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Prevalence of Peripheral and Autonomic Neuropathy in Newly Diagnosed Type II (Noninsulin-Dependent) Diabetes Klaus P. Ratzmann Martin Raschke lngrid Gander Erika Schimke

ABSTRACT

Institute of Diabetes and Metabolic Disorders, Berlin, Germany

Type II (noninsulin-dependent) diabetes (NIDDM) can be preceded by a relatively long period of disturbed glucose metabolism. Therefore, the prevalence of neuropathy and its possible relationship to metabolic abnormalities were investigated in 95 newly diagnosed type II diabetics (upper age limit was set at 55 years) with a mean age of 49.7 years (men/women ratio 1: 1). The study program was as follows: Detailed history, clinical investigation of peripheral nerves, sensory assessment to touch and pain (pinprick), vibration sensation using established techniques, and motor nerve conduction velocities (MNCV) of the fibular (peroneal) and ulnar nerves. Three cardiovascular autonomic function tests were performed: the Valsalva maneuver, standing (ratio between RR-interval,.,: RR-interval,,,), and deep breathing (maximum/minimum heart rate). Vascular diseases were diagnosed using a conventional la-lead resting electrocardiogram (ECG) and impedance measurement of the lower extremities. The results were as follows: abnormal vibration sensation in 80.0%, abnormalities of MNCV in 15.7%, abnormal sensations to touch or pinprick in 14.7%, and loss of reflexes in 13.6%. If peripheral neuropathy was defined as having at least three of the four abnormalities plus neuropathic symptoms, the prevalence was 6.3% (6 of 95 patients). Abnormalities of the three cardiovascular autonomic function tests were much less prevalent in type II diabetic patients (2.1-7.3%). In conclusion, the study showed that peripheral and autonomic neuropathy is not common at diagnosis in middle-aged type II diabetic patients without signs of microvascular or macrovascular complications. (The Journal of Diabetic Complications 5;1:1-5, 1991.)

INTRODUCTION

Reprint requests to be sent to: Dr. Klaus P. Ratzmann, Institute of Diabetes and Metabolic Disorders, Klosterstr. 71-72. Berlin, Germany 1020. Submitted for publication January 1990; accepted in revised form September 1990.

Neuropathy is a common complication of diabetes mellitus. The precise cause of diabetic neuropathy is not known, although previous studies offer substantial evidence of a metabolic component in the pathogenesis of diabetic neuropathy’-4 and suggest that tight metabolic control may improve nerve function in patients with type I (insulin-dependent) diabetes mellitus.’ 6 Type II diabetes can be preceded by a relatively long period of disturbed glucose metabolism. Therefore, diabetic neuropathy may already exist when diabetes is diagnosed. Only one systematic controlled study on the prevalence of diabetic neuropathy at diagnosis of type II diabetes is available. Thus, we wished to estimate the prevalence of polyneuropathy in newly diagnosed type II diabetic patients and to assess a possible relationship between neuropathy and metabolic abnormalities.

SUBJECTS AND METHODS Subjects

@ 1991 Elsevter Science PublMng 0891-6632191/$3.50

Co, ‘nc

Originally, we wished to examine an unselected group of newly detected type II diabetic patients aged less than 55 years who were diagnosed in the Institute of Diabetes and Metabolic Disorders of East Berlin. All patients of this age group in the East Berlin community 1

RATZMANN ET AL.

2

regularly attended our outpatient clinic for diagnostic purposes.7.8 Because the data of all diabetic patients in the East Berlin area are registered in a central computer, it is possible to study the diagnostic and therapeutic pattern in unselected geographically defined diabetic populations.’ The diabetic population in the present study is representative of the newly diagnosed type II diabetic patients in the defined age group. Diabetes mellitus was diagnosed according to the criteria of the World Health Organization (WHO):’ fasting plasma glucose levels 2 7.8 mmoHL on more than one occasion or an elevated plasma glucose concentration after an oral glucose tolerance test (75 g glucose dose) on more than one occasion (2 hr plasma glucose level 2 11.1 mmol/L). The criteria for inclusion of patients in the study were established type II diabetes within 10 days and age less than 55 years. According to the consensus statement of the San Antonio Conference,” confounding disorders, including lumber root disease, significant peripheral vascular disease, and nondiabetic neuropathy should be excluded systematically. Exclusion criteria were alcohol abuse and other alternative causes of peripheral neuropathy (eg, thyroid disease, vitamin B12 deficiency, radiculopathy). According to the selection and exclusion criteria, 95 newly diagnosed type II diabetic patients were selected to participate in the study.

Methods Because no distinguishing features are unique to diabetic neuropathy, all other likely causes of peripheral neuropathy or disorders that mimic peripheral neuropathy were excluded by careful history and physical examination by one experienced neurologist. Symptoms for peripheral neuropathy were defined as typical and severe symptoms of pain, dysesthesia, or paresthesia in the limb. Neuropathic pain was defined typically as burning, worse at night, unrelated to exercise, and with no other discernible cause. A standard neurologic examination included reflex measurement in the upper and lower extremities, sensory assessment of touch (cotton wool) and pain (pinprick). Vibration sensation threshold was measured on the lateral malleolus and hallux using a biothensiometer (WTZ Instrument, Berlin, F.R.G.). Previous work in our department has established the reproducibility of these techniques and a normal range for subjects aged less than 55 years, as that of other investigators.” Motor nerve conduction studies were performed unilaterally in the left arm and left leg using a three channel electromyograph (DISA), type 14 A 30) with surface electrodes, thermostatically regulated skin temperature control, and supramaximal stimuli. Motor nerve conduction velocities (MNCV) of the fibrular and ulnar nerves were recorded. According to the recommendations of the San Antonio Conference on Diabetic Neuropathy, our laboratory has standardized these measures by using our own population standards.‘O Each individual measurement was repeated and compared with the age-standardized mean value of the normal population (mean + 2 SD).” The autonomic nervous system was examined by three tests of heart rate control as generally recommended.‘0~‘3~‘4 Valsalva maneuver (Valsalva ratio), deep breathing (maximum/minimum heart rate), and standing

(30:15 ratio). The latter measures were compared with our laboratory age-standardized normal values of an appropriate control population as recommended by the American Diabetes Association. The following were used as measures for microvascular and macrovascular disease: direct ophthalmoscopy after pupillary dilatation by the same experienced ophthalmologist, determination of urinary protein excretion by means of sulfosalicylic acid or Nephur-test strips, serum creatinine according to a kinetic method,15 conventional 12-lead resting ECG and computerized bioimpedance measurement of lower extremities.16 Blood glucose concentration was determined enzymatically, and HbA, (normal range 7.0 I 0.4%) was measured by a calorimetric technique.” Serum cholesterol, HDL cholesterol, and triglyceride levels were measured by standard hospital laboratory methods.”

Statistical

Analysis: Results are mean -c SEM. Correlation coefficients were assessed by a verified computer program using linear regression analysis.

RESULTS Baseline

Characteristics: Sixty-three of 95 newly diagnosed type II diabetic patients had no overt diabetic symptoms (69.2%) despite having elevated fasting blood glucose and HbA, levels (Table 1). In this population of diabetic subjects without peripheral vascular disease, neither cases of retinopathy nor clinical nephropathy were found. Table 1 shows details of the baseline characteristics of the patients studied. Symptoms, Clinical mt?ntS of Peripheral

Examination, and Objective MeasureNerve Function: Neuropathic symp-

toms were pain in four patients (4.2%) and paresthesias or dysesthesias in the lower limbs in 23 patients (24.2%). Only one patient had both pain and paresthesias. The results of clinical examination, sensory threshold testing, and electroneurography are shown in Figure 1. Among single findings, loss of reflexes (13 of 95 patients) and abnormal sensations to touch or pinprick (14 of 95 patients) were recorded in 13.6 and 14.7%, respectively. Abnormalities MNCV were found in 15 of 95 patients (15.7%). The most frequent abnormality was a reduced vibration perception threshold (76 of 95 patients, 80.0%).

TABLE 1

Characteristics of 95 Newly Diagnosed Type 2 Diabetic Patients Parameter

Age at onset (yr) Sex (M/F) Body mass index (kg/m*) Fasting blood glucose (mmol/L) HbA,(%) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Creatinine (kmol/L) HDL, high-density lipoprotein.

Mean

f

SEM

49.7 5 0.5 48:47 29.8 k 0.5 11.3 f 0.3 8.9 2 0.3 5.6 2 0.1 1.2 2 0.1 2.1 ” 0.2 75.1 2 2.1

3

NEUROPATHYIN TYPE 2 NIOOM

I Vibration

MNCV

Sensat

ion

Reflexes

Sensation FIG. 1.

Frequency of abnormal signs and results of diagnostic tests in 95 new/y diagnosed type /I diabetic patients

Prevalence

of Polyneuropathy by Various Criteria: If peripheral neuropathy was defined as having at least three of four abnormalities (loss of reflexes, abnormal sensation, reduced MNCV, or reduced vibration sensation threshold) 9 of 95 newly diagnosed Type II diabetic patients (9.5%) had peripheral polyneuropathy. When neuropathic symptoms, defined by the presence of pains and paresthesias in the lower limbs, signs (loss of reflexes, abnormal sensation to touch or pinprick), electrophysiologic findings, and assessment of vibration sensation threshold were used as criteria, 6 patients (6.3%) had peripheral neuropathy. Table 2 shows metabolic data of patients with and without peripheral polyneuropathy. As shown in Table 2, neuropathy was not associated with either parameter of metabolic control (fasting blood glucose, HbA,, plasma lipids) or with signs of vascular

TABLE 2

Characteristics of Patients With and Without Peripheral Neuropathy (Mean f SEM) Peripheral Neuropathy Without (n = 89)

Parameter

48 k 0.8

Age (yr) Fasting blood glucose (mmoliL) HbA, (%) Cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Frequency of retinopathy Abnormal impedance measurements Electrocardiogram (abnormal findings)

11 7 8.8 5.3 1.3 3.2

2 k f 2 t 0 0 4

0.3 0.3 0.1 0.1 0.2

With (n = 8) 48 12.0 8.8 5.5 1.3 3.5

5 1.2 -c 0.6 r 0.9 k 0.9 2 0.2 + 0.7 0 0 0

disease. In accordance with these results, we failed to demonstrate any correlation between measures of peripheral polyneuropathy, ie, symptoms, clinical signs, neurophysiologic findings, and fasting blood glucose concentration (coefficients of correlation analyses ranged from -0.14 to 0.01).

Cardiovascular

Autonomic Neuropathy Assessment: The results of the Valsalva maneuver, heart rate response to standing and beat-to-beat variation during forced respiration are shown in Table 3. If autonomic neuropathy is considered as having two abnormalities of the three cardiovascular autonomic function tests, only one patient (prevalence ~1% percent) had autonomic neuropathy.

DISCUSSION Only one study has been made of the prevalence of peripheral and autonomic neuropathy in newly diagnosed type II diabetic patients.’ Thus, our results are necessarily comparable with that study. Because other causes of neuropathy must be excluded by careful history, physical examination, and appropriate diagnostic tests in this study, and because neuropathy must accompany currently accepted diagnostic criteria for diabetes, a nondiabetic control group was not included in our study. A relationship between the degree of hyperglycemia and changes in sensory and autonomic nerve function TABLE 3

Abnormalities of Three Cardiovascular Autonomic Function Tests in 95 Patients

Test

n

(%)

Valsalva maneuver Standing

2

2.1

4 7

4.2 7.3

Deep breathing HDL. high-density

lipoprotein

RATZMANN ET AL.

4 has been demonstrated in young patients with Type I diabetes.4 In addition, an association between reduced vibration sensation perception and poor metabolic control has been shown in Type II diabetics.lg In this study, 69% of all newly diagnosed Type II diabetic patients had no overt diabetic symptoms at the time of diagnosis. This observation corresponds well with the knowledge that Type II diabetes may be preceded by a relatively long period of disturbed glucose metabolism. The reduction of vibration sensation of the lower extremities in 80% of all newly diagnosed Type II diabetics could be interpreted in connection with the result. The high frequency of abnormal findings of vibration sensation threshold should be interpreted in connection with the relatively high variability of the method (coefficient of variation 8-20%).20 Hillson et al.” showed that hyperglycemia is one correlate of the deterioration in vibration sense in the feet of Type II diabetic patients within 5 years of diagnosis. Thus, reduction in hyperglycemia in our newly diagnosed diabetic patients may be accompanied by improvement of vibration sense.” Electrodiagnostic evaluation plays an important role in diagnosing diabetic neuropathy;” the method is more sensitive in detecting neuropathy than are clinical sensory tests of the vibration threshold.” Our results show that about 15.0% of newly diagnosed Type II diabetics had reduced MNCV in comparison with age-matched control subjects. Our observation corresponds well with the results of Lethinen et al.,’ who reported a prevalence of polyneuropathy according to electrophysiologic criteria of 15.2% in newly diagnosed Type II diabetic patients. Nerve conduction studies primarily reflect the functional status of large myelinated motor nerve fibers in the lower extremities, but normal results do not rule out neuropathy.” On the other hand, abnormal electrophysiologic results may occur without neurologic symptoms or signs. With regard to neuropathic symptoms, the frequency of paresthesias was slightly higher in our study as compared with the results of Lethinen et al.’ (24.2 vs. 17.2%). To classify diabetic neuropathy, the consensus statement of the San Antonio Conference recommended at least one measure from each of the following categories: clinical symptoms, clinical examination, quantitative sensory testing, and electrodiagnostic studies.” According to this criteria, we found peripheral polyneuropathy in 6.3% of newly diagnosed Type II diabetic patients. Lehtinen et al.’ reported polyneuropathy in newly detected Type II diabetics in 2.3%, defined by clinical signs and by electrophysiologic criteria in 15.2%, respectively. Palumbo et al.‘* described symptoms and signs of polyneuropathy in 4% of Type II diabetics in the first 5 years after the diagnosis. In contrast to Lehtinen et al.’ we failed to demonstrate any correlation between degree of hyperglycemia and measures of peripheral neuropathy. Cardiovascular autonomic function tests, ie, heart rate response to Valsalva maneuver, deep breathing and standing, have been validated and shown to be reliable and reproducible for evaluation of autonomic dysfunction.‘* Objective signs of neuropathy have been shown to correlate well with abnormal cardiovascular autonomic function tests.23 In addition, abnormalities in heart

rate response predict development of symptomatic neuropathy in diabetics.24 In our study, the frequency of abnormal cardiovascular autonomic function tests ranged from 2.2 to 7.2%. Lehtinen et al.’ reported abnormal R-R-interval variation during deep breathing in 3.3% in Type II diabetic patients at diagnosis. An abnormality of more than one autonomic function test on more than one occasion is desirable to establish the presence of autonomic dysfunction. If autonomic neuropathy was defined as having at least two abnormalities of cardiovascular autonomic function tests, only one patient had autonomic neuropathy. Young et al.4 described an association of neuropathy and microvascular complications, independent of glycemia, in young patients with Type I diabetes. Like Sjoberg et al.25 we found no relation between motor, sensory, and autonomic abnormalities and glycemic control and no association between microvascular or macrovascular lesions. In conclusion, the present study showed that peripheral and autonomic neuropathy is not common at diagnosis in middle-aged Type II diabetic patients without signs of microvascular or macrovascular complications. On the basis of single symptoms, clinical signs, or neurophysiologic measures, however, the patients show a variety of abnormalities.

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Prevalence of peripheral and autonomic neuropathy in newly diagnosed type II (noninsulin-dependent) diabetes.

Type II (noninsulin-dependent) diabetes (NIDDM) can be preceded by a relatively long period of disturbed glucose metabolism. Therefore, the prevalence...
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