Clinical Differences of Diabetic Polyneuropathy or Carpal Tunnel Syndrome in Patients with Diabetes

Introduction

Patients with diabetes often suffer from diabetic polyneuropathy (DPN) and carpal tunnel syndrome (CTS). ^1-3 DPN, which is defined as chronic, symmetric, length-dependent sensorimotor polyneuropathy, is known to frequently occur in patients with diabetes, thus

당뇨병환자에서 당뇨병성신경병증과 손목터널증후군의 임상적 차이

양서연, 김대열

울산대학교 의과대학 서울아산병원 재활의학과

Clinical Differences of Diabetic Polyneuropathy or Carpal Tunnel Syndrome in Patients with Diabetes

Seoyon Yang, Dae Yul Kim

Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Received February 6, 2015

Revised (1st) April 14, 2015, (2nd) May 15, 2015, (3rd) May 19, 2015 Accepted May 19, 2015

Corresponding Author: Dae Yul Kim

Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Asanbyeongwon-gil 86, Songpa-gu, Seoul 138- 736, Korea.

Tel: 82-2-3010-3800, Fax: 82-2-3010-6964, E-mail: dykimsmart@gmail.com

Objective: To investigate whether there are clinical differences in patients with diabetic peripheral polyneuropathy (DPN)

Method: 587 patients with diabetes mellitus who had an electrodiagnostic study to investigate whether they had DPN or

Results: Of the 587 diabetic patients, 111 patients had DPN, CTS or both. Among 111 patients, 47 had DPN (42.3%), 29

Patients who had both DPN and CTS had higher levels of Hb1Ac, PP2, albumin/creatinine ratio, and longer duration of diabetes than the patients who had only DPN or CTS.

Conclusion: These results suggest that patients with both DPN and CTS showed a higher level of Hb1Ac, PP2, a longer

Key Words: diabetic polyneuropathy, carpal tunnel syndrome, diabetes

Copyright © by Korean Association of EMG Electrodiagnostic Medicine

This is an Open Ac cess article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

J Korean Assoc

Electrodiagn Med EMG ^{ORIGI NAL ART} ISSN 1229-6066 ^ICLE

http://dx.doi.org/10.18214/jkaem.2015.17.1.14

J Korean Assoc EMG Electrodiagn Med 17(1):14-19, 2015

affecting approximately 50% of diabetic patients. ^4,5 CTS is the second most common neuropathy that occurs in diabetic patients. ² It occurs more frequently in patients with diabetes compared with the general population, ^6,7 and the prevalence of CTS is approxi mately 15~25%. ⁸

Nerve conduction study (NCS) is a useful electro- diagnostic method for detecting damage to large nerve fibers. ⁹ NCS helps to make the accurate diagnosis of DPN or CTS. As polyneuropathy symptoms may be confused with the symptoms induced by CTS, the diagnosis of CTS is usually difficult in patients with DPN. ^10,11 Various studies have been conducted regarding DPN or CTS in patients with diabetes. Studies have suggested useful electrodiagnostic tests for the diagnosis of DPN and CTS ^9,10,12-14 and tried to determine possible risk factors which caused patients to develop DPN or CTS. ^4,15,16 Among these risk factors, how much they contribute to the development of either DPN or CTS has not yet been investigated. Therefore, this study was performed to determine whether there are differences in the risk factors between patients with DPN and those with CTS and to compare the risk factors in these patients.

Materials and Methods

1) Study subjects

587 with diabetes were referred to the Department of Rehabilitation Medicine at Asan Medical Center for a screening test for DPN from 2009 to 2011. Patients who had diabetes for more than one year were enrolled in our study. Patients who previously had peripheral neuropathy or radiculopathy or who could not tolerate electrodiagnosic studies were excluded. Both upper and lower extremities were evaluated for any abnormalities of muscle power, muscle tone or sensation test.

A 4-channel electrophysiological unit (Medelec ^® by Company of Oxford, United Kingdom) was used for NCS.

The skin temperature was controlled in order to be above 32 ^o C for the upper limb and 31 ^o C for the lower limb, so as to avoid the possible pitfalls of NCS. Motor NCSs were measured from the median, ulnar, peroneal, and tibial

nerves. Antidromic sensory NCSs were measured from the median, ulnar, superficial peroneal, and sural nerves.

F-responses were obtained after 10 stimuli were given at a frequency of 1/s from the median, ulnar, peroneal, and tibial nerves. The shortest latency, which was determined to be the onset of the first deflection from the baseline, was recorded as the minimal F-response. H-reflexes were also obtained.

The results were interpreted as abnormal when latencies or nerve conductions were slower or when amplitudes were lower than the standard values used in our electrodiagnostic laboratory. ⁹ CMAP was defined as abnormal if the onset latency was above 4.2 ms for median and ulnar nerves, 6.2 ms for the peroneal nerve, and 5 ms for the tibial nerve. Peak-to-peak amplitudes were found to be abnormal below 5 mV for both median and ulnar nerves, 2 mV for the peroneal nerve, and 5 mv for the tibial nerve. CV velocities were defined as abnormal if the values were below 50 m/s for median and ulnar nerves and 40 m/s for peroneal and tibial nerves.

SNAP was defined as abnormal if the peak latencies were above 3.6 ms for median and ulna nerves, 4.2 ms for the superficial peroneal nerve, and 3.9 ms for sural nerve. The onset to peak amplitudes was considered abnormal if the values were below 20 V for the median nerve, 10 V for the ulnar nerve, 5 V for the superficial peroneal nerve, and 10 V for the sural nerve. An F-response was defined when the amplitude exceeded 20 V and abnormal values were defined when a minimal F-response exceeded greater than 50 m/s for peroneal and tibial nerves. NCSs were performed on one side of the body, and if abnormal NCS were shown on one side, the other side was further investigated. Distal symmetric polyneuropathy was defined as existing if there were abnormalities of at least 3 parameters of the nerve conduction study (distal latency, amplitude, conduction velocity, and minimal F response) in two, separate nerves, including the sural nerve.

The severity of CTS was measured and classified as mild,

moderate or severe according the EDX criteria. ¹⁷ Mild

CTS was defined as when there was prolonged (relative

or absolute) median sensory or mixed SNAP distal latency

with or without SNAP amplitude below the lower limit of normal. Moderate CTS was defined as when there were abnormal median sensory latencies and prolongation of median motor distal latency. Severe CTS was defined as when there were prolonged median motor and sensory distal latencies, and with either an absent SNAP or low amplitude or absent thenar CMAP. When the results of nerve conduction study met electrodiagnostic criteria of both distal symmetric polyneuropathy and CTS which were mentioned above, patients were classified to have both DPN and CTS.

According to the NCS results, patients were divided into DPN, CTS, or DPN+CTS groups. Demographic characteristics of patients, such as age, gender, height, weight, body mass index (BMI), and diabetes duration were reviewed. Sensory tests, such as the current perception threshold (CPT, Neurometer ^® by Neurotron, Baltimore, MD, U.S.A.) and the vibration perception threshold (VPT, CASE IV ^TM System by WR Medical Electronics Co., Maplewood, MN, U.S.A.), were performed to assess the presence of small-fiber neuropathy. CPT was determined on the index finger and great toe of patients by a neurometer and using different frequencies (2,000 Hz, 250 Hz, and 5 Hz). Results of the serum test for Hb1Ac, fasting blood sugar (FBS), postprandial 2 hr (PP2), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and albumin/creatinine (alb/cr) ratio were reviewed to investigate the presence of known risk factors of DPN such as hyperlipidemia or hyperglycemia. ¹⁸

2) Statistical analysis

SPSS version 18 was used for all statistical analysis. The differences in the characteristics of diabetic patients with DPN or CTS were analyzed using the Mann-Whitney U test. The Kruskal-Wallis test was used to determine the differences in parameters of the diabetic patients with DPN, CTS or both. A confidence interval of 95%, p < 0.05, was used for statistical significance.

Results

Among the 587 patients, 111 had abnormal findings on NCS. Among them, 47 patients (42.3%) had DPN, 29 patients (26.1%) had CTS, and 35 patients (31.5%) had both DPN and CTS. The patients’ demographic characteristics, including age, gender, presence of symptoms, retinopathy, and abnormal findings of CPT and VPT are listed in Table 1.

The duration of diabetes, levels of Hb1Ac or PP2, and albumin/creatinine ratio showed significance when comparing patients with DPN, CTS or both, This showed that patients who had a longer duration of diabetes, higher levels of Hb1Ac or PP2, and renal disease were more likely to suffer from both DPN and CTS than patients with only one of these factors (Table 2).

Discussion

Patients with diabetes suffer from DPN which is a somatic neuropathy induced by diabetes mellitus.

The diagnosis of DPN usually includes symptoms, electrodiagnostic studies, and sensory and autonomic function testing. ¹⁹ CTS results from the compression of

Table 1. Demographic Characteristics of Patients with Diabetes

DPN (n = 47) CTS (n = 29) DPN+CTS (n = 35) Age (years) 64.8 ± 6.0 62.9 ± 8.9 61.6 ± 9.4 Gender

Male 38 (80.9%) 13 (44.8%) 17 (50.0%)

Female 9 (19.1%) 16 (55.2%) 17 (50.0%) Symptoms

Yes 18 (38.3%) 6 (20.7%) 11 (31.4%)

No 29 (61.7%) 23 (79.3%) 24 (79.3%) Retinopathy

Yes 21 (44.7%) 5 (17.2%) 14 (40.0%)

No 26 (55.3%) 24 (82.8%) 21 (60.0%) Abnormal CPT

Yes 11 (23.4%) 0 (0.0%) 7 (20.0%)

No 36 (76.6%) 29 (100.0%) 28 (80.0%)

Abnormal VPT

Yes 5 (10.6%) 0 (0.0%) 7 (20.0%)

No 42 (89.4%) 29 (100%) 28 (80.0%)

Values are the mean ± SD or number (%)

CPT: current perception threshold, VPT: vibration perception threshold

the median nerve at the wrist and its life-time cumulative incidence rate is approximately 8%. ^20,21 The diagnosis is made based on a patient’s history, physical examination or electrodiagnostic findings. NCS was used as the major diagnostic tool in our study as it is known to be useful in detecting the presence of DPN ²² and CTS. ³

Risk factors of DPN are chronic hyperglycemia, undiagnosed type 2 diabetes, high alcohol intake, smoking, diabetes duration, low socioeconomic status, oxidative injury, renal failure, vascular insufficiency, and cardiovascular factors. ^4,15,19 Female gender, farming, and the wrist depth width radio are risk factors of CTS in diabetic patients. ¹⁶ The risk factors for developing both DPN and CTS are not yet understood.

Patients who do not have symptoms of DPN may be under-diagnosed, ²³ and diabetic patients with CTS may not suffer from symptoms induced by CTS. Lee et al. ²⁴ reported that the electrodiagnostic severity did not correlate with the symptom severity or the patient functional status in CTS. Patients who have already been experienced these complications may not be

aware of the necessity to strictly control their disease. In addition, patients who have symptoms caused by these complications may not recognize the source of their pain and this may delay their seeking the treatment they need. In our study, the results showed that only 38.3% of DPN patients and 20.7% of CTS patients had symptoms and this suggested that patients may or may not have symptoms caused by DPN or CTS. Therefore, determining the risk factors which contribute to the development of DPN and CTS is necessary and may help to determine which patients require further evaluation, such as NCS, of possible combined neuropathy which they may already have.

Kim et al. ²⁵ reported that diabetic patients with CTS had a longer duration of diabetes than diabetic patients without CTS as it seemed than patients who had been suffering from diabetes for long time were more susceptible to CTS. Symptoms such as pain and paresthesia seemed to occur less frequently in diabetic patients with CTS than in CTS patients without diabetes, and which suggested that the former patients may not Table 2. Parameters Comparing the Three Groups

DPN (n = 47) CTS (n = 29) DPN+CTS (n = 35) p-value

Age (years) 64.9 ± 7.7 62.2 ± 9.4 61.6 ± 9.4 0.48

Height (cm) 169.4 ± 7.5 158.2 ± 8.8 162.2 ± 8.7 0.52

Weight (kg) 73.1 ± 6.9 69.3 ± 13.2 70.6 ± 13.3 0.52

BMI (kg/m

) 25.5 ± 2.2 27.4 ± 3.4 26.7 ± 4.2 0.08

DM duration (years) 14.0 ± 11.1 10.3 ± 7.2 15.7 ± 8.4 0.01*

Serum

Hb1Ac, % (mmol/mol) 7.5 ± 11.1 7.1 ± 0.9 13.9 ± 1.2 0.04*

FBS (mmol/L) 128.3 ± 30.8 128.9 ± 26.3 144.8 ± 44.7 0.67

PP2 (mmol/L) 201.7 ± 57.7 197.7 ± 55.0 260.3 ± 70.6 0.04*

C-peptide (ng/mL) 2.2 ± 29.5 2.7 ± 1.4 2.4 ± 1.1 0.30

Lipid

Cholesterol (mg/dL) 161.5 ± 36.6 171.8 ± 28.5 174.6 ± 35.2 0.40

TG (mg/dL) 133.4 ± 79.6 123.1 ± 42.8 154.9 ± 177.4 0.82

HDL (mg/dL) 46.9 ± 14.7 53.8 ± 12.7 51.1 ± 12.7 0.69

LDL (mg/dL) 86.6 ± 27.7 102.1 ± 26.6 101.0 ± 25.1 0.35

Apolipoprotein (mg/dL) 71.3 ± 21.6 76.3 ± 31.5 80.1 ± 16.5 0.59

Alb/Cr ratio (mg/g) 34.3 ± 13.3 16.9 ± 21.0 150.8 ± 392.8 0.04*

The values are mean ± SD, *p < 0.05 using the Kruskal-Wallis test

BMI: body mass index, FBS: fasting blood sugar, PP2: postprandial 2hr, TG: triglycerides, HDL: high-density lipoprotein, LDL: low-density lipoprotein, Alb/Cr

ratio: Albumin/creatinine ratio

recognize their symptoms as much as the latter CTS patients who do not have diabetes. This correlates with our study results which showed that many diabetic patients with CTS did not complain of having symptoms.

Perkins et al. ³ reported the prevalence of approxi- mately 30% CTS in diabetic patients with DPN and that the prevalence of asymptomatic CTS in diabetic patients is high. They explained that when DPN is present, the susceptibility of the median nerve to pressure in the carpal tunnel is more likely to occur. The median nerve may be injured in the carpal tunnel due to local vascular compromise, endoneurial ischemia, and impaired axonal transport. They also suggested that the nerve can be metabolically injured.

Previous studies have shown that current perception threshold at three frequencies (2,000 Hz, 250 Hz, 50 Hz,) were higher in diabetic patients compared with normal subjects and suggested that CPT testing can be useful to assess diabetic sensory neuropathy. ^26,27 Other study has shown that VPT was sensitive technique to confirm clinical neuropathy and emasure abnormal nerve conduction. ²⁸ The results of our study showed that some patients, 23.4% and 10.6%, showed abnormal results of CPT and VPT, respectively (Table 1). Also our study has shown the abnormal results of albumin/creatinine (alb/

cr) ratio, which can be suggestive of the presence of renal dysfunction (Table 2).

DPN is caused by various pathologic mechanisms, such as metabolic, ischemic or compressive, but the exact mechanism is not yet fully known. As hyperglycemia and glucotoxicity induce structural damage of myelinated and unmyelinated fibers, ²⁹ this results in DPN. Other factors, such as diabetes duration, patient age, blood pressure, body weight, and lipid levels, are known be risk factors of DPN. ³⁰ Our study showed that the duration of diabetes was important in the development of DPN. In addition, when compared with diabetic patients with CTS, diabetic patients with DPN had suffered from diabetes for longer periods of time. Parameters such as Hb1Ac, PP2, the diabetes duration, and the presence of renal disease, were related to the development of DPN rather than of CTS.

Conclusion

Our results suggest that patients who had diabetes for a long time are at greater risk of having DPN than CTS. Also, patients who have high levels of Hb1Ac, PP2, and renal complications are at risk for developing both DPN and CTS. Therefore, nerve conduction studies are recommended for patients who have these risk factors to be screened out for both DPN and CTS.

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