Risk Assessment on Diabetic Peripheral Neuropathy from a Cohort of Patients in China

Human living styles and life has been troubled by diabetes
for many decades that arises from 451 million patients (ages
from 18-99 years) worldwide in 2017


ISSN: 2574 -1241 Introduction
Human living styles and life has been troubled by diabetes for many decades that arises from 451 million patients (ages from 18-99 years) worldwide in 2017. Approximately 85-95 of patients are diagnosed with T2DM in developed countries, and higher proportion in developing countries, which is emerged as an imminent global health crisis [1][2][3][4][5]. In China, the incidence of T2DM reached at 10.4% in 2013, and twice was arisen from fat population. However, un-diagnosed diabetes or threshold diabetes of a large population is an imperative threat that is looming ahead.
About 30-50% diabetes is developed and ailed with Diabetic Peripheral Neuropathy (DPN) sooner or later [2]. DPN is one of the major progressive complications of diabetes mellitus, which is continuously assaulted by hyperglycemia and aggravated by high risk factors, and is defined as the presence of peripheral nerve dysfunction in diabetics after exclusion of other causes. However, those high-risk factors may be varied upon different demographic features and T2DM development. Human DPN is characterized by nerve fiber loss, axonal degeneration, and segmental demyelization with a decrease in nerve conduction velocity due to decreased intraepidermal nerve fiber density and reduced myelin thickness of the nerve sheath, so DPN is one of the most insidious, asymptomatic complications of diabetes, but it could results in irreversible foot ulcer, insensate foot injury, lower-extremity amputation and mortality in diabetic patients [6][7][8].
In addition, DPN dramatically change patients' life style, adding heavy economic burdens. Therefore, it is imperative screening out high-risk factors of DPN be conducted to predict DPN for earlier diagnosis and save patients' foot and lives. The American Diabetes Association (ADA) recommends the following screening tests for early diagnosis of DPN: 1) Pinprick; 2) Sense of temperature; 3) Sense of vibration; 4) Sense of touch (10g monofilament (Nylon) test) [8].

Clinical Tests
According to previous studies and guidance [9,10], the clinical specialist for performing tests received professional training and earned a certificate to complete the screening tests independently.
The clinical tests should be performed in a quiet environment, and the participant should close his/her eyes when being tested and then recognize the perception of the pressure or pin stick at right site (indicated in (Figures 1A-1H). These clinical tests were depicted as below Sense of Touch: Using 10G Nylon monofilament to pressure the standard 10 points as shown in (Figures 1E & 1G). The contact time was 2 seconds with interval of 2-3 seconds between sites.
Perception of 10 points is defined as "normal", but loss of 2 or more of 10 points' perception was defined as "weaker", and loss of 10 points' perception was defined as "missing." Sense of Vibration: 128 Hz tuning fork vibration test was used by a sensor meter-VPT made by Beijing Lanxun Times Technology Company, and the scale of the vibrator was 0-8s. The tuning fork was placed on the surface of the first metacarpal joint of the foot toe. The amplitude of vibration was progressively increased from zero to a barely detectable vibration amplitude (threshold) at which the patient was just able to sense the vibration. The best cutoff value was proven to 10.54 V. Thresholds between0 to 10 volts were considered normal, 11-15 volts slightly abnormal (threshold), 16-25 volts moderately abnormal, and >25 volts severely abnormal.

Temperature Discrimination:
The temperature stick was placed on the dorsum of the foot to exam the temperature discrimination. Patients were instructed to lie back, close their eyes, and relax, and then were asked to determine if the temperature stick touched to the back of their feet felt warm or cool. An inability to distinguish cool from warm was considered an "abnormal" test result.

Pinpricking Pain (Needle Tingling Test):
The examiner uses a 40-g pin to touch the abdomen of the patient's first, third and fifth toes. Patients who did not feel being touched in any position are considered an "abnormal" result. Palpation of dorsal plantar artery B.
Palpation of posterior tibial artery C.
Sense of temperature D.
Sense of vibration E.
Sense of touch(10g Nylon needle) F.
Positions and locations of touch and pinpricking on feet. H.
Locations and thresholds of VPT.

Statistical Analysis
SPSS19.0 software was used for statistical analysis. The quantitative data were expressed as ± and statistical differences were conducted byt test used between groups. The counting data were expressed as an example number (percentage)[ n (%)] and Chi-square test ( X2) was used to analyze the risk factors of peripheral neuropathy, the level of test was 0.10, the cut-off value was 0.15, and the difference was statistically significant (p < 0.05) .

Diagnosis of DPN
A total of 1000 patients with diabetes were included in this study, of which 67 patients who lost some data were excluded.
As shown in (

Prevailing Risk Factors in Predicting and Diagnosis of DPN
The single factor analysis with statistical significance was used as the independent variable, and the multiple factor nonconditional logistic regression analysis was performed with the peripheral neuropathy of diabetes as the dependent variable, and odds ratios (ORs) were obtained between the comparison groups of DPN and Non-DPN with 95% confidence interval (CI). The results were illustrated in (Table 3 and Figure 6). The prevailing risk factors of percentages for DPN were ranked by order: clinical abnormal sensation (25.2%) > sense of Nylon pressure (10.3%) >pinpricking pain (9.9%) >sense of vibration (9.6%) >sense of temperature > tendon reflex, which was in line with the analysis in ( Figure 5).

Discussion
With the increasing incidence of diabetes, the peripheral neuropathy of diabetes has been attracting more and more attention. However, the incidence of diabetic peripheral neuropathy varies from different studies due to different screening methods and standards. The prevalence of DPN was 42.2% in the present study, which was higher than the prevalence of 30% from a previous system review study [4,[9][10][11]. The reason for such a difference might be ascribed to the difference by the diagnostic approaches and in different countries. However, a big variation of the prevalence of painful DPN from 35.7% to 65.3% was observed in the Middle East and North Africa region [12][13][14]. Among the 5 physical tests, the abnormal rate of temperature discrimination and vibration perception was higher than others. It suggests that we should pay attention to these two high risk factors from screening work.
Among the clinical symptoms of DPN, pain received much more attention than necessary [13]. However, our results demonstrated that numbness accounted for the largest proportion of abnormal sense, and diabetic retinopathy held a great proportion as well, both which should drag people's attention and alert. Furthermore, if the patient complains of numbness, pain or itching of the lower limbs, he or she may have been troubling in the quality of life, pain disturbances, and decreased sleep quality [14][15][16][17]. As regards to patients without clinical symptoms, 24.4% (170/698) patients had been diagnosed with DPN in this study.
It suggests that more details and attention should be paid to asymptomatic patients to reduce the rate of missed diagnosis of peripheral neuropathy. In our study, the risk of developing DPN increases with age and a longer history of the disease higher clinical symptoms of pain or numbness, and higher positive rates of VPT, CPT and nylon stress perception than patients without DPN, which is in line with previous reports [12,18]. Age is an independent risk factor for peripheral neuropathy [19]. It is widely believed that aging is driven by the accumulation of molecular and cellular damage in the body over time. As with peripheral neuropathy, both large and small fibers can be damaged by axonal injury or demyelization [19,20]. The high proportion of women in the DPN group compared to the non-DPN group suggests that women are more likely to develop DPN than men; this finding is consistent with previous studies [20]. In the level of education, the patients in the DPN group were mainly at middle school level or below, and the patients in the non-DNP group were mainly at middle school level or above. In medication, the proportion of DPN group was higher than that of non-DPN group in oral medication and Combined Control Regimen.
Previous studies reported that patients treated with a combination of insulin and metformin who developed DPN were twice more than patients treated with metformin alone [14,21].
There were no significant differences in smoking and drinking between DPN and no DPN group, which is consistent with previous studies [19][20][21][22][23][24]. Higher Glycated hemoglobin strongly indicated that it is associated with DPN in T2DM, which might be considered as a reliable biomarker for screening for DPN [22].Kiyokazu et al suggested that hyperglycemia combined with dyslipidemia could induce mild peripheral motor and sensory nerve injury, but had no significant effect on sensory nerve conduction velocity [1]. In the literature, the risk of DNP was found to be associated with smoking [23]. However, the current study did not find the above coherence and association but was aligned with a previous study by Sendi et al [24]. The presence of Proteinuria, especially above 500 MGG, should alert clinicians to medicate or manage neuropathic pain in DPN patients [25]. Studies by Pan et al. have shown that retinopathy is an independent risk factor for DPN [26,27], and this conclusion has also been confirmed in our results.
DPN is the primary risk factor for the development of diabetic foot ulcers [28] and is implicated in 50-75% of no traumatic Amputations [29]. It is important to note that in general, foot loss of sensation is latent and could not felt by the patient in time.
Patients with DPN often have larger shoe sizes, calluses, crevices, or skin changes [3]. The degree of pathological severity and clinical symptoms are often inconsistent and mismatched, and up to 50 % of DPN patients remain asymptomatic [30]. In this study, there were about 43% (170/394) of DPN patients who didn't have sensory abnormalities. Therefore, so early diagnosis of DPN presents a great challenge. The major problem with the development of DPN is that the process of pathogenesis is subtle and gradually progressed.
Elder patients are inclined to be oblivious to the symptoms of pain, numbness or other paresthesia and take it for granted for old process [30,31]. Therefore, we should educate patients how to prevent diabetes from DPN.

Conclusion
The incidence of DPN and PAD in hospitalized patients was 42% and 5.6% respectively. Most of the patients with peripheral neuropathy are over 40 years old, prevailing risk factors including clinical abnormal sensation, abnormal sense of Nylon pressure, higher pinpricking pain, abnormal sense of vibration, loss sense of temperature discrimination, loss of tendon reflex, with longer than 10 years of diabetes, with diabetic retinopathy, kidney disease and lower limb vascular disease, accompanied by abnormal itching, numbness or pain, paresthesia without obvious cause. These higher risks should alert clinicians to reinforce the details in screening and take timely intervention in DPN.