Diabetes Reseurch and CI#fical Practice, 4 (I 988) 215--222 Elsevier 21,5

DRC 0018(1

Diabetic neuropathy as a heterogeneous syndrome: multivariate analysis of clinical and neurological findings

Hideyuki Sasaki, Kishio Nanjo, Machi Yamada , Keigo Naka, Hiroto Bessho, Hiroyoshi Kikuoka , Eiichi Satogami, Gensaku Matsumoto , Masanao Emoto and Kei Miyamura

First D~Tartment ~/" Medicine. Wakayama Universit.v of Medical Science, 1-7 Bancho. Wakayama. 640. Japan

(Reccivcd 17 February 1987, revision received 2 September 1987, accepted 14 September 1987)

KO" words: Neuropathy, diabetic; Nerve conduction velocity: Vibratory perception threshold: R-R interval coelficient of variation: Multivariate analysis

Summary

We quantitatively assessed peripheral and autonomic nerve function in diabetic patients and compared them with various parameters of their diabetic status. Motor and sensory nerve conduction velocity (MCV, SCV), vibratory perception threshold (VPT) and the coefficient of variation of the ECG R- R interval (CV R-R) were measured in 85 diabetic patients aged 20-59 years. These values were compared with those of age- matched healthy subjects. Moreover, in 53 patients, MCV, SCV, VPT and CV R-R were investigated by multivariate analysis in relation to clinical parameters. In diabetics, MCV, SCV and CV R-R were signifi- cantly lower and VPT was higher than in age-matched healthy controls. The prevalence of impaired values in diabetics was 70% for VPT in the toe, 60% for SCV, and 55% for MCV, CV R-R and VPT in the finger. Impairments of MCV, SCV, CV R-R and VPT were closely correlated with diabetic retinopathy, proteinuria and duration of disease. Categorical regression analysis (multivariate analysis) revealed that the impairment of conduction velocity was closely related to diabetic retinopathy and to hypo- or areflexia, that the impair- ment of the vibratory perception threshold was related to ischemic claanges in ECG and to hypo- or areflexia, and that the reduction of CV R-R was related to orthostatic hypotension and to proteinuria. These findings suggest that diabetic neuropathy progresses in parallel with other complications, and that it is a heterogeneous syndrome rather than a single entity.

Introduction

Diabetic neuropathy has a wide variety of clinical manifestations, and its pathogenesis is thought to

Address for correspondence: H. Sasaki, First Department of Medicine, Wakayama University of Medical Science. 1-7 Ban- cho, Wakayama, 640, Japan.

be heterogeneous [1]. Tests such as nerve conduc- tion studies [2-7], measurements of vibration [8,9], thermal sensitivity [10] and measurement of heart rate variation [11] have been used to evaluate the degree of diabetic neuropathy. However, there have been few reports in which careful and repeated neurological examinations have been performed on

0168-8227/88"$03.50 ~ ' 1988 Elsevier Science Publishers B.V. (Biomedical Division)

216

the same subjects at the same time and the results analyzed in relation to the clinical findings. In this study we investigated the motor and sensory nerve conduction velocities (MCV, SCV) and vibratory perception threshold (VPT) as quantitative periph- eral nerve function tests. The coefficient of variation of the R-R interval in ECG (CV R-R) was mea- sured as an objective quantitative autonomic nerve function test. In general, the neurological functions of diabetics deteriorate with the severity of the dis- ease, the age of the patient, and the duration of involvement. Multivariate analysis, therefore, is more useful to investigate the factors involved in diabetic neuropathy than are other methods of sta- tistical analysis. In order to elucidate the pattern of development of diabetic neuropathy, we analyzed the results of these nerve function tests in relation to various clinical parameters by simple and mul- tivariate analysis.

Materials and methods

Patients with diabetes mellitus of various degrees of severity who were hospitalized in our institution were included in this study. MCV and SCV were measured in 47 healthy controls and 85 diabetics. VPT was measured in 80 healthy controls and 59 diabetics. CV R-R was measured in 118 healthy controls and 85 diabetics. The subjects ranged in age from 20 to 59 years. All tests were carried out in a quiet room with an ambient temperature of 25-27°C. MCV of the ulnar and peroneal nerves and SCV of the median and sural nerves were de- termined by the same investigator using conven- tional methods. VPT was measured on the palmar aspects of the distal phalanx of the index finger and the tip of the big toe at frequencies of 63 and 125 Hz using a vibrometer (AU-02 RION). CV R-R was measured after 15 min of resting in a supine position using an R-R interval analyzer (Auto- nomic R100 M.E.C.).

MCV, SCV and VPT were defined as impaired if they were more than two standard deviations from the mean for healthy controls or could not be measured. CV R-R was assessed only in 58 dia-

betics aged 40-59 years and judged as impaired if it was below 2% [12]. Comparisons between the groups were made with the unpaired Student's t- test and the chi-square test.

In 53 diabetics, MCV, SCV, VPT and CV R-R were subjected to categorical regression analysis (multivariate analysis) in relation to clinical con- ditions, including subjective symptoms (numbness, tingling and burning sensations), hypo- or areflexia, orthostatic hypotension, diabetic retinopathy, pro- teinuria, cataract, ischemic change in the ECG and similar symptoms.

Results

Table 1 shows the distribution by age of the mean values and standard deviations of the results for nine neurological tests in diabetics and healthy con- trols. Even in the healthy subjects, MCV, SCV and CV R-R gradually decreased and VPT increased with aging. Specifically, VPT in the toe increased significantly in the fifth decade, and CV R-R de- creased in the fourth decade compared with the third decade. In diabetics, MCV, SCV and CV R- R were significantly lower and VPT was higher than in age-matched healthy controls.

Table 2 shows the prevalence of impaired values. The prevalence of impaired values in diabetics was about 70% for VPT in the toe: it was 60% for SCV, and 55% for MCV, CV R-R and VPT in the finger. Furthermore, in 20-63% of diabetics with neither retinopathy nor proteinuria, impairment of these functions was observed.

Table 3 shows the correlations between MCV, SCV, VPT, CV R-R and the various clinical parameters using simple statistical methods. Pro- teinuria showed a significant correlation with all neurological tests. Diabetic retinopathy showed a significant correlation with the results of the neuro- logical tests except for VPT in the finger. These findings suggest that diabetic neuropathy advances in parallel with other complications. The neuro- logical functions in these tests tended to deteriorate with increasing duration of diabetes. The diabetics on insulin treatment showed more severely im-

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TABLE 2

PREVALENCE OF IMPAIRED VALUES IN DIABETICS

The number of patients with impaired values/The total number of patients.

Diabetics Diabetics without retinopathy or proteinuria

No. % No. %

MCV of the ulnar nerve 49/85 MCV of the peroneal nerve 25/45

SCV of the median nerve 53/85 SCV of the sural nerve 29/47

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CV of R-R interval 32/58

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56.6 13/27 48.1 61.1 16/31 51.6

73.6 17/27 63.0 66.1 16/31 51.6

55.2 4/20 20.0

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Table 4 shows the result of categorical regression analysis (multivariate analysis) in 53 diabetics. The values represent partial correlation coefficients which indicate the degree of contribution of clinical factors (items) to the results of the neurological examinations. In this analysis, it was judged that there was a close relationship between the nerve functions ahd the clinical parameters when the par- tial correlation coefficient was above 0.300. The

slowing of MCV and SCV was closely correlated to diabetic retinopathy, subjective symptoms and hy- po- or areflexia. The impairment of VPT was relat- ed to ischemic change in the ECG, subjective symp- toms and hypo- or areflexia. The reduction in CV R - R was related to subjective symptoms, protein- uria and orthostatic hypotention.

Discussion

To evaluate nerve function, it is necessary to be familiar with the physiological changes associated

with aging. In this study, we found a considerable age difference in every test and reaffirmed that con- sideration of the patient 's age was necessary to evaluate the results of nerve function tests.

Many nerve function tests have been carried out in patients with diabetic neuropathy, but there have been few reports [6-8,13] in which the results of the tests were analyzed by multivariate analysis. Sev- eral investigators have reported [2-5,8] that diabetic nerve conduction retardation occurs in the lower extremity before the upper, and in sensory nerves before motor nerves [4]. In this study, the preva- lence of impaired nerve conduction velocity was higher in SCV than in MCV, but there was no dif- ference between the lower and upper extremities. It is well known that vibration sensitivity in diabetics is often impaired. Recently, vibration sensitivity has been determined quantitatively [8], and it has been reported [9] that deterioration of the vibration sen- sitivity correlates with hyperglycemia. In this study, a high prevalence of impaired VPT in the big toe was observed, suggesting that measurement of VPT is a useful method for detecting the early stages of diabetic neuropathy. Diabetic autonomic neuro- pathy has been evaluated quantitatively by mea- surement of heart rate variation [11,12]. In this

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study, impairment ofCV R-R was observed in dia- betics. However, the prevalence of impairment was somewhat lower than that obtained by tests of the peripheral somatic nerve functions. Even among the patients with neither retinopathy nor protein- uria, our neurological tests revealed abnormal val- ues in 20-63%. Diabetic neuropathy, therefore, seemed to occur earlier than other complications.

Using simple statistical analysis, there were sig- nificant correlations between the results of these nerve function tests and the following clinical parameters: diabetic retinopathy, proteinuria, dur- ation of the illness, the type of therapy and the de- gree of impairment of the deep tendon reflex. Dia- betic neuropathy, therefore, was thought to worsen with the progress of diabetes.

Categorical regression analysis, however, re- vealed that the clinical factors which were closedly related to the impairment of MCV, SCV, VPT and CV R-R were different. Impaired nerve conduction velocity was closely correlated with diabetic retino- pathy and subjective symptoms, suggesting the pos- sible involvement of microangiopathy in the im- pairment of nerve conduction. There have been re- ports on reduced nerve blood flow in the sciatic nerves in streptozotocin-induced diabetic rats [14], and close relationships between developing neural and microvascular complications in young insulin- dependent diabetics [6]. Laor et al. [7] also reported that nerve conduction studies could discriminate between patients with and without retinopathy. These findings suggest the presence of a common factor for the pathogenesis of nerve conduction dis- turbance and microangiopathy. The impairrnent of VPT was related to ischemic changes in the ECG, subjective symptoms and hypo- or areflexia. This suggests that impaired vibratory sensation is closely related to macroangiopathy rather than microan- giopathy. Further studies on this problem should be made. The reduction in CV R R was related to the subjective symptoms, the severity of nephro- pathy and orthostatic hypotension. Since CV R-R indicates autonomic nerve function, close relation- ships between CV R-R and orthostatic hypoten- sion are to be expected. As it has been reported that a reduction of CV R-R is observed even in non-

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diabetic patients with chronic renal failure [15,16], renal dysfunction might have an unfavorable influ- ence on the autonomic nerve function.

From these results, each of the nerve function tests carried out in this study is thought to reflect different aspects of diabetic neuropathy, and they appear to be useful for clarifying the heterogeneity of diabetic neuropathy.

Acknowledgement

We are greatly indebted to Dr. J.B. Jaspan, As- sociate Professor, Department of Medicine, Chi- cago University, Chicago, IL, for reading the manuscript.

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