abnormal ankle reflex was significantly correlated to numbness, and to the sum of sensorimotor and autonomic symptoms. An abnormal vibration perception was significantly correlated to numbness, to paresthesia pain, and to the sum of sensorimotor and autonomic symptoms. A higher percentage of Type 2 diabetic subjects had symptoms of neuropathy and the most frequent symptoms were numbness, muscle cramps and postural hypotension. D 2004 Elsevier Inc. All rights reserved. Keywords: Diabetes; Polyneuropathy; Prevalence; Sensorimotor symptoms; Autonomic symptoms
1. Introduction Diabetic polyneuropathy (PNP) is a common condition in patients suffering from diabetes. It is a well-known risk factor for diabetic foot ulceration and is often accompanied by troublesome or painful symptoms. The pathogenesis of diabetic PNP remains unclear. A combination of metabolic and vascular factors have been implicated in its etiology (Cameron & Cotter, 1997; Stevens, Feldman, & Greene, 1995). A detailed diagnosis of PNP is time consuming, as it must include signs and symptoms, quantitative sensory tests, nerve conduction studies, and measures of autonomic
* Corresponding author. Tel.: +43-1-80110-2874; fax: +43-1-801102778. E-mail address: [email protected] (T. Ka¨stenbauer). 1056-8727/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(03)00071-0
nerve function (Proceedings of a consensus development conference on standardized measures in diabetic neuropathy, 1992). Selecting reliable and simple tests for daily routine is necessary in order to cope with the increasing number of diabetic patients. Depending on the tests used, data concerning the prevalence of diabetic PNP vary in the literature. Following representative investigations, the overall prevalence of diabetic PNP in Europe is about one third in Type 1 and Type 2 diabetes (Fedele et al., 1997; Tesfaye et al., 1996). In clinical practice, diabetic PNP can be diagnosed by simple bedside tests investigating the integrity of peripheral sensory nerves. These tests were shown to provide reliable results and are recommended for regular application in diabetic patients (Armstrong, Lavery, Vela, Quebedeaux, & Fleischli, 1998). On the other hand, diabetic patients often report subjective symptoms of PNP and believe to
28
T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
suffer from it although they are unable to report the frequency, severity, and time of occurrence of their symptoms. Therefore, the prevalence of the symptoms of diabetic PNP might be overrated in clinical routine. In a large US population based survey, the symptoms of sensory neuropathy were found to be present in more than 30% of cases (Harris, Eastman, & Cowie, 1993). The aim of the present study was to analyze the prevalence and severity of neuropathic symptoms in diabetic outpatients and to determine the prevalence of symptomatic neuropathy diagnosed by the Michigan Neuropathy Screening Instrument (MNSI). These measures were compared between Type 1 and Type 2 diabetic subjects and, the associations between the measures and clinical signs of neuropathy were analyzed.
hammer. Results were considered abnormal when no reflex was seen in one or both extremities. The vibration perception threshold (VPT) was measured with a neurothesiometer (NT; A. Horwell, London, UK), which was rested vertically with its own weight at the pulp of the great toe and was balanced with a light grip. The vibration was gradually increased until the patient reported his/her perception of it. A short break between measurements ensured comparable responses of sensory nerves. The first reading was discarded and the final result for the NT was recorded as the mean value from the remaining six readings. A reading of > 25 V was considered abnormal. The study protocol was approved by the local ethics committee, and a written informed consent was obtained from all patients.
2. Methods 3. Results The study comprised 350 consecutive Type 1 and Type 2 diabetic subjects visiting the outpatient department of the diabetes center at the Hospital Lainz for their routine diabetes control between March and November 2001. Diabetic PNP was diagnosed using the MNSI (Feldman et al., 1994), which was shown to be a reliable screening tool (Bax, Fagherazzi, Piarulli, Nicolucci, & Fedele, 1996). The MNSI includes a clinical foot inspection, a test of ankle reflexes and of vibration perception, and a questionnaire concerning symptoms. The original questionnaire (15 single questions) was amended with five questions on autonomic neuropathy and to include a six-point scale to rate the severity of symptoms: 0 = none, 1 = very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe. During the foot inspection, the investigators discussed every positive symptom with the subjects in order to obtain high data quality. Worthy of mention is the fact that only typical symptoms of diabetic neuropathy were recorded; they had to have occurred mainly at rest or at night on a regular or frequent basis over the last 3 – 6 months, and they should also have improved during activity (for sensory symptoms alone). Furthermore, the questions were grouped in order to distinguish between sensorimotor (numbness, paresthesia, burning pain, dysesthesia, cramps during night, or resting) and autonomic (postural hypotension, gustatory sweating, gastroparesis, diarrhea/constipation, erectile dysfunction) nerve dysfunction. Two investigators did independently rate the severity of neuropathic symptoms in 30 diabetic subjects to calculate the interobserver coefficient of variance for the amended symptom score; the CV was less than 10%. The patients’ feet were inspected for deformities, infections, hyperkeratosis, fissures, and active foot ulceration. Foot care was rated on a five-point scale, and smoking behavior was evaluated. The response of the ankle reflex (Achilles tendon reflex) was investigated in sitting position with a standard reflex
A total of 94 Type 1 (26.9%) and 256 Type 2 diabetic subjects were included in this study. Their mean age, duration of diabetes, body mass index, and A1c are given in Table 1. Type 2 diabetic subjects were about 25 years older than Type 1 subjects ( P < .0001) and had a significantly ( P < .0001) higher body mass index, but a significantly ( P < .01) lower duration of diabetes. The percentage of males and the mean A1c values were comparable between the two groups. 3.1. Clinical foot inspection The clinical foot inspection yielded an abnormal result in about 50% of Type 1 and about 75% of Type 2 diabetic subjects (Table 2). In particular, the frequency of fissures/ mycosis and foot deformities was significantly ( P < .0001) higher among Type 2 patients. Four Type 2 subjects had a minor foot ulcer. All measures of peripheral PNP were more pronounced among Type 2 diabetic subjects; VPT was nearly doubled ( P < .0001), as was the percentage of abnormal ankle reflex tests ( P < .0001) and that of an abnormal MNSI ( P < .0001; Table 2). Table 1 Characteristics of the investigated Type 1 and Type 2 diabetic subjects (n = 350)
N Age, years Male, % Height, cm Body mass index, kg m Diabetes duration, years Alc, % Currently smoking, %
2
Type 1
Type 2
Pa
94 38.4 F 12.8 57.4 173 F 10 25.4 F 5.1 16.0 F 12.8 7.6 F 1.1 36.2
256 64.0 F 11.6 50.8 168 F 14 29.2 F 5.5 10.3 F 8.3 7.9 F 1.3 17.2
< .0001 NS .0004 < .0001 .002 NS .0002
Data represent number, mean F S.D., or percentage. a Chi-square test or Mann – Whitney U test.
T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
3.2. Symptoms of diabetic PNP In general, Type 2 diabetic subjects had more frequent and more severe symptoms of peripheral PNP than did Type 1 subjects. More than one half of Type 2 and nearly a third of Type 1 diabetic subjects suffered from at least one symptom of neuropathy (Table 3). The severity of sensorimotor and autonomic symptoms was significantly ( P < .01) higher in the former group. When evaluating single symptoms, Type 2 diabetic subjects suffered significantly more often from paresthesia ( P < .05) and burning pain ( P = .05) (Table 3). Excluding erectile dysfunction, which was present in 13.0% of male Type 1 and 24.6% of male Type 2 diabetic subjects ( P = .08), less than 10% of the study population suffered from symptoms of autonomic nerve dysfunction. The prevalence of symptomatic diabetic PNP, diagnosed by an abnormal MNSI together with the presence of any symptom, was more than doubled among Type 2 diabetic subjects (16.0% vs. 37.5%, P < .001) (Table 3). 3.3. Correlations of symptoms with nerve function tests and risk factors Spearman rank correlations were calculated to determine associations between symptoms and clinical signs of diabetic PNP. Because the correlations did not differ between Type 1 and Type 2 diabetic patients, we pooled all data for the correlation analysis. A total of 191 (54.6%) subjects had an abnormal ankle reflex test and 101 (28.9%) subjects had an abnormal elevated vibration sense (VPT > 25 V). Subjects with an abnormal ankle reflex had in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor plus autonomic symptoms. The corresponding percentages for subjects with an abnormal VPT were 59.4%, 46.5%, and 34.7%, respectively. An abnormal ankle reflex was significantly correlated to numbness (r = .20, P < .001), to the sum of sensorimotor (r = .20, P < .001), and to autonomic (r = .19, P < .001) symptoms in general. An abnormal vibration perception was significantly correlated to numbness (r = .36, P < Table 2 Clinical foot inspection and MNSI
Feet abnormal, % Hyperkeratosis, % Mycosis/fissures, % Deformities, % Active foot ulcer, n Ankle reflex abnormal, % VPT, V VPT abnormal,b % MNSI, points (maximum 8) MNSI abnormal ( >2), %
Type 1
Type 2
Pa
46.8 24.5 24.5 8.5 0 35.1 12.3 F 9.6 9.6 1.76 F 1.55 29.8
75.4 29.3 52.7 28.5 4 61.7 23.4 F 13.2 37.1 3.05 F 1.64 63.7
< .0001 NS < .0001 < .0001 NS < .0001 < .0001 < .0001 < .0001 < .0001
Data represent number, mean F S.D., or percentage. a Chi-square test or Mann – Whitney U test. b VPT > 25 V.
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Table 3 Symptoms of diabetic polyneuropathy and the prevalence of symptomatic neuropathy Type 1
Type 2
Pa
Sensorimotor symptom, % Numbness Paresthesia Burning pain Dysesthesia Muscle cramps
13.8 6.4 8.5 5.3 12.8
21.5 16.8 16.8 6.6 21.9
NS .013 .052 NS 0.056
Autonomic symptoms, % Orthostatic dizziness Gustatory sweating Gastroparesis Diarrhea/obstipation ED, % of male
7.4 3.2 3.2 2.1 13.0
10.9 5.5 7.4 5.5 24.6
NS NS NS NS NS
All symptoms, % Any neuropathic symptom Symptomatic neuropathyb
29.8 16.0
52.3 37.5
.0002 .0001
Severity of symptoms, points Sensorimotor Autonomic
1.31 F 3.11 0.69 F 2.3
2.23 F 3.74 1.27 F 2.31
.004 .002
Data represent mean F S.D. or percentage. ED = erectile dysfunction. a Chi-square test or Mann – Whitney U test. b MNSI > 2 points and presence of any neuropathic symptom.
.0001), to paresthesia (r = .21, P < .001), and to the sum of sensorimotor (r = .21, P < .0001) and autonomic (r = .33, P < .0001) symptoms. No associations were registered between symptoms and the duration of diabetes, gender, height, and A1c. The age of subjects was significantly correlated to the sum of sensorimotor (r = .24, P < .001) and autonomic (r = .23, P < .001) symptoms.
4. Discussion During this study, 350 Type 1 and Type 2 diabetic subjects were investigated for their symptoms of peripheral PNP. This in-hospital study population is representative of diabetic subjects attending the diabetic outpatient department for their routine control; it did not include patients attending the hospital for the treatment of severe complications of diabetes. Although the symptoms of diabetic PNP are common in individuals with diabetes, only a few reports in the published literature deal with these encumbering conditions. The comparison to other studies is somewhat difficult because most were population-based (Dyck, Davies, Litchy, & O’Brien, 1997; Franklin, Kahn, Baxter, Marshall, & Hamman, 1990; Harris et al., 1993) and not hospital-based (Maser et al., 1990). In the San Luis Valley Diabetes Study, the prevalence of neuropathy was reported with 25.8% in Type 2 diabetic patients, whereas neuropathy was diagnosed by the history of symptoms and by an
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T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
abnormal ankle reflex (Franklin et al., 1990). This number was comparable to the prevalence of symptomatic neuropathy found in the present study (16.0% in Type 1 and 37.5% Type 2 diabetes). At the 1989 National Health Interview Survey in the US, a representative sample of 2405 people with diabetes were investigated by means of structured interviews for their symptoms and determinants of sensory neuropathy (Harris et al., 1993). The subjects were questioned with regard to numbness (which was reported in 28.2% of cases), painful sensations, or paresthesia (26.8%), and for an impaired ability to differentiate between hot and cold (9.8%) over the last 3 months. Compared to the present clinical-based study, the prevalence of numbness, paresthesia, and burning pain was higher among the US population based survey, which might be due to the more careful recording of symptoms in the present study to avoid overrating. In concordance with the US data (Harris et al., 1993), numbness was the most frequent symptom of diabetic PNP. In the present study, muscle cramps in the lower extremities (12.8% among Type 1 and 21.9% among Type 2 patients) and erectile dysfunction (13.0% and 24.6%) among male subjects were also very common. Another population-based study, the Rochester Diabetic Neuropathy Study, reported about two thirds of 380 diabetic subjects (26.8% Type 1 diabetes) having evidence for some variety of neuropathy; but only 13% had neuropathic symptoms (Dyck et al., 1997). However, single sensory symptoms (numbness with 3.1%, paraesthesia 3.6%, and pain 5.1%) were less frequent when compared to the current study, although these prevalences were obtained from patients who had an abnormal baseline neuropathic evaluation. The authors also pointed to the increased frequency of symptoms when patients answered a questionnaire by their own (Dyck et al., 1997). In general, symptoms of autonomic nerve dysfunction are rare. Among Type 1 diabetic patients, the prevalence of most autonomic symptoms was less than 5%; the most frequent symptoms were orthostatic dizziness, gastroparesis, and reduced awareness of hypoglycemia (Maser et al., 1990). A slightly lower (5%) percentage suffered from erectile dysfunction (Maser et al., 1990), which was somewhat lower than in Type 1 diabetic patients of the present study (13%). A greater percentage of Type 2 diabetic subjects had symptoms of sensorimotor and autonomic neuropathy than Type 1 patients had. However, the different prevalence was statistically significant for paresthesia and burning pain only. When combining symptoms, the frequency of abnormal results increased, and those of a neuropathic nature were found more frequently in Type 2 diabetic subjects than in Type 1 subjects (52.3% vs. 29.8%). The difference was even more evident when the severity was analyzed. Type 2 diabetic patients had more severe sensorimotor symptoms too, as indicated by an elevated mean severity grade by more than one point. At least in Type 1 diabetic patients, the development and progression of diabetic neuropathy is associated with met-
abolic control and the duration of diabetes (Tesfaye et al., 1996; The Diabetes Control and Complications Trial Research Group, 1995). In Type 2 subjects, the use of insulin in addition to poor diabetic control was the main predictor of distal neuropathy (Franklin, Shetterly, Cohen, Baxter, & Hamman, 1994). In contrast, the UK Prospective Diabetes Study (UKPDS) Group (1998) could not demonstrate a lower progression of neuropathy defined by vibration perception in intensively treated Type 2 diabetic subjects. However, all these correlations were obtained in the presence of peripheral neuropathy and not specifically in association with symptoms of neuropathy. We registered a significant correlation of symptoms with age; no association with the duration of diabetes, gender, height (reflecting nerve length), and A1c was registered. The development of symptoms did not necessarily parallel the presence or progression of neuropathy in many subjects. This is confirmed by the finding of significant but only weak (r = .20 – .36) correlations of the different symptoms with an abnormal ankle reflex or an abnormal vibration perception. The presence of a single neuropathic symptom does not permit the diagnosis of peripheral diabetic PNP, although often defined as such in daily routine. Because a detailed diagnosis in accordance with the suggestions of the Concensus Conference on Diabetic Neuropathy (1992) is not feasible in many cases, a short screening program such as the MNSI could be reliably used. About one third of Type 1 and about one half of Type 2 diabetic subjects suffered from at least one typical neuropathic symptom. The most frequent single symptoms were numbness and muscle cramps in the lower extremities. Further, the frequency of symptomatic neuropathy was doubled in Type 2 diabetic patients, affecting more than one third of these patients. Neuropathic patients, especially those with an abnormal vibration sense (Kastenbauer, Sauseng, Sokol, Auinger, & Irsigler, 2001; Young, Breddy, Veves, & Boulton, 1994), are at risk for diabetic foot complications.
Acknowledgments We would like to thank Mrs. Sujata Wagner for the revision of the manuscript.
References Armstrong, D. G., Lavery, L. A., Vela, S. A., Quebedeaux, T. L., & Fleischli, J. G. (1998). Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Archives of Internal Medicine, 158, 289 – 292. Bax, G., Fagherazzi, C., Piarulli, F., Nicolucci, A., & Fedele, D. (1996). Reproducibility of Michigan Neuropathy Screening Instrument (MNSI). A comparison with tests using the vibratory and thermal perception thresholds. Diabetes Care, 19, 904 – 905. Cameron, N. E., & Cotter, M. A. (1997). Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes, 46, S31 – S37.
T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31 Dyck, P. J., Davies, J. L., Litchy, W. J., & O’Brien, P. C. (1997). Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology, 49, 229 – 239. Fedele, D., Comi, G., Coscelli, C., Cucinotta, D., Feldman, E. L., Ghirlanda, G., Greene, D. A., Negrin, P., Santeusanio, F., Italian Diabetic Neuropathy Committee. (1997). A multicenter study on the prevalence of diabetic neuropathy in Italy. Diabetes Care, 20, 836 – 843. Feldman, E. L., Stevens, M. J., Thomas, P. K., Brown, M. B., Canal, N., & Greene, D. A. (1994). A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care, 17, 1281 – 1289. Franklin, G. M., Kahn, L. B., Baxter, J., Marshall, J. A., & Hamman, R. F. (1990). Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley diabetes study. American Journal of Epidemiology, 131, 633 – 643. Franklin, G. M., Shetterly, S. M., Cohen, J. A., Baxter, J., & Hamman, R. F. (1994). Risk factors for distal symmetric neuropathy in NIDDM. The San Luis Valley diabetes study. Diabetes Care, 17, 1172 – 1177. Harris, M., Eastman, R., & Cowic, C. (1993). Symptoms of sensory neuropathy in adults with NIDDM in the US population. Diabetes Care, 16, 1446 – 1452. Kastenbauer, T., Sauseng, S., Sokol, G., Auinger, M., & Irsigler, K. (2001). A prospective study of predictors for foot ulceration in type 2 diabetes. Journal of the American Podiatric Medical Association, 91, 343 – 350.
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Maser, R. E., Pfeifer, M. A., Dorman, J. S., Kuller, L. H., Becker, D. J., & Orchard, T. J. (1990). Diabetic autonomic neuropathy and cardiovascular risk. Pittsburg epidemiology of diabetes complications Study III. Archives of Internal Medicine, 150, 1218 – 1222. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy (1992). Diabetes Care, 15, 1079 – 07. Stevens, M. J., Feldman, E. L., & Greene, D. A. (1995). The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. Diabetic Medicine, 12, 566 – 579. Tesfaye, S., Stevens, L. K., Stephenson, J. M., Fuller, J. H., Plater, M., Ionescu, T. C., Nuber, A., Pozza, G., & Ward, J. D. (1996). Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia, 39, 1377 – 1384. The Diabetes Control and Complications Trial Research Group. (1995). The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine, 122, 561 – 568. UK Prospective Diabetes Study (UKPDS) Group. (1998). Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 352, 837 – 853. Young, M. J., Breddy, J. L., Veves, A., & Boulton, A. J. (1994). The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care, 17, 557 – 560.
The prevalence of symptoms of sensorimotor and autonomic neuropathy in Type 1 and Type 2 diabetic subjects Thomas Ka¨stenbauer a,*, Paul Irsigler b, Susanna Sauseng a, Angelika Grimm a, Rudolf Prager a,c a
L. Boltzman Institute of Metabolic Diseases and Nutrition, Hospital Lainz, Wolkersbergenstrasse 1, 1130 Vienna, Austria b Hanusch Hospital, Vienna, Austria c 3rd Medical Department of Metabolic Diseases and Nephrology, Hospital Lainz, Vienna, Austria Received in revised form 24 April 2003; accepted 13 May 2003
Abstract The aim of this study was to analyze the prevalence and severity of sensorimotor and autonomic neuropathic symptoms within an outpatients diabetic population. A total of 350 consecutive Type 1 (26.9%) and Type 2 diabetic subjects were investigated using the Michigan Neuropathy Screening Instrument (MNSI). The original questionnaire was extended with questions on autonomic neuropathy and to include a six-point scale to rate the severity of symptoms, which were recorded accurately in order to avoid overrating. More than one half of Type 2 and nearly a third of Type 1 diabetic subjects suffer from at least one neuropathic symptom; the former suffered significantly more often from paresthesia ( P < .05) and burning pain ( P = .05). Less than 10% of the study population had autonomic symptoms. The prevalence of symptomatic polyneuropathy (PNP), diagnosed by an abnormal MNSI together with the presence of any symptom, was 16.0% in Type 1 and 37.5% ( P < .001) in Type 2 diabetic subjects. Subjects with an abnormal ankle reflex (54.6%) had in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor plus autonomic symptoms. The corresponding percentages for subjects with an abnormal vibration perception threshold (VPT; 28.9%) were 59.4%, 46.5%, and 34.7%, respectively. An abnormal ankle reflex was significantly correlated to numbness, and to the sum of sensorimotor and autonomic symptoms. An abnormal vibration perception was significantly correlated to numbness, to paresthesia pain, and to the sum of sensorimotor and autonomic symptoms. A higher percentage of Type 2 diabetic subjects had symptoms of neuropathy and the most frequent symptoms were numbness, muscle cramps and postural hypotension. D 2004 Elsevier Inc. All rights reserved. Keywords: Diabetes; Polyneuropathy; Prevalence; Sensorimotor symptoms; Autonomic symptoms
1. Introduction Diabetic polyneuropathy (PNP) is a common condition in patients suffering from diabetes. It is a well-known risk factor for diabetic foot ulceration and is often accompanied by troublesome or painful symptoms. The pathogenesis of diabetic PNP remains unclear. A combination of metabolic and vascular factors have been implicated in its etiology (Cameron & Cotter, 1997; Stevens, Feldman, & Greene, 1995). A detailed diagnosis of PNP is time consuming, as it must include signs and symptoms, quantitative sensory tests, nerve conduction studies, and measures of autonomic
* Corresponding author. Tel.: +43-1-80110-2874; fax: +43-1-801102778. E-mail address: [email protected] (T. Ka¨stenbauer). 1056-8727/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(03)00071-0
nerve function (Proceedings of a consensus development conference on standardized measures in diabetic neuropathy, 1992). Selecting reliable and simple tests for daily routine is necessary in order to cope with the increasing number of diabetic patients. Depending on the tests used, data concerning the prevalence of diabetic PNP vary in the literature. Following representative investigations, the overall prevalence of diabetic PNP in Europe is about one third in Type 1 and Type 2 diabetes (Fedele et al., 1997; Tesfaye et al., 1996). In clinical practice, diabetic PNP can be diagnosed by simple bedside tests investigating the integrity of peripheral sensory nerves. These tests were shown to provide reliable results and are recommended for regular application in diabetic patients (Armstrong, Lavery, Vela, Quebedeaux, & Fleischli, 1998). On the other hand, diabetic patients often report subjective symptoms of PNP and believe to
28
T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
suffer from it although they are unable to report the frequency, severity, and time of occurrence of their symptoms. Therefore, the prevalence of the symptoms of diabetic PNP might be overrated in clinical routine. In a large US population based survey, the symptoms of sensory neuropathy were found to be present in more than 30% of cases (Harris, Eastman, & Cowie, 1993). The aim of the present study was to analyze the prevalence and severity of neuropathic symptoms in diabetic outpatients and to determine the prevalence of symptomatic neuropathy diagnosed by the Michigan Neuropathy Screening Instrument (MNSI). These measures were compared between Type 1 and Type 2 diabetic subjects and, the associations between the measures and clinical signs of neuropathy were analyzed.
hammer. Results were considered abnormal when no reflex was seen in one or both extremities. The vibration perception threshold (VPT) was measured with a neurothesiometer (NT; A. Horwell, London, UK), which was rested vertically with its own weight at the pulp of the great toe and was balanced with a light grip. The vibration was gradually increased until the patient reported his/her perception of it. A short break between measurements ensured comparable responses of sensory nerves. The first reading was discarded and the final result for the NT was recorded as the mean value from the remaining six readings. A reading of > 25 V was considered abnormal. The study protocol was approved by the local ethics committee, and a written informed consent was obtained from all patients.
2. Methods 3. Results The study comprised 350 consecutive Type 1 and Type 2 diabetic subjects visiting the outpatient department of the diabetes center at the Hospital Lainz for their routine diabetes control between March and November 2001. Diabetic PNP was diagnosed using the MNSI (Feldman et al., 1994), which was shown to be a reliable screening tool (Bax, Fagherazzi, Piarulli, Nicolucci, & Fedele, 1996). The MNSI includes a clinical foot inspection, a test of ankle reflexes and of vibration perception, and a questionnaire concerning symptoms. The original questionnaire (15 single questions) was amended with five questions on autonomic neuropathy and to include a six-point scale to rate the severity of symptoms: 0 = none, 1 = very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe. During the foot inspection, the investigators discussed every positive symptom with the subjects in order to obtain high data quality. Worthy of mention is the fact that only typical symptoms of diabetic neuropathy were recorded; they had to have occurred mainly at rest or at night on a regular or frequent basis over the last 3 – 6 months, and they should also have improved during activity (for sensory symptoms alone). Furthermore, the questions were grouped in order to distinguish between sensorimotor (numbness, paresthesia, burning pain, dysesthesia, cramps during night, or resting) and autonomic (postural hypotension, gustatory sweating, gastroparesis, diarrhea/constipation, erectile dysfunction) nerve dysfunction. Two investigators did independently rate the severity of neuropathic symptoms in 30 diabetic subjects to calculate the interobserver coefficient of variance for the amended symptom score; the CV was less than 10%. The patients’ feet were inspected for deformities, infections, hyperkeratosis, fissures, and active foot ulceration. Foot care was rated on a five-point scale, and smoking behavior was evaluated. The response of the ankle reflex (Achilles tendon reflex) was investigated in sitting position with a standard reflex
A total of 94 Type 1 (26.9%) and 256 Type 2 diabetic subjects were included in this study. Their mean age, duration of diabetes, body mass index, and A1c are given in Table 1. Type 2 diabetic subjects were about 25 years older than Type 1 subjects ( P < .0001) and had a significantly ( P < .0001) higher body mass index, but a significantly ( P < .01) lower duration of diabetes. The percentage of males and the mean A1c values were comparable between the two groups. 3.1. Clinical foot inspection The clinical foot inspection yielded an abnormal result in about 50% of Type 1 and about 75% of Type 2 diabetic subjects (Table 2). In particular, the frequency of fissures/ mycosis and foot deformities was significantly ( P < .0001) higher among Type 2 patients. Four Type 2 subjects had a minor foot ulcer. All measures of peripheral PNP were more pronounced among Type 2 diabetic subjects; VPT was nearly doubled ( P < .0001), as was the percentage of abnormal ankle reflex tests ( P < .0001) and that of an abnormal MNSI ( P < .0001; Table 2). Table 1 Characteristics of the investigated Type 1 and Type 2 diabetic subjects (n = 350)
N Age, years Male, % Height, cm Body mass index, kg m Diabetes duration, years Alc, % Currently smoking, %
2
Type 1
Type 2
Pa
94 38.4 F 12.8 57.4 173 F 10 25.4 F 5.1 16.0 F 12.8 7.6 F 1.1 36.2
256 64.0 F 11.6 50.8 168 F 14 29.2 F 5.5 10.3 F 8.3 7.9 F 1.3 17.2
< .0001 NS .0004 < .0001 .002 NS .0002
Data represent number, mean F S.D., or percentage. a Chi-square test or Mann – Whitney U test.
T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
3.2. Symptoms of diabetic PNP In general, Type 2 diabetic subjects had more frequent and more severe symptoms of peripheral PNP than did Type 1 subjects. More than one half of Type 2 and nearly a third of Type 1 diabetic subjects suffered from at least one symptom of neuropathy (Table 3). The severity of sensorimotor and autonomic symptoms was significantly ( P < .01) higher in the former group. When evaluating single symptoms, Type 2 diabetic subjects suffered significantly more often from paresthesia ( P < .05) and burning pain ( P = .05) (Table 3). Excluding erectile dysfunction, which was present in 13.0% of male Type 1 and 24.6% of male Type 2 diabetic subjects ( P = .08), less than 10% of the study population suffered from symptoms of autonomic nerve dysfunction. The prevalence of symptomatic diabetic PNP, diagnosed by an abnormal MNSI together with the presence of any symptom, was more than doubled among Type 2 diabetic subjects (16.0% vs. 37.5%, P < .001) (Table 3). 3.3. Correlations of symptoms with nerve function tests and risk factors Spearman rank correlations were calculated to determine associations between symptoms and clinical signs of diabetic PNP. Because the correlations did not differ between Type 1 and Type 2 diabetic patients, we pooled all data for the correlation analysis. A total of 191 (54.6%) subjects had an abnormal ankle reflex test and 101 (28.9%) subjects had an abnormal elevated vibration sense (VPT > 25 V). Subjects with an abnormal ankle reflex had in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor plus autonomic symptoms. The corresponding percentages for subjects with an abnormal VPT were 59.4%, 46.5%, and 34.7%, respectively. An abnormal ankle reflex was significantly correlated to numbness (r = .20, P < .001), to the sum of sensorimotor (r = .20, P < .001), and to autonomic (r = .19, P < .001) symptoms in general. An abnormal vibration perception was significantly correlated to numbness (r = .36, P < Table 2 Clinical foot inspection and MNSI
Feet abnormal, % Hyperkeratosis, % Mycosis/fissures, % Deformities, % Active foot ulcer, n Ankle reflex abnormal, % VPT, V VPT abnormal,b % MNSI, points (maximum 8) MNSI abnormal ( >2), %
Type 1
Type 2
Pa
46.8 24.5 24.5 8.5 0 35.1 12.3 F 9.6 9.6 1.76 F 1.55 29.8
75.4 29.3 52.7 28.5 4 61.7 23.4 F 13.2 37.1 3.05 F 1.64 63.7
< .0001 NS < .0001 < .0001 NS < .0001 < .0001 < .0001 < .0001 < .0001
Data represent number, mean F S.D., or percentage. a Chi-square test or Mann – Whitney U test. b VPT > 25 V.
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Table 3 Symptoms of diabetic polyneuropathy and the prevalence of symptomatic neuropathy Type 1
Type 2
Pa
Sensorimotor symptom, % Numbness Paresthesia Burning pain Dysesthesia Muscle cramps
13.8 6.4 8.5 5.3 12.8
21.5 16.8 16.8 6.6 21.9
NS .013 .052 NS 0.056
Autonomic symptoms, % Orthostatic dizziness Gustatory sweating Gastroparesis Diarrhea/obstipation ED, % of male
7.4 3.2 3.2 2.1 13.0
10.9 5.5 7.4 5.5 24.6
NS NS NS NS NS
All symptoms, % Any neuropathic symptom Symptomatic neuropathyb
29.8 16.0
52.3 37.5
.0002 .0001
Severity of symptoms, points Sensorimotor Autonomic
1.31 F 3.11 0.69 F 2.3
2.23 F 3.74 1.27 F 2.31
.004 .002
Data represent mean F S.D. or percentage. ED = erectile dysfunction. a Chi-square test or Mann – Whitney U test. b MNSI > 2 points and presence of any neuropathic symptom.
.0001), to paresthesia (r = .21, P < .001), and to the sum of sensorimotor (r = .21, P < .0001) and autonomic (r = .33, P < .0001) symptoms. No associations were registered between symptoms and the duration of diabetes, gender, height, and A1c. The age of subjects was significantly correlated to the sum of sensorimotor (r = .24, P < .001) and autonomic (r = .23, P < .001) symptoms.
4. Discussion During this study, 350 Type 1 and Type 2 diabetic subjects were investigated for their symptoms of peripheral PNP. This in-hospital study population is representative of diabetic subjects attending the diabetic outpatient department for their routine control; it did not include patients attending the hospital for the treatment of severe complications of diabetes. Although the symptoms of diabetic PNP are common in individuals with diabetes, only a few reports in the published literature deal with these encumbering conditions. The comparison to other studies is somewhat difficult because most were population-based (Dyck, Davies, Litchy, & O’Brien, 1997; Franklin, Kahn, Baxter, Marshall, & Hamman, 1990; Harris et al., 1993) and not hospital-based (Maser et al., 1990). In the San Luis Valley Diabetes Study, the prevalence of neuropathy was reported with 25.8% in Type 2 diabetic patients, whereas neuropathy was diagnosed by the history of symptoms and by an
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T. Ka¨stenbauer et al. / Journal of Diabetes and Its Complications 18 (2004) 27–31
abnormal ankle reflex (Franklin et al., 1990). This number was comparable to the prevalence of symptomatic neuropathy found in the present study (16.0% in Type 1 and 37.5% Type 2 diabetes). At the 1989 National Health Interview Survey in the US, a representative sample of 2405 people with diabetes were investigated by means of structured interviews for their symptoms and determinants of sensory neuropathy (Harris et al., 1993). The subjects were questioned with regard to numbness (which was reported in 28.2% of cases), painful sensations, or paresthesia (26.8%), and for an impaired ability to differentiate between hot and cold (9.8%) over the last 3 months. Compared to the present clinical-based study, the prevalence of numbness, paresthesia, and burning pain was higher among the US population based survey, which might be due to the more careful recording of symptoms in the present study to avoid overrating. In concordance with the US data (Harris et al., 1993), numbness was the most frequent symptom of diabetic PNP. In the present study, muscle cramps in the lower extremities (12.8% among Type 1 and 21.9% among Type 2 patients) and erectile dysfunction (13.0% and 24.6%) among male subjects were also very common. Another population-based study, the Rochester Diabetic Neuropathy Study, reported about two thirds of 380 diabetic subjects (26.8% Type 1 diabetes) having evidence for some variety of neuropathy; but only 13% had neuropathic symptoms (Dyck et al., 1997). However, single sensory symptoms (numbness with 3.1%, paraesthesia 3.6%, and pain 5.1%) were less frequent when compared to the current study, although these prevalences were obtained from patients who had an abnormal baseline neuropathic evaluation. The authors also pointed to the increased frequency of symptoms when patients answered a questionnaire by their own (Dyck et al., 1997). In general, symptoms of autonomic nerve dysfunction are rare. Among Type 1 diabetic patients, the prevalence of most autonomic symptoms was less than 5%; the most frequent symptoms were orthostatic dizziness, gastroparesis, and reduced awareness of hypoglycemia (Maser et al., 1990). A slightly lower (5%) percentage suffered from erectile dysfunction (Maser et al., 1990), which was somewhat lower than in Type 1 diabetic patients of the present study (13%). A greater percentage of Type 2 diabetic subjects had symptoms of sensorimotor and autonomic neuropathy than Type 1 patients had. However, the different prevalence was statistically significant for paresthesia and burning pain only. When combining symptoms, the frequency of abnormal results increased, and those of a neuropathic nature were found more frequently in Type 2 diabetic subjects than in Type 1 subjects (52.3% vs. 29.8%). The difference was even more evident when the severity was analyzed. Type 2 diabetic patients had more severe sensorimotor symptoms too, as indicated by an elevated mean severity grade by more than one point. At least in Type 1 diabetic patients, the development and progression of diabetic neuropathy is associated with met-
abolic control and the duration of diabetes (Tesfaye et al., 1996; The Diabetes Control and Complications Trial Research Group, 1995). In Type 2 subjects, the use of insulin in addition to poor diabetic control was the main predictor of distal neuropathy (Franklin, Shetterly, Cohen, Baxter, & Hamman, 1994). In contrast, the UK Prospective Diabetes Study (UKPDS) Group (1998) could not demonstrate a lower progression of neuropathy defined by vibration perception in intensively treated Type 2 diabetic subjects. However, all these correlations were obtained in the presence of peripheral neuropathy and not specifically in association with symptoms of neuropathy. We registered a significant correlation of symptoms with age; no association with the duration of diabetes, gender, height (reflecting nerve length), and A1c was registered. The development of symptoms did not necessarily parallel the presence or progression of neuropathy in many subjects. This is confirmed by the finding of significant but only weak (r = .20 – .36) correlations of the different symptoms with an abnormal ankle reflex or an abnormal vibration perception. The presence of a single neuropathic symptom does not permit the diagnosis of peripheral diabetic PNP, although often defined as such in daily routine. Because a detailed diagnosis in accordance with the suggestions of the Concensus Conference on Diabetic Neuropathy (1992) is not feasible in many cases, a short screening program such as the MNSI could be reliably used. About one third of Type 1 and about one half of Type 2 diabetic subjects suffered from at least one typical neuropathic symptom. The most frequent single symptoms were numbness and muscle cramps in the lower extremities. Further, the frequency of symptomatic neuropathy was doubled in Type 2 diabetic patients, affecting more than one third of these patients. Neuropathic patients, especially those with an abnormal vibration sense (Kastenbauer, Sauseng, Sokol, Auinger, & Irsigler, 2001; Young, Breddy, Veves, & Boulton, 1994), are at risk for diabetic foot complications.
Acknowledgments We would like to thank Mrs. Sujata Wagner for the revision of the manuscript.
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