|Year : 2019 | Volume
| Issue : 2 | Page : 123-128
Distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy among diabetic patients in Ilorin: Prevalence and predictors
Abiodun Bello1, Sikiru Biliaminu2, Kolawole Wahab1, Emmanuel Sanya1
1 Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria
2 Department of Chemical Pathology, University of Ilorin Teaching Hospital, Ilorin, Nigeria
|Date of Web Publication||10-Jun-2019|
Dr. Abiodun Bello
Department of Medicine, University of Ilorin Teaching Hospital, PMB 1459, Ilorin
Source of Support: None, Conflict of Interest: None
Background: Peripheral neuropathy contributes to morbidity and mortality among diabetic patients. Objectives: We aimed to determine the prevalence of distal symmetrical polyneuropathy (DSP) and cardiovascular autonomic neuropathy (CAN) and their predictors among diabetic patients in Ilorin, North-central Nigeria. Materials and Methods: This was a cross-sectional study in which 175 consenting diabetic patients were recruited consecutively. We assessed DSP using the Michigan Neuropathy Screening Instrument (MNSI), and it was defined by MNSI symptom score ≥7 or physical examination score ≥2. CAN was assessed using five tests of cardiovascular autonomic function, and abnormalities in ≥2 tests defined CAN. Logistic regression analysis was used to identify the predictors of DSP and CAN. Results: The prevalence of DSP and CAN was 41.7% and 26.9%, respectively, while 19.4% had both. Hypertension (odds ratio [OR]: 2.401; 95% confidence interval [CI]: 1.169–4.930, P = 0.017) and poor glycaemic control (OR: 2.957; 95% CI: 1.488–5.878, P = 0.002) independently predicted DSP. Hypertension (OR: 2.215; 95% CI: 1.023–4.414, P = 0.043) and serum creatinine (OR: 1.035; 95% CI: 1.014–1.056, P ≤ 0.001) were independent predictors of CAN. Conclusion: DSP and CAN are common among diabetic patients, and thus efforts should be made to prevent their occurrence by intensifying blood pressure and glucose control while regularly monitoring renal function.
Keywords: Diabetic neuropathy, predictors, prevalence
|How to cite this article:|
Bello A, Biliaminu S, Wahab K, Sanya E. Distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy among diabetic patients in Ilorin: Prevalence and predictors. Niger Postgrad Med J 2019;26:123-8
|How to cite this URL:|
Bello A, Biliaminu S, Wahab K, Sanya E. Distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy among diabetic patients in Ilorin: Prevalence and predictors. Niger Postgrad Med J [serial online] 2019 [cited 2019 Jul 21];26:123-8. Available from: http://www.npmj.org/text.asp?2019/26/2/123/259916
| Introduction|| |
The prevalence of diabetes mellitus (DM) has attained pandemic proportions and has continued to increase rapidly. Between 1980 and 2014, the number of adults living with diabetes has increased from 108 million to 422 million as a result of increase in prevalence and population growth. Complications of diabetes are protean, with affectation of virtually all organ systems, including the nervous system where peripheral nerves are prone to damage.
The neuropathies occurring in diabetes are known to be heterogeneous by their presentation, pattern of neurologic involvement, clinical course, risk factors and underlying mechanisms. Diabetic peripheral neuropathy is a common and important long-term complication of DM, occurring in about 50% of patients. The two forms of diabetic neuropathy commonly studied are the distal symmetrical polyneuropathy (DSP) and cardiovascular autonomic neuropathy (CAN), owing to their contribution to foot ulcers, lower-limb amputations and cardiovascular morbidity and mortality. DSP is usually progressive with a prevalence of about 7.5% at diagnosis and rising up to 50% after 25 years. In Nigeria and beyond, the prevalence of DSP among diabetic patients ranges between 31.2% and 71.1%,, whereas that of CAN ranges from 12.4% to 44.3%., Only few studies in sub-Saharan Africa have evaluated the combination of DSP and CAN among diabetic patients; as such, information about their co-occurrence is sparse.
Owing to the fact that peripheral nerve damage in diabetic patients is mostly irreversible, prevention of its occurrence has been the focus, and this has led to continued search for modifiable risk factors associated with its development. Four prominent theories, which are not mutually exclusive, have been proposed as pathophysiologic mechanisms for chronic microvascular complications of DM. These include the formation of advanced glycosylation end products, increased glucose metabolism via the sorbitol pathway, increased formation of diacylglycerol leading to activation of protein kinase C and increased flux through the hexosamine pathway. A possible unifying mechanism is that hyperglycaemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all four of the pathways described above. Several risk factors have been identified from both cross-sectional and prospective studies including but not limited to duration of diabetes, glycaemic control, age, dyslipidaemia, hypertension and weight.,,,
This study was thus carried out to determine the combined prevalence and predictors of clinically diagnosed DSP and CAN using the Michigan Neuropathy Screening Instrument (MNSI) and a battery of five non-invasive tests of cardiovascular function among patients diagnosed with DM.
| Materials and Methods|| |
This was a hospital-based cross-sectional study conducted at the University of Ilorin Teaching Hospital (UITH), a tertiary hospital serving a catchment population of about 10 million in North-Central Nigeria. In accordance with the principles of Helsinki declaration on studies involving human subjects, ethical approval was obtained from the Ethical Review Committee (ERC) of UITH, Ilorin. The study was approved on June 20, 2013, by the hospital's ERC with protocol number ERC.PIN 2013/05/0061. Each participant signed a written informed consent after the purpose of the study was explained to them in clear, unambiguous terms. Consecutively consenting adult patients (≥18 years) who were on follow-up for DM at the Medical Outpatient Department of the hospital and met the inclusion criteria – all diabetic patients who were 18 years and above – were recruited into the study over a year between March 2014 and March 2015. The required sample size was obtained using Fisher's statistical formula for estimating minimum sample size in descriptive health studies (n = Z2pq/d2). The degree of accuracy was set at 0.05, standard deviation was set at 1.96 at 95% confidence level and a prevalence rate of 12.4% was used based on a previous study carried out in Nigeria. The calculated minimum sample size for this study was 166.9 which was rounded up to 167, while 175 patients were eventually recruited into the study.
DM was defined as a fasting plasma glucose ≥7 mmol/L (126 mg/dL) or 2 h post-prandial ≥11.1 mmol/L (200 mg/dl) at the time of first diagnosis. Excluded were patients with any acute illness and those with clinical evidence of uraemia and hypoglycaemia in the preceding 24 h. Other exclusion criteria included presence of suspected hereditary peripheral neuropathy, known cardiac arrhythmias, atrioventricular blocks or frequent extrasystoles and use of drugs known to interfere with cardiac autonomic function tests or cause peripheral neuropathy. Patients who had positive human immunodeficiency virus and Venereal Disease Research Disease Laboratory serology tests were also excluded from the study.
A structured questionnaire was used to obtain demographic and relevant clinical information including symptoms of DSP and CAN. Height (m) and weight (kg) were measured while body mass index (BMI) was calculated. Blood pressure (BP) was measured with a mercury sphygmomanometer (Accoson, Ayrshire, UK) with a standard cuff (25 cm × 12 cm) in sitting position on the right arm after at least 5-min rest. The measurement was repeated after 5 min, and the average was calculated for systolic and diastolic BP.
The MNSI was used to assess patients for DSP and the questionnaire aspect was interviewer-administered by the authors. It is a simple validated instrument for the identification of symptoms and signs of clinically evident neuropathy., It consists of a 15-item questionnaire and a structured examination involving foot inspection, ankle deep tendon reflexes and vibration sense assessment. The MNSI has been previously validated and found to have sensitivity and specificity of about 80% and 90%, respectively. It thus correlates fairly well with nerve conduction studies. We used a 128-Hz tuning fork to assess vibration sense and a 10-g monofilament to assess touch. Queen Square tendon hammer was used to test for deep tendon reflexes. The MNSI score was determined using the MNSI manual. For this study, DSP was defined operationally as at least seven positive responses on the MNSI questionnaire or a score ≥2.0 on the MNSI examination; cut-offs that were defined by prior validation studies. We assessed CAN using the five non-invasive autonomic function tests proposed by Ewing and Clarke. The tests were carried out in the morning in a quiet room within the cardiorespiratory assessment unit of the hospital after 15-min rest and a 5-min rest between each test. The sequence of testing was as follows: Valsalva manoeuvre, heart rate variation during deep breathing, heart rate response to standing, BP response to standing and BP response to sustained hand grip. Cut-off values used were as described by Ewing and Clarke. CAN was operationally defined as presence of two or more out of five abnormal tests.
Ten millilitres of venous blood was drawn under aseptic conditions for serum creatinine, glycosylated haemoglobin (HB), serum lipids and triglycerides. Poor glycaemic control was defined as HBA1c ≥7%. Hypertension was defined as BP ≥140/90 mmHg or patients on antihypertensive medications. Hyperlipidaemia was defined as total cholesterol >5.2 mmol/L, triglycerides >1.7 mmol/L or low-density lipoprotein-cholesterol >3.4 mmol/L, according to Adult Treatment Panel-III guidelines of the National Cholesterol Education Program.
Data obtained were analysed using the IBM SPSS Statistics for Windows, Version 20.0 (Armonk, NY, USA). Frequencies, mean ± standard deviations and median with interquartile range were generated as applicable. Chi-square and Fisher's exact tests were used to test the difference between categorical variables, whereas Student's t-test was used for continuous variables. Factors significantly associated with the development of DSP and CAN were determined using univariate and multivariate logistic regression analyses, with results presented as adjusted odds ratio (OR) with corresponding 95% confidence interval (CI).
| Results|| |
A total of 175 patients (with a mean age of 59.38 ± 13.04 years [range: 20–85]) who met the inclusion criteria were studied. Females constituted 56%, giving a female-to-male ratio of 1.27:1. These and other demographic characteristics and anthropometric and laboratory parameters are shown in [Table 1]. Type 2 DM was present in 168 (96.0%) patients, whereas the remaining 4.0% had Type 1 DM. The median duration of diabetes was 5 years with an interquartile range of 2–14 years. Among the patients, 74 (40.0%) had poor glycaemic control.
|Table 1: Sociodemographic, clinical and laboratory characteristics of the participants|
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Among the tests of parasympathetic function, heart rate variation to deep breathing had the highest percentage of abnormal tests (35.3%), followed by heart rate changes to Valsalva manoeuvre. These results and frequencies of other tests of CAN are shown in [Table 2]. The prevalence of DSP among the patients was 41.7%, whereas CAN was present in 47 patients, giving a frequency of 26.9%. A combination of DSP and CAN was found in 34 patients, giving a prevalence of 19.4% as shown in [Table 2].
|Table 2: Tests of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy|
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In univariate logistic regression analysis, factors that predicted the presence of DSP included poor glycaemic control (OR: 3.225; 95% CI: 1.715–6.065, P < 0.001), presence of hypertension (OR: 2.412; 95% CI: 1.270–4.578, P = 0.007), age ≥ 60 years (OR: 1.963; 95% CI: 1.052–3.663, P = 0.034) and duration of diabetes ≥8 years (OR: 2.487; 95% CI: 1.333–4.639, P = 0.004). Factors found to be associated with the presence of CAN in univariate logistic regression analysis were presence of hypertension (OR: 2.164; 95% CI: 1.087–4.309, P = 0.028), BMI ≥25 kg/m2 (OR: 2.137; 95% CI: 1.082–4.220, P = 0.029) and serum creatinine (OR: 1.038; 95% CI: 1.017–1.059, P = <0.001). In multivariate logistic regression analysis, factors found to be independently associated with the occurrence of DSP were poor glycaemic control (OR: 2.957; 95% CI: 1.488–5.878, P = 0.002) and presence of hypertension (OR: 2.401; 95% CI: 1.169–4.930, P = 0.017); whereas presence of hypertension (OR: 2.125; 95% CI: 1.023–4.414, P = 0.043) and serum creatinine (OR: 1.035; CI: 1.014–1.056, P = 0.001) were found to independently predict the occurrence of CAN. These results are shown in [Table 3] and [Table 4].
|Table 3: Factors associated with distal symmetrical polyneuropathy on multivariate analysis|
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|Table 4: Factors associated with cardiovascular autonomic neuropathy on multivariate analysis|
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| Discussion|| |
This study assessed the prevalence and predictors of the two most common and clinically important types of diabetic peripheral neuropathy – DSP and CAN. There are many reports in Africa on these two types, but many of the published studies did not determine their co-occurrence among the patients.
The frequency of DSP in this study was quite high, occurring in almost half of the patients (41.8%), and this value is within the range quoted in the literature in Nigeria, other parts of Africa and the rest of the world.,, The prevalence is, however, higher than the 31.2% reported by Ibrahim et al. in a similar study. The lower prevalence obtained in that study could have been due to the use of a different screening tool – United Kingdom Screening Test, a lower mean duration of diabetes among the patients and the fact that the patients were younger. Another important observation in our study was the low MNSI symptom scores, a finding that has been reported by Herman et al. in a study conducted to determine the sensitivity, specificity and predictive values of the MNSI. Only 39% of the 73 subjects with an eventual diagnosis of DSP had MNSI symptom scores ≥7, which is the required cut-off for the diagnosis of DSP. A reason for this finding is the low sensitivity of the MNSI symptom score when used without the physical examination component. As such, when selecting patients in the diabetic clinic for neuropathy screening, simple tests such as monofilament testing, vibration perception and ankle reflexes should be carried out along with the symptom scoring. These tools are cheap, are readily available and are simple enough for a resource-poor country like ours.
The frequency of CAN in this study was 26.9%, implying that about one out of every four diabetic patients is at risk of the deleterious effects of autonomic dysfunction. This is higher than the 12.4% reported by Ofoegbu in Enugu, South-eastern Nigeria, which used only Valsalva manoeuvre for the diagnosis of CAN. Thus, it is possible that some patients in the latter study classified as normal might have had abnormalities in other modalities of tests, hence the low prevalence observed. However, in the same region of the country, Eze et al. found a higher prevalence of 44.3%, and this is likely attributable to methodological differences. In that study, a modified Ewing and Clarke's method was used to assess CAN whereby diastolic BP change to sustained handgrip was substituted for resting tachycardia.
Among the tests of parasympathetic function, heart rate variation to deep breathing had the highest frequency of abnormal values in this study followed by Valsalva manoeuvre. Odusan et al., in their work among diabetic patients, however, found heart rate response to standing as the most common abnormality among the parasympathetic function tests. The two tests of parasympathetic function (heart rate variation to deep breathing and Valsalva manoeuvre) with the highest frequencies of abnormality as found in this study, together with BP response to standing, are the three tests recommended by a consensus panel of the American Diabetes Association and the American Academy of Neurology to be included in the tests of cardiovascular autonomic function. These three tests of parasympathetic function are ideal because of their high reliability, reproducibility, sensitivity and specificity.
Our study revealed that about one out of every five patients had a combination of DSP and CAN, and this represents an increased risk of poor cardiovascular outcomes in addition to the risk of foot ulcers and limb amputation. We also found a significant association between DSP and occurrence of CAN which implies that patients who have symptoms and signs of DSP should also be screened for CAN.
A major specific objective of this study was to determine the risk factors associated with the development of peripheral neuropathy among the studied patients. Four out of every ten patients in this study had poor glycaemic control as measured by HbA1c. Patients with poor glycaemic control have about three times the odds of developing DSP independent of other risk factors. The effect of glycaemic control on the development of neuropathy among diabetic patients has been well highlighted in findings from the Diabetes Control and Complications Trial where the incidence of peripheral neuropathy was reduced in patients who had intensive blood glucose control., The relevance of this finding is that more research should be done in the area of health education and intensive control of blood glucose among diabetic patients in order to reduce the risk of DSP. This intensive therapy should be discussed with patients and initiated early to reduce the occurrence of DSP and its sequelae.
Similarly, this study shows that the presence of hypertension results in a 2.4-fold increase in the risk of developing DSP. The role of hypertension as a risk factor for the development of neuropathy has been highlighted by previous studies., Strict BP control was found to reduce the incidence of microvascular complications including peripheral neuropathy among diabetic patients in the United Kingdom Prospective Diabetes Study 38. The presence of elevated systemic BP along with other vascular risk factors such as hyperglycaemia, hyperlipidaemia and smoking could increase the risk of the development of DSP among diabetic patients. The presence of hypertension and serum creatinine remained an independent predictor of the occurrence of CAN. This implies that diabetic patients who are hypertensive have 2-fold increased risk of developing CAN compared to their normotensive peers. Similarly, with every unit increase in serum creatinine, the odds of developing CAN increase by 3.5%. These findings have earlier been reported by Odusan et al. among diabetic patients in the country. In their study, systemic hypertension and serum creatinine were among the factors associated with the presence of CAN in diabetic patients. Thus, in addition to treating the BP to target, renal function should be regularly assessed in patients with diabetes as part of a holistic care of all cardiovascular risk factors in them.
In this study, duration of diabetes did not reach statistical significance as an independent predictor of the development of DSP or CAN although there was a trend toward a direct relationship on univariate binary logistic regression analysis. This is an unusual finding because it is established that the incidence of peripheral neuropathy increases as the duration of diabetes increases. However, in this study, this finding may be attributed to the short median duration of diabetes which is about 5 years among the patients.
Although our study was limited by its hospital-based cross-sectional nature and inability to carry out serum levels of Vitamin B12 and nerve conduction studies due to high cost and the fact that they are not readily available, the findings are significant and contribute to the current state of knowledge concerning peripheral neuropathy in DM. These will be useful in reducing morbidity and mortality associated with the disease, which has assumed a pandemic proportion with escalating burden in Nigeria. This study was funded by the researchers, and the authors have no conflicts of interest to declare.
| Conclusion|| |
This study showed that DSP and CAN are quite common among diabetic patients, with about one in five patients having a mixed form of the two. In addition, diabetic patients who have high BP, poor blood glucose control and declining renal function are at risk of peripheral neuropathy. Early screening for peripheral neuropathy and its risk factors is thus encouraged in all patients.
I would like to sincerely thank all the co-authors who contributed in no small way to the success of this article. I also acknowledge the other support received from members of the neurology and endocrinology units.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016;387:1513-30.
Llewelyn JG, Tomlinson DR, Thomas PK. Diabetic Neuropathies. Peripher Neuropathy. 4th
ed.. Philadelphia: Elsevier; 2005.
Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al.
Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285-93.
Pirart J. Diabetes mellitus and its degenerative complications: A prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1978;1:168-88.
Ibrahim A, Owolabi LF, Borodo MM, Ogunniyi A. Clinical profile of diabetic sensorimotor polyneuropathy in a tertiary hospital in Northwestern Nigeria. Niger J Basic Clin Sci 2015;12:13-9. [Full text]
Owolabi MO, Ipadeola A, Adeleye JO. Aggregate cardiovascular risk is a stronger statistical correlate of clinically evident diabetic peripheral neuropathy than hbA1c alone. J Natl Med Assoc 2010;102:707-12.
Ofoegbu E. Cardiac autonomic neuropathy among diabetic patients in Enugu, Nigeria. Glob J Med Sci 2005;4:53-8.
Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, et al.
Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: The diabetes control and complications trial/Epidemiology of diabetes interventions and complications study (DCCT/EDIC). Circulation 2009;119:2886-93.
Ugoya SO, Echejoh GO, Ugoya TA, Agaba EI, Puepet FH, Ogunniyi A. Clinically diagnosed diabetic neuropathy: Frequency, types and severity. J Natl Med Assoc 2006;98:1763-6.
Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002;288:2579-88.
The effect of intensive diabetes therapy on the development and progression of neuropathy. The diabetes control and complications trial research group. Ann Intern Med 1995;122:561-8.
Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al.
Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-50.
World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of WHO Part 1. Geneva: World Health Organization; 1999.
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281-9.
Moghtaderi A, Bakhshipour A, Rashidi H. Validation of Michigan Neuropathy Screening Instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg 2006;108:477-81.
Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J (Clin Res Ed) 1982;285:916-8.
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-97.
American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care 2011;34:S11-61.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., et al.
The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA 2003;289:2560-72.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III). JAMA 2001;285:2486-97.
Ndip EA, Tchakonte B, Mbanya JC. A study of the prevalence and risk factors of foot problems in a population of diabetic patients in Cameroon. Int J Low Extrem Wounds 2006;5:83-8.
Herman WH, Pop-Busui R, Braffett BH, Martin CL, Cleary PA, Albers JW, et al.
Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: Results from the diabetes control and complications trial/Epidemiology of diabetes interventions and complications. Diabet Med 2012;29:937-44.
Eze C, Onwuekwe I, Ogunniyi A. The frequency and pattern of cardiac autonomic neuropathy (CAN) in type 2 DM patients in a diabetic clinic in Enugu, South-East Nigeria. Niger J Med 2013;22:24-31.
Odusan O, Familoni OB, Raimi TH. Correlates of cardiac autonomic neuropathy in Nigerian patients with type 2 diabetes mellitus. Afr J Med Med Sci 2008;37:315-20.
Kahn R. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Clinical measures. Diabetes Care 1992;15:1081-3.
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553-79.
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK prospective diabetes study group. BMJ 1998;317:703-13.
Forrest KY, Maser RE, Pambianco G, Becker DJ, Orchard TJ. Hypertension as a risk factor for diabetic neuropathy: A prospective study. Diabetes 1997;46:665-70.
[Table 1], [Table 2], [Table 3], [Table 4]