Prevalence of peripheral neuropathy and painful peripheral neuropathy in Turkish diabetic patients

Based on World Health Organization data, the number of diabetic people worldwide is predicted to increase from 171 million in 2000 to at least 366 million by 2030 (^{Wild et al., 2004}). Prevalence of diabetes is higher in developing countries (^{International Diabetes Federation, 2006}). In the Turkish Diabetes Epidemiology Study, the prevalence of diabetes in Turkey was 7.2% and that of glucose intolerance was 6.7% (^{Satman et al., 2002}).

Complications from diabetes are also expected to increase in prevalence worldwide. Diabetic peripheral neuropathy (DPN) is a complication of diabetes, which may result in complete sensation loss (^{Boulton et al., 2005; Carrington et al., 2001; Vinik et al., 2000}). Diminished sensation associated with DPN presents a significant risk factor for subsequent diabetic ulcers and nontraumatic amputations (^{Cabezas-Cerrato, 1998; Frykberg et al., 1998}).

DPN is the most common complication, but it is commonly underrecognized and therefore underdiagnosed (^{Jensen et al., 2006}). Also, many patients and physicians are not aware of the causal relationship of DPN and pain (^{Park et al., 2004}). Periodic clinical examination is essential for all patients, and the modalities should be sensitive for early detection of neuropathic signs (^{Jensen et al., 2006; Park et al., 2004}).

Painful DPN is described as a superficial burning pain associated with other sensory symptoms affecting feet and lower extremities (^{Kastenbauer et al., 2004; Marchettini et al., 2004; Sibbald et al., 2003; Sommer, 2003}). Among patients with diabetes, 10% to 20% experience pain due to neuropathy (^{Galer et al., 2000; Gordois et al., 2003; Van Acker et al., 2009; Veves et al., 1993}).

There are several methods for detection of DPN ranging from quantitative methods, such as nerve conduction studies, vibration sense testing, pinprick test, and thermal tests, to validated questionnaires. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale, provided by ^{Bennett (2001)}, is one of the easy and useful tools to identify neuropathic symptoms and signs; however, there is no agreed gold standard for the detection of DPN. Although the pathogenesis of DPN is complex and involves multiple pathways, early detection and accurate diagnosis before the onset of symptoms are most important in delaying or reversing the progression of DPN.

Recent studies have demonstrated that neuropathy is a preventable, treatable disease, and early diagnosis is essential for this condition (^{Park et al., 2004}). Consequently, exploration of pathogenesis of diabetic complications is crucial, and such efforts will eventually lead to a better outcome in diabetic patients in the long run.

The aim of this study was to determine the prevalence of DPN and neuropathic pain (NeP), using clinical examination and electromyography (EMG; nerve conduction studies) in patients with diabetes attending university outpatient clinics in Turkey.

MATERIALS AND METHODS

This multicenter, cross-sectional study of patients attending university hospital outpatient clinics in Turkey was conducted in compliance with Good Clinical Practice, including the International Conference on Harmonization Guidelines and the most recent version of the Declaration of Helsinki. Signed informed consent was obtained from all patients before enrollment. University hospitals that include neurology, algology, and endocrinology departments were entered in the study. In 14 university hospitals, 1,113 patients with type 1 or type 2 diabetes mellitus who applied to diabetes outpatient clinics were randomly selected for inclusion in this study. Diagnosis was established according to American Diabetes Association guidelines. Eligible patients who did not have any other disorder as a potential cause for peripheral neuropathy were entered in the study. After enrollment and endocrinologic evaluation, all patients were referred to neurology departments for motor system evaluation and nerve conduction studies and to algology departments for sensory system evaluation and LANSS pain scale testing.

Demographic data and diabetic history of all patients were collected. DPN can be diagnosed either by clinical examination alone or electrophysiologic examination together with the clinical findings, although electrophysiologic diagnosis of DPN is mostly recommended. In this study, to determine the prevalence of DPN by clinical examination alone (clinical prevalence) or by electrophysiologic examination (EMG-supported prevalence), both clinical diabetic neuropathy score (DNS) and electrophysiologic DNS have been calculated separately.

Patients were administered the following neuropathy scales and tests.

Clinical Diabetic Neuropathy Score

Clinical neurologic examination to obtain the clinical DNS included the assessment of sensory modalities, muscle strength tests, and reflexes on both sides. The sensory assessments were performed at the dorsum of the great toe: vibration threshold (by an electronic vibrometer, 0–2 score); light touch sensation with a 10-g filament (0–2 score); and pain with a disposable pin (0–2 score). The muscle strength tests included finger spread (0–3 score); great toe extension (0–3 score); and ankle dorsiflexion (0–3 score). The reflexes (0–2 score) of biceps brachii, triceps brachii, quadriceps femoris, and Achilles were evaluated. The sum of all these parameters evaluated bilaterally produced the clinical DNS (ranging from 0 to 46). A clinical DNS >6 correlates with the presence of clinical DPN (^{Comi et al., 1999; Lunetta et al., 1998}).

EMG-Supported Diabetic Neuropathy Score

The EMG-supported DNS is a composite score consisting of quantitative neurologic examination and nerve conduction studies (^{Fedele et al., 1997}). Clinical neurologic examination and EMG nerve conduction measurements were performed as described previously (^{Fedele et al., 1997}). The standardized objective neurologic examination was used to obtain the clinical DNS (0–46 score), and nerve conduction studies were used to obtain the number of abnormal nerve conductions. The clinical DNS and the number of abnormal nerve conductions were used to attain the EMG-supported DNS (0–4 score).

Nerve conduction studies (peroneal and median motor conduction studies and median, ulnar, and sural sensory conduction studies) were performed on the nondominant side with the skin temperature >32°C in the upper limb and >31°C in the lower limb. The nerve was considered abnormal if the conduction velocity (adjusted for age), amplitude, or motor distal latency was abnormal. The number of abnormal nerve conductions ranged from 0 to 5.

EMG-supported DNS was computed from the clinical DNS and the number of abnormal nerve conductions. EMG-supported DNS, indicating the severity of neuropathy, ranged from 0 to 4 (0 = no neuropathy; 1 = borderline condition; 2 = mild neuropathy; 3 = moderate neuropathy; and 4 = severe neuropathy) (Table 1). If the EMG-supported DNS was >1, the patient was considered to have EMG-supported DPN (mild, moderate, or severe neuropathy).

EMG examinations were conducted at each center, using the center's own equipment; however, all centers used the same recording and stimulating electrodes (HUSH Bar Electrode 9013S0351, HUSH Digital Ring Electrode 9013S0301, HUSH Disc Electrode Pair 9013S0401, and Hand-Held Saline Soak Stimulating Electrode 9013L0361; Alpine BioMed) and electronic infrared thermometers (DermaTemp DT-1001 infrared surface skin scanner; Exergen). All centers used the same standardized techniques and reference values for nerve conduction studies, as defined in the study protocol.

Leeds Assessment of Neuropathic Symptoms and Signs

The LANSS pain scale was validated for use in Turkey (^{Bennett, 2001; Yucel et al., 2004}) and was used to distinguish NeP from nociceptive pain. A score ≥12 is classified as indicative of NeP.

Statistical Analysis

Descriptive statistical methods were used to summarize data. The prevalences were presented as percentages. The specificity, sensitivity, and positive and negative predictive values of all diagnostic tests were evaluated. Concordance between diagnostic tests was evaluated using Cohen's kappa values. For discrete variables, the proportions of a given characteristic were compared using the χ² test, Fisher exact test, or the Kolmogorov-Smirnov test, where appropriate. Bivariate evaluation of differences in the means of continuous measurements was tested using Student t test or the Mann-Whitney U test, according to variable characteristics. Multiple group comparisons were performed by one-way analysis of variance and Tukey honest significant differences test for post hoc analysis. Logistic regression analysis was used for multivariate analysis of dichotomous endpoint variables. A P value <0.05 was considered to indicate statistical significance; all resulting P values were two tailed.

RESULTS

Patient demographics are given in Table 2. Among 1,113 patients included in the study, 8.2% had type 1 diabetes and 91.8% had type 2 diabetes. Mean duration of diabetes was 8.28 ± 6.6 years. Nerve conduction studies were performed on 1,102 of 1,113 patients, and LANSS was performed on 975 patients who reported pain.

Clinical Diabetic Neuropathy Score

The prevalence of clinical DPN determined by clinical neurologic examination (clinical DNS >6) was 40.4% (450 of 1,113 patients), without significant gender difference (41.1% in males and 39.9% in females).

EMG-Supported Diabetic Neuropathy Score

By combining nerve conduction studies with clinical DNS, the prevalence of EMG-supported DPN was 62.2% (685 of 1,102 patients), without gender difference (61.8% in males and 62.5% in females). Of these 685 patients, 16.9% had mild neuropathy, 46.3% had moderate neuropathy, and 36.8% had severe neuropathy. Of patients with clinical DPN (DNS >6), 86.8% had also EMG-supported DPN (DNS >6), whereas 56.5% of all patients with EMG-supported DPN had also clinical DPN. However, 45.4% of all patients with no clinical DPN (DNS ≤ 6) had EMG-supported DPN. Of 1,102 with nerve conduction studies, 5.4% had clinical DNS >6 without having EMG-supported DPN (Fig. 1).

Both EMG-supported DPN and clinical DPN showed a negative correlation with educational level (Fig. 2A) and a positive correlation with age (Fig. 2B). The prevalence of EMG-supported DPN was lower in the participants with a higher educational level; the condition grew more serious with increased age.

Leeds Assessment of Neuropathic Symptoms and Signs Scores

NeP (LANSS score ≥12) was established in 16.0% of 975 patients who reported pain. The prevalence of NeP in 1,113 patients was 14%. NeP was significantly higher in women (10.3% in males and 17.2% in females). The prevalence of NeP was 22.0% in patients with clinical DPN and 8.6% in patients without clinical DPN. The prevalence was 17.4% in patients with EMG-supported DPN and 8.6% in patients without EMG-supported DPN. The duration of diabetes in patients with NeP was significantly longer than in patients without NeP (P = 0.001; Table 3).

In a logistic regression model, age (odds ratio = 1.03, P = 0.005) and duration of diabetes (odds ratio = 1.07, P < 0.001) were found to be significant independent predictors for clinical DPN. The prevalence of clinical DPN increased with the duration of diabetes, from 25.0% in patients with diabetes for <5 years to 57.3% in those with diabetes for 15 to 19 years (P < 0.001).

DISCUSSION

In this study, the prevalence of clinical DPN determined by clinical neurologic examination (clinical DNS >6) was 40.4%, without significant gender difference. By combining nerve conduction studies with clinical DNS, the prevalence of DPN was 62.2%, without gender difference. Of patients with clinical DPN (DNS >6), 86.8% had also EMG-supported DPN (DNS >6), whereas 56.5% of all patients with EMG-supported DPN had also clinical DPN. However, 45.4% of all patients with no clinical DPN (DNS ≤6) had EMG-supported DPN by nerve conduction studies. In a recent study, ^{Bouhassira et al. (2007)} reported the prevalence of DPN as 43% and painful DPN as 14%. They found that 51% of the patients had DPN and 18% had painful DPN in a subgroup of patients with type 2 diabetes. This cross-sectional study was carried out in 40 diabetes clinics, using the Neuropen test without electrophysiologic evaluation (^{Bouhassira et al., 2007}). The prevalence determined in both of the studies may be an overestimate of the prevalence in the population of diabetic patients in general, because the patients with active complications may be more prone to attend these clinics. In fact, in a recent population-based study with postal survey, prevalence of clinical DPN was found to be 26.4% (^{Davies et al., 2006}).

There are several different methods for detection of DPN, ranging from clinical findings, quantitative methods, such as nerve conduction studies, vibration sense testing, pinprick test, and thermal tests, to validated questionnaires (^{Jensen et al., 2006; Park et al., 2004}). ^{Comi et al. (1999)} suggested that the screening program, based on Diabetic Neuropathy Index and DNS, was valid for the detection and staging of DPN for large epidemiologic studies. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy (^{England et al., 2005}). The combination of neuropathic symptoms and signs and electrodiagnostic methods provides a most accurate diagnosis of distal symmetric polyneuropathy. Electrodiagnostic findings should be included as a part of the case definition because they provide a higher level of specificity for the diagnosis. In this study, we observed that diabetic patients with NeP were significantly more likely to have moderate or severe neuropathy, according to EMG findings, than patients without NeP. The prevalence of NeP among patients with DPN was 24.4%, which concurred with recently published data (^{Jensen et al., 2006}). Nerve conduction velocity is sensitive for myelin dysfunction, whereas amplitude change is an indicator of axonal damage. Because diabetic neuropathy is axonal neuropathy, amplitude change is used as a parameter for neuropathy, as well as conduction velocity and motor distal latency.

Both DPN by nerve conduction studies and clinical DPN by neurologic examination showed a negative correlation with educational level and positive correlation with age. The prevalence of DPN was lower in those with a higher educational level, and the condition grew more serious with increased age. ^{Comi et al. (1999)} did not find a correlation between the severity of DPN and age; however, they reported a positive correlation with the duration of diabetes. The results of our study showed that the duration of diabetes was an independent predictor of DPN in patients attending university hospital outpatient clinics. Prevalence of DPN (clinical DNS >6) was highest (57.3%) in patients with a disease duration of 15 to 19 years (compared with 25% in those with diabetes for <5 years). This finding is consistent with the observations of a previous study showing a DPN prevalence of 64.1% among patients with an average age of 58 to 59 years and disease duration of 12.4 to 15.6 years (^{Fedele et al., 1997}).

Although DPN is the most common complication of diabetes, there is a lack of awareness of relationship between DPN and pain (^{Jensen et al., 2006; Park et al., 2004}). The LANSS pain scale, provided by ^{Bennett (2001)}, is one of the easy and useful tools used to identify neuropathic symptoms and signs (^{Kaki et al., 2005}). In our study, a LANSS score ≥12 was present in 16.0% of patients who reported pain. The prevalence of NeP was 14%. LANSS scores were higher in females than in males and in patients with longer disease duration (P = 0.001). In logistic regression analysis, gender and DPN were the major predictors of NeP in our patient population.

In conclusion, the results of this study demonstrate that DPN affects 40.4% of patients with diabetes attending university outpatient clinics in Turkey and that the prevalence of NeP in this population is 14.0%. Combining nerve conduction studies with clinical examination, more than half (62.2%) of patients had mild to severe neuropathy and 24.4% of patients with DPN also experienced NeP. Up to the present, there have been no effective methods to prevent the development of diabetic complications; only the therapeutic modalities have been used to prevent the progression of symptoms. However, early detection and accurate diagnosis of DPN and painful DPN may provide a symptomatic treatment and help to prevent the progression of nerve damage.

ACKNOWLEDGMENT

The authors thank Pfizer and the investigators who participated in the study (see Appendix).

APPENDIX

Study Investigators

Berrin Aktekin (NC), Hasan Altunbas (EC), Hulya Aydin, Mustafa Kemal Balci, Umit Karayalcin, Bilge Karsli (AC), Gokhan Yazicioglu, Arif Yegin (Akdeniz University Medical School); Ibrahim Asik, Yesim Ates, Mine Ozduman Cin, Sevim Gullu (EC), Yuksel Kesik, Nermin Mutluer (NC), Ozden Sener, Filiz Tuzuner (AC) (Ankara University Medical School); Hacer Bozdemir, Geylan Isik (AC), Sinan Kirim, Filiz Koc, Hayri Ozbek, Yakup Sarica (NC), Tamer Tetiker (EC), Deniz Yerdelen (Cukurova University Medical School); Firat Bayraktar, Yuksel Erkin (AC), Ayse Karci, Ibrahim Oztura (NC), Ali Saklamaz, Ihsan S. Sengun, Sena Yesil (EC) (Dokuz Eylul University Medical School); Nilgun Arac (NC), Ibrahim Aydogdu (AC), Elvan Erhan, Fulden Sarac, Fusun Saygili (EC), Pelin Taskin, Burhanettin Uludag, Ibrahim Yegul, Candeger Yilmaz (Ege University Medical School); Adem Boyaci, Ali Ozdemir Ersoy, Cumali Gökce, Fahrettin Kelestimur (EC), Emel Koseoglu (NC), Meral Mirza, Fatih Ugur (AC) (Erciyes University Medical School); Said Berilgen, Serpil Bulut (NC), Ramiz Colak (EC), Halil Dogan, Rifat Kilic, Selami Ates Onal (AC), Demet Yasar (Firat University Medical School); Metin Arslan, Goksun Ayvaz (EC), C. Avni Babacan (AC), Oya Yalcin Cok, Bijen Nazlier (NC), Ovunc Akyildiz Ozon, H. Ayse Bora Tokcaer (NC), Bilge Tuncer, Zulal Yesilbudak, Murat Yilmaz, Ilhan Yetkin (Gazi University Medical School); Aysegul Atmaca, Ulku Aypar (AC), Sevim Erdem, Saadet Ozgen, Altan Sahin, Ersin Tan (NC), Cagri Temucin (Hacettepe University Medical School); Mehmet Ali Akalin, Taner Damci, Feray Karaali, Kader Keskinbora, Meral Kiziltan (NC), Zeynep Osar (EC), Mustafa Senocak, Ali Ferit Pekel (AC), Ozay Tiryakioglu, Nurten Uzun (Istanbul University Cerrahpasa Medical School); Baris Baslo, Esen Cavuslu, Elif Kocasoy Orhan, Suleyman Ozyalcin, Ilhan Satman (EC), Gul K. Talu, Yucel Yilmaz (Istanbul University Istanbul Medical School); Vildan Altunayoglu, Cavit Boz, Mehmet Salih Colak (NC), Erdem Nail Duman (AC), Cihangir Eren, Onder Ersoz, Sibel Gazioglu, Mehmet Ozmenoglu, Munir Telatar (EC), Kubilay Ukinc (Karadeniz Teknik University Medical School); N. Sema Akalin (EC), Hasan Aydin, Oguzhan Deyneli, Zeynep Eti (AC), Baris Isak, F. Yilmaz Gogus, Oguzhan Onultan, Arzu Takil, Tulin Tanridag (NC), Zeynep Unal, Dilek Yavuz (Marmara University Medical School); and Cevdet Duran, Canan Ersoy, Erdinc Erturk, Alp Gurbet, Sazi Imamoglu (EC), Necdet Karli, Arzuay Kamis, Fatma Nur, Ercan Tuncel, Nesimi Uckunkaya (AC), Mehmet Zarifoglu (NC) (Uludag University Medical School). EC, Endocrinology Coordinator; NC: Neurology Coordinator; AC: Algology Coordinator.

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