|Ahead of print
Prevalence of peripheral neuropathy in children with type 1 diabetes mellitus
Gururaju Daasara1, Vykuntaraju K Gowda2, Nijaguna Nanjundappa1, Vani H Nagarajappa1, Sanjay K Shivappa1
1 Department of Pediatric Medicine, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
2 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
|Date of Submission||05-Sep-2021|
|Date of Decision||02-Jan-2022|
|Date of Acceptance||02-Mar-2021|
|Date of Web Publication||12-Jul-2022|
Vykuntaraju K Gowda,
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru 560029, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: To study the prevalence of peripheral neuropathy (PN) in type 1 diabetes mellitus (DM) and its association with clinical neuropathy and glycemic control by using nerve conduction studies (NCS). Materials and Methods: This cross-sectional study was conducted in a tertiary care center from January 2018 to May 2019. Type 1 DM with at least a five-year duration was included. Demographic, clinical, and laboratory details were collected and analyzed. Results: A total of 95 (40 boys) children with a mean age of 11.8 ± 3.4years were included. Neuropathy was clinically noted in 9 out of 95 (9.4%) patients and by NCS in 46 out of 95 (48.4%) patients. The PN has a significant association with the duration of illness (P-0.05) and HbA1c (P < 0.001). The sensitivity and specificity of detecting neuropathy by HbA1c was 63.0% and 63.3%, respectively. For every unit increase in HbA1c, the odds ratio for nerve conduction increases by 55.2%. Conclusion: The prevalence of neuropathy is high in children with type 1 DM. The duration of illness and poor glycemic control are major risk factors.
Keywords: HbA1c, nerve conduction studies, neuropathy, type 1 diabetes mellitus
| Introduction|| |
The world over, approximately 11,06,500 children are living with type 1 diabetes mellitus (DM). An estimated 1,28,500 children in India are afflicted with type 1 DM. Prevalence rates are expected to increase and are responsible for a growing proportion of global health expenditure. The poorly controlled DM causes complications such as neuropathy, retinopathy, and nephropathy. Peripheral neuropathy (PN) is one of the commonly encountered complications, leading to significant morbidity. The timely intervention and prevention of such a complication will reduce morbidity and improve the quality of life. The nerve conduction studies (NCS) is a noninvasive technique that helps to diagnose neuropathy. The objective of this study is to find out the prevalence of PN in children with type 1 DM and its association with clinical neuropathy, glycemic control, and the duration of illness using NCS.
| Materials and Methods|| |
This cross-sectional study was conducted in a tertiary care hospital in Bangalore from January 2018 to May 2019. Children with type 1 DM with a disease duration of at least five years were assessed for eligibility and included. The weight, height, body mass index (BMI), and blood pressure (BP) were recorded. Symptoms suggestive of small fiber neuropathy such as pain, tingling or a pins and needles sensation, burning pain, allodynia, and hyperesthesia were considered. Symptoms suggestive of autonomic neuropathy were also considered. Pinprick sensation, temperature sensation, hyperalgesia, vibration perception, and ankle reflex were examined in all participants. A tuning fork (128Hz), cold and warm water, and a reflex hammer were used for the evaluations. Skin findings such as dry, cracked, or shiny skin, with decreased moisture were noted. The ophthalmological examination was done by a pediatric ophthalmologist who looked for diabetic changes.
The NCS was performed after explaining the procedure. It was done by using the standard “Alleger’s Scorpio Electromyography machine.” The examination was done in a calm room with an optimal temperature of 24-degree Celsius and optimal lighting. Skin temperature was checked and recorded a normal approximately 34-degree Celsius before conducting NCS. Median, ulnar, tibial, sural, and peroneal nerves were selected. The NCS was conducted by the same technician and reported by the same pediatric neurologist. Amplitudes, velocities, and distal latencies were considered abnormal, if values were outside the ± 2.5 standard deviation of the normal pediatric values. The reference for NCS was taken from a clinician’s approach to the neuromuscular disorders of infancy, childhood, and adolescence. We defined axonal neuropathy as a reduction in compound muscle action potentials (CMAPs)/sensory nerve action potential (SNAPs) more than 80% of 2.5 SD below normal with no electrophysiological evidence of demyelination. Demyelinating neuropathy was diagnosed if any of the following criteria were met: (1) Conduction velocity was less than 75% of 2.5 SD below the normal expected for age; (2) distal latency was prolonged more than 130% of 2.5 SD above the normal expected for age; and (3) the presence of conduction block (proximal CMAP amplitude) was less than 50% of the distal CMAP amplitude. The abnormalities in more than two nerves were considered as neuropathy.
At the time of visit, samples for blood glucose, HbA1c, liver function test, lipid profile, vitamin B12, thyroid stimulating hormone (TSH), urea, and creatinine were taken. We calculated estimated glomerular filtration rate (eGFR). HbA1c reports related to the previous one year were collected; mean was calculated and designated as good, fair, and poor control based on HbA1c range of ≤7.5, 7.6–9.9 and ≥10, respectively.
The Excel and SPSS (SPSS Inc, Chicago v 18.5) software were used. The results were averaged (mean + standard deviation) for each parameter for continuous data. The normality of the data was assessed by using Shapiro-Wilk test. The comparison between the groups was carried out by using the following parametric tests, one-way Analysis of Variance (Anova), Student’s “t” test, and Chi-Square (χ2) test for (r x c tables). In all the tests cited earlier, a “p” value of less than 0.05 was accepted as indicating statistical significance. Multivariate logistic regression has been used in SPSS 25 version to conclude the results.
The study was approved by the institutional ethical committee (no: IGICH/ACA/IEC/18). Informed written consent was obtained.
| Results|| |
Out of the 112 children examined, 95 (40 males) were included and 17 were excluded. The 12 children were excluded due to the non-cooperation of the children, and the remaining five children were excluded due to the attenders not giving consent for the test. The mean age of the study population is 11.8 ± 3.46 years. Evidence of clinical PN was noted in 9 out of 95 (9.4%) patients. The retinopathy was not noted in any child. The prevalence of PN was 48.4% (46/95) by NCS. The maximum prevalence of PN was seen in children in the age group of 10–15 years (43.5%). There is no difference in the lipid profile, vitamin B12 level, TSH, urea, creatinine, and eGFR between the two groups. [Table 1] shows NCS in relation to the duration of the disease and HbA1c levels. [Table 2] shows the distribution of glycemic control and the type of neuropathy.
|Table 1: The comparison of mean duration of illness and mean HbA1c between the normal and the neuropathic population and the comparison of glycemic control with the prevalence of neuropathy|
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|Table 2: The distribution of glycemic control between types of neuropathies|
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As per multivariate logistic regression, there is a significant prevalence of PN and its association with glycemic control (Omnibus Chi-square x2 (2) = 17.371, <0.05). The model explained 22.3% variance in the glycemic control among children and it was able to identify 63.2% cases accurately. The sensitivity of the model was 63.0%, and the specificity of the model was 63.3%. The overall results show that for every unit increase in glycemic control the odd ratio for nerve conduction increases by 55.2%.
| Discussion|| |
This study assessed 95 children with type 1 DM with a duration of at least five years after diagnosis by NCS. The male to female ratio was 1:1.3 compared with 1:1.6 according to the study by Lee et al. This study showed a female preponderance. The mean age of the present study population was 11.8 ± 3.46 years, which was comparable to previous studies, as depicted in [Table 3].,,,
|Table 3: The comparison of prevalence of neuropathy, mean duration of disease, mean HbA1c, and significance of risk factors with the development of neuropathy with other studies|
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In the present study, PN was observed to be 48.4%, which is less compared with previous studies by Toopchizadeh et al, Bao et al, Cenesiz et al, and Lee et al, which showed PN to be 57.5%, 68.4%, 60%, and 70.3%, respectively. These studies had smaller sample sizes and showed a higher prevalence of neuropathy than the current study, which examined a larger sample size and negated a possible sampling bias. Our results were comparable to Singh DP et al, where 56% of subclinical neuropathy was reported in type I DM from India.
Both metabolic and ischemic mechanism may play a role in the pathophysiology of diabetic neuropathy in type I DM. When tissues are exposed to hyperglycemia, intracellular glucose gets converted to sorbitol, leading to a decrease in the levels of myoinositol and causing tissue damage. Hyperglycemia causes glycosylation of protein. Elevated glucose converts myelin to glycosylated myelin, which is endocytosed by macrophages and leads to segmental demyelination. These advanced glycosylated end (AGE) products modify not only myelin, but also tubulin, neurofilaments, and actin. This alteration in cytoskeleton causes axonal atrophy, degeneration, and impaired axonal transport. Recently, it was found that the receptors for AGE (RAGE) interact with AGEs of the peripheral nerve, activate the transcription of proinflammatory genes, which leads to increased oxidative cellular damage. In the hypoxic theory, hyperglycemia causes inflammation of endoneural, epineural, and perineural blood vessels, leading to ischemia of peripheral nerves. This results in a decrease of motor conduction velocity and axoplasmic transport. Other factors that may contribute to peripheral neuropathy are oxidative stress, genetic variation, and autoimmunity.
The mean duration of disease in the present study was 6.4 ± 2.14 years, similar to previous studies.,, No significant association was evident between the age of onset and neuropathy, for instance as depicted in Toopchizadeh et al. There was a statistically significant correlation between PN and the duration of illness(‘p’ = 0.05) that is comparable to previous studies,, however prospective long-term studies are required.
The mean HbA1c values of 10.9 ± 1.82 were comparable to previous studies.,, A statistically significant (“p”<0.001) association between neuropathy and mean HbA1c was noted in the current study, which was similar to previous studies.,,,,, However, there are studies,, that suggest that pathological NCS and glycemic control are not necessarily related. The probable reason for this disparity may be good glycemic control from the beginning of the disease to prevent the development of neuropathy, as reported by Ziegler et al in a 24-year prospective study, which suggests that good glycemic control prevents the development of neuropathy. The sensitivity and specificity of detecting neuropathy by HbA1c is 63.0% and 63.3%, respectively. For every unit increase in HbA1c the odds ratio for nerve conduction increases by 55.2%. The clinical evidence of PN (9.5%) in the current study is comparable to the 5.2%, 27.5%, 5.4%, and 13.2% of previous studies. Of the 46 patients, 39 children had motor demyelinating and seven had motor axonal PN. These parameters were not assessed in other studies.
Ophthalmic evaluation showed no features of diabetic retinopathy, which was similar to previous studies., In the present study, all children had normal BMI, lipid profile, and eGFR levels. The limitation of the present study is that it is a cross-sectional study and other causes of neuropathy could not be assessed due to economic constraints.
| Conclusion|| |
The prevalence of diabetic PN was 48.4%. The increasing disease duration and poor glycemic control are major risk factors. The NCS are more sensitive than the clinical evaluation for diagnosing neuropathy.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]