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CORRELATIONS BETWEEN THE SEVERITY OF DIABETIC PERIPHERAL NEUROPATHY AND OTHER MICROVASCULAR COMPLICATIONS IN A GROUP OF PATIENS WITH DIABETES

Eduard ADAMESCU¹,Carmen DOBJANSCHI¹,²,Alexandru POPA²

1Clinical Hospital,,NicolaeăMalaxa”,ăBucharest,Romania 2Institution 2UniversityăofăMedicineăandăPharmacy,,CarolăDavila”,Bucharest,Romania

Abstract: Aims-to evaluate a group of patients with diabetes mellitus(DM) and to present possible correlations between the severity of diabetic peripheral neuropathy(DPN) and the seriousness of the other microvascular complications. Materials and methods-200 patients with type 2 DM were evaluated.We analyzed the presence of micro and macrovascular chronic DM complications(reported in the medical records),HbA1c, lipid profile, body mass index (BMI). The severity of DPN was estimated with Toronto Score(TS) . Results: The prevalence of diabetic retinopathy (DR) increases with the severity of DPN (H(3) = 14.50, p 0.002). The lot without DR has a TS significantly smaller than the group with non-proliferative retinopathy (p=0,002) and proliferative retinopathy( p=0,012). There is a statistically significant correlation between TS and severity of renal disease ( p=0.036). Conclusions:The severity of DPN, appreciated with TS, is a good indicator to appreciate the risk of occurrence and severity of other chronic complications independent of metabolic control. Keywords: diabetes mellitus, neuropathy, Toronto Score, retinopathy, chronic kidney disease.

INTRODUCTION Prevalence of type 2 diabetes mellitus (DM) increased in most of the countries in the world, becoming a real epidemic [1], and for Romania, type 2 DM prevalence recently reported is of 11%, compared to the highest prevalence in Europe [2]. One of the main objectives of diabetes mellitus management is to identify as soon as possible the chronic complications and to adopt a therapeutic attitude according to its stage. Taking into account that among the microvascular chronic complications of diabetes (neuropathy, retinopathy and nephropathy) there is a common pathophisyology substratum [3], we expect to be certain correlations between the occurrence or the severity of one of them and the onset and the progression of the other. Diabetic neuropathy is the most frequent of chronic complications of diabetes mellitus and it affects the peripheral and/or autonomic nervous system [4,5].The early recognision of neuropathy is important because up to 50% of DPN may be asymptomatic and patients are at risk for insensate injury to their feet[5].. At the first evaluation of the patients with type 2 diabetes mellitus is also monitored the presence of all chronic complications.The Toronto Score is a new, easy and accurate method to diagnose DPN, which may detect early complications, still asymptomatic. [4,6]

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The aim of this work is to present possible associations between the severity of DPN determined by Toronto Score and the seriousness of the other microvascular complications. MATERIAL AND METHOD 200 patients with type 2 DM, without a history of stroke or alcohol abuse , aged between 62.07±10,81 and with an average duration of diabetes of 9.20 ±7,03 years were evaluated. It was also monitored the level of glycated haemoglobin (HbA1c), the lipid profile, the body mass index (BMI)(kg/m²) and the presence of microvascular chronic complications (neuropathy, retinopathy, diabetic nephropathy), macrovascular (ischemic heart disease-IHD, peripheral arterial disease-PAD), and hypertension (HT), recorded in the medical records. The stage of kidney disease was appreciated depending on the glomerular filtration rate, estimated according to MDRD formula [7]. Depending on the glomerular filtration rate(GFR)(ml/min/1,73m³), the patients were classified in the following categories of kidney disease (KD): stage 0/1 – GFRă≥ă90ă;ăstageă2ă– GFR = 60-89 ; Chronic kidney disease (CKD) stage 3 – GFR = 30-59; CKD stage 4 – GFR = 15-29; CKD stage 5 – GFR < 15 (kidney failure). The diagnosis of DR and the classification were established following the fundoscopic examination by an single examiner. The severity of peripheral DN was estimated with the help of Toronto Score. The “Torontoă Clinicală Scoringă System”ă (TCSS)ă isă aă protocolă validatedă byă comparisonăwith the results of the biopsies of sciatic nerve and closely correlated with the electrophysiological evaluation [6]. Within it are investigated anamnestic symptoms at the level of the foot ,ataxia, presence of symptoms of neuropathy at the level of upper limbs, the ankle and patellar reflexes are verified, and, as instrumental methods, there is verified the perception of temperature (with TipTherm), fine touch sensitivity (with Semmes-Weinstein monofilament), vibration (with Rydel-Seiffer tuning fork), sting and proprioception test. The protocol is applied for each separate foot. The maximum possible score is of 30 points. The interpretation of the score is as follows: 0-5 = absence of neuropathy; 6-8 = mild neuropathy; 9-11 = moderate neuropathy,ă andă ≥12ă ţă severeă neuropathyă [6].Allă patientsă signedă ană informedăconsent prior to inclusion in the study. Statistical analysis: The values were expressed as means ± SD for normally distributed data. The comparisons between groups were carried out by using ANOVAăforăquantitativeăvariablesăandătheăχ2ătestăforăcategoricalăvariables. RESULTS The group comprised 200 patients with type 2 DM, (107 women, 93 men), with an average age of 62.07±10,81, and the average duration of evolution of diabetes of 9.20 ±7,03 years. Anthropometric and biochemical characteristics of patients are presented in Table 1. Macrovascular chronic complications (IHD, PAD) were present in 81 % of the patients with type 2 diabetes, and the microvascular ones (neuropathy, retinopathy,

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nephropathy) were emphasized in 82 % of the subjects (DPN 82%, DR 35%, CKD 36%). Most of the patients presented mild forms of neuropathy (24%) and moderate (22%), and 36% had severe neuropathy. Table 1: Anthropometric and biochemical characteristics of patients with type 2 diabetes mellitus and the prevalence of chronic complications

All values have been expressed as mean±SD or %.

We found a statistically significant correlation and positive between the classification of neuropathy based on Toronto Score and the duration of diabetes mellitus(τţ0,39,ă pţ0,001,ă r2=0,16). We also found a statistically significant correlation and positive between the Toronto Score and BMI (τţ0,29,ă pţ0,001,ăr2=0,09). Thus, it is confirmed that the increased BMI is a risk factor in the progression and evolution of diabetic neuropathy.Regarding metabolic imbalance, weădidănotăfindăstatisticallyăsignificantădifferences(p˃0,05)ăofătheămeanăofăHbA1c and serum lipids values, depending on the presence and severity of DPN. Non proliferative DR was present in 26% of the patients, non proliferative DR with macular edema in 3% and proliferative DR in 6% of the patients. It was noticed that the prevalence of DPN increases with the severity of DR (H(3)=14,50 p=0,002). The group of patients who do not have DR has a Toronto Score significantly smaller than the group with non proliferative retinopathy (p=0,002) and proliferative retinopathy(p=0,012). We did not find statistically significant

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differences (p˃0,05)ăofătheămeansăofăHbA1c and serum lipids values depending on the presence and the severity of diabetic retinopathy . There is a statistically significant correlation and positive between Toronto Score and CKD appreciated through eGFR (τţ0,19,ăpţ0,036, r2=0,04) (Table2).. Table 2: Correlations between the level of Toronto Score and other chronic complications in type2 DM

Toronto Score

(points)

0-5 6-8 9-11 ≥12 P value

DR(-) (%) 87,5 77,3 70 39,4

Non-proliferative

DR

12,5 13,6 25 42,4 p=0,002

Non-proliferative

DR

+ macular edema

0 4,5 0 3 NS

Proliferative DR 0 4,5 0 15,2 p=0,012

CKD(-)(%) 75,5 78 75 42

CKD 24,5 22 25 58 p=0,036

Hypertension(-

)(%)

37,5 17,5 0 0

Hypertension 62,5 92,5 100 100 p=0,001

IHD(-)(%) 50 31,8 25 15,2

IHD 50 68,2 75 84,8 p=0,012

PAD(-)(%) 100 77,3 75 15,2

PAD 0 22,7 25 84,8 p=0,001

DAN(-)(%) 100 95,5 90 55,5

DAN 0 4,5 10 54,5 p=0,001

(-) = without diabetic retinopathy(DR), hypertension, ischemic heart disease(IHD), peripheral arterial disease(PAD),diabetic autonomic neuropathy(DAN); CKD(-)=RFG˃60ml/min/1,73m³;

All patients with moderate and severe DPN also had hypertension. DPN severity was statistically significantassociated with hypertension (p=0,001), PAD (p=0,001) but also with IHD (p=0,012).DAN was most frequently associated with severe DPN (p=0,001).

DISCUSSIONS

In type 2 DM are described non specific vascular alterations which involve especially the major blood vessels (coronary, cerebral and of lower limbs arteries), as well as specific alterations at the level of arterial and capillary endothelium

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(retina, renal glomerulus, vasa nervorum) [4]. In patients with type 2 diabetes in the current study were presented both the macrovascular chronic complications and the microvascular ones. DPN is the most frequent chronic complication of DM usually due to chronic hyperglycemia [8]. This study confirmed the prevalence of DPN as the highest in (82%) of microvascular chronic complications of type2 DM, as compared to DR (35%) and CKD (36%). Although the association with microvascular chronic complications was more frequently recorded in type 1 DM [4,5], there have been studies that emphasized the relation between DPN and DR in patients with type2 DM [9]. The severity of DPN appreciated with Toronto Score was correlated in this study with the age, BMI and the diabetes duration , having as possible explanation the long exposure to hyperglycemia. However, we did not find significant differences between the mean glucose level measured on the occasion of the study(HbA1c) and the severity of DPN. There was reconfirmed and extended the association between DPN and other microvascular chronic complications, but especially with DR. DR was associated, as it was expected, with the diabetes duration, DPN and CKD.[10] Regarding the dyslipidemia which was reported in other studies as risk factor [11], we did not find any significant association. The Toronto Score is a new method, easy and accurate to diagnose DPN, which can detect early complications, still in asymptomatic stages [12]. Supporting the assumption of the study, we may assert that the severity of diabetic retinopathy is associated with the severity of diabetic neuropathy, determined with the help of Toronto Score, in case of type 2 diabetes mellitus. Patients without retinopathy have a TS significantly smaller as compared to those with non proliferative DR or proliferative DR who associate a higher score for peripheral neuropathy.Due to the high estimate prevalence of DPN and PAD in patients with diabetes,the recognision and appropriate management is important[5]. The association between severe DPN and PAD was supported by this study too, and confirms the association of an increased risk for foot ulcerations [4,13]. In patients with type 2 diabetes the early detection of both macrovascular chronic complications and of microvascular ones is a priority and it may be performed by simple means as Toronto Score. The level of TS could be considered a predictor for other chronic complications of type2 DM. An increased TS recommends the continuation of investigations to identify and stage the other microvascular complications. CONCLUSIONS The seriousness of diabetic neuropathy, appreciated with TS, is a good indicator to appreciate the risk of occurrence and severity of other chronic complications of type 2 DM, independently of the degree of metabolic imbalance.

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