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Height is a risk factor for development of peripheral insensate neuropathy

Peripheral neuropathy affects 2-8% of adults, with an increasing incidence increase in age. It is an incapacitating complication often seen in diabetics, because of its potentiality to cause lower extremity ulceration, deformation and amputation. With early detection, proper history and focused laboratory testing, we can identify the underlying cause in ~75% of the cases and prevent morbid and expensive complications.


INTRODUCTION
Peripheral insensate neuropathy (PIN) is defined as presence of one or more insensate areas. 1,2 PIN is a wellacknowledged problem and numerous determinants are associated with it like age, gender, race, glycemic control, malnutrition, toxins, drugs, alcohol, etc. 1,3,4 Peripheral neuropathy affects 2-8% of adults, with an increasing incidence increase in age. 5 It is an incapacitating complication often seen in diabetics, because of its potentiality to cause lower extremity ulceration, deformation and amputation. 6 With early detection, proper history and focused laboratory testing, we can identify the underlying cause in ~75% of the cases and prevent morbid and expensive complications. [7][8][9] Height is a valuable and useful predictor of PIN. As the height increases, the length of the nerve fiber also increases, so the surface area of axons available for toxin exposure and neuronal injury is more. The risk of PIN increases with increase in body height. Various studies have proven the interrelationship of body height wand peripheral neuropathy among diabetics. [1][2][3]10 It is still obscure if there is any specific threshold in the affiliation of height and the risk for PIN in the general Indian population.
Early screening of PIN by health care personnel, tight glycemic control among diabetics, cessation of alcohol and smoking, correction of nutritional deficiencies, avoiding toxins and drugs and other preventive care are considered as key public health strategies against costly foot complications. 7,8 A simple device, the Semmes Weinstein monofilament pf 5.07/10 gm is recommended by International Diabetes Federation, American Diabetes Association and World Health Organization for screening of peripheral neuropathy by healthcare personnel at all levels of care. 8 Previous studies have shown that presence of one or more insensate area to be highly predictive of ulcer formation and the monofilament has been found to have high sensitivity (~85%) and specificity (~80%) for development of ulcers and deformities. [11][12][13] The association of body height and peripheral neuropathy has not been thoroughly investigated in the Indian population; there has been only one previous study that has concluded height as an independent risk factor. 2 Thus, this needs further exploration in the Indian context and a threshold height for screening needs to be settled upon.

A cross sectional study was conducted in Mahatma
Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth University, Puducherry, India in the years 2017-2018, which included an examination of 760 people, with ages >30 years by random sampling, who attended the outpatient department. Informed consent was taken from the individuals and so was an institutional clearance from Mahatma Gandhi Medical College and Research Institute Sri Balaji Vidyapeeth, Puducherry, India.

Inclusion criteria
• People with age more than 30 years.

Exclusion criteria
• People with foot ulcers, • People with calluses on the feet, • People with Age <30 years.

Methodology
A detailed history was taken, with appropriate attention to sensory symptoms of neuropathy, drug ingestion, toxin exposure, diabetic and hypertensive status, smoking and alcohol consumption. A detailed examination was done, with emphasis on height and weight.
Individuals' blood was taken and was measured for complete blood count, fasting blood glucose, postprandial blood glucose and glycosylated hemoglobin with their consent.

Peripheral insensate neuropathy assessment
The semmes weinstein monofilament of 5.07/10 gm force was used on the feet of patients while their eyes were kept closed. 11 The sensation was checked at 3 sites on the individual feet ( Figure 1).
The filament was applied at the specified sites ( Figure 1) until it buckled. The site was considered insensate if there were: • Two incorrect responses.
• Two responses which were ambiguous.
• One incorrect response and one ambiguous response.
The sites were tested in a random order. PIN was marked as present if there were one or more insensate areas.
The parameters which were analyzed were:Hypertension

RESULTS
This study included the examination of 760 patients who attended the outpatient department, where the mean height was 164.9cm. The prevalence of PIN was 3.2% (4.7% in males and 2.5% in females) ( Table 1). The height which was adjusted for the gender analysis was not found to be significant ( Figure 2). The people with hypertension and diabetes were found be at a higher risk for PIN. The prevalence of PIN among the hypertensive group was 8.5% as compared to 5.4% among the diabetics (Figure 3, 4).
The duration of hypertension and diabetes was directly proportional to the prevalence PIN; this was found to be statistically significant. Glycemic control was risk factor with higher HbA1c levels correlating with higher frequency of PIN, but this was not found to be statistically significant. PIN prevalence increases as the age advances, irrespective of the gender (<40years-1.6%,>70years -5.1%). Among the people, PIN was found to be highest between the ages of 60-70 years (7.8%) ( Figure 5).
The mean height was 168.1 cm among men and it was 157.6cm among women. For analysis, authors segregated the people into quartiles to find relationship between height and PIN, regardless of gender, age, diabetic and the hypertensive statuses, anemia, BMI, alcohol intake and smoking. Authors found that the threshold of prevalence of PIN increased with increase in height, as seen in the fourth quartile (p=0.002) ( Figure 6).     As shown in (Table 2), author also found a similar association between the height and the PIN across the stratification of diabetes, the hypertension, gender and BMI. Authors accomplished this by arranging the individuals with known risk factors in quartiles of height; author found that the fourth quartile had more prevalence of PIN. In the study population, the risk of PIN was significantly higher among males >171.5cm and among females, it was >167.5 cm.
In present study, author also found a statistically significant association between PIN and smoking and the alcohol consumption while we did not find a significant association between BMI and PIN.

DISCUSSION
In this cross-sectional study, authors confirmed that PIN is associated with increasing age, diabetes, hypertension, alcohol consumption and smoking. 1,2 Authors also found that being tall and male was a similarly important risk factor.
The methodology for defining PIN (PIN) in the study was similar to the previous studies such as Cheng [1][2][3]17 The difference between the genders can also be explained on the basis of biomechanics of foot as seen in the study of Dinh et al. 18 In present study, gender was not a significant factor for development of PIN.
In present study the prevalence of PIN increases as the age advances (p=0.09). Prevalence roughly increased by 10% from 41-50 to 51-60 years, comparable to Gregg EW et al, and almost tripled in age group 61-70 years, however there was a drop in above 70 years age group, the reason is not known. 16 As compared to previous studies, the prevalence of PIN increases as the age advances irrespective of diabetic status. Attribution of increase in PIN with age may be because of decreased nerve fibers, reduction in nerve diameter and change in fiber membrane and conduction velocity as shown in the studies of Huang CR et al, and Chu NS et al. 19,20 In present study, prevalence was more than twice as high for individuals with diagnosed diabetes (5.4%) as compared to those without diabetes (2.5%). It was comparable to previous studies such as Cheng  The prevalence of PIN was more in individuals with longer duration of diabetes as compared to individuals with shorter duration. Individuals with higher HbA1C levels were also found to have higher frequency of peripheral neuropathy than individuals with tight glycemic control. These findings were similar to those seen in other studies. 16,24,[26][27][28] Hypertension was found to be significantly associated with prevalence of PIN in our study (p<0.001).
Prevalence of PIN in hypertensive group was 8.5% as compared to 2.2% in non-hypertensive group, which was almost quadruple that of the non-hypertensive group.
Studies have shown hypertension is one of the modifiable risk factors of PIN which play a significant role in prevalence of PIN as suggested in present study, due to both micro and macovascular complications that accompany hypertension. 24,29 The prevalence of PIN was more in patients with longer duration of hypertension than patients with shorter duration of hypertension. 30,31 Very few studies have shown an association between BMI and PIN. 32 Present study, PIN was not associated with increasing BMI which was supported by a recent meta-analysis that also came to a similar conclusion. 33 Height was found to be a significant, independent and effective predictor of PIN. [1][2][3][4]15,34,35 The individuals in the study were divided into quartiles based on their heights. The prevalence of PIN was 1.5% in the first quartile, 0.5% in the second quartile, 4.6% in the third quartile and 6.7% in the fourth quartile. The above data confirmed and established that PIN was associated with increase in height. This correlation was found to be statistically significant (p=0.002).
In present study to find out the significance of height as an important variable and to rule out the association of other variables like diabetes, hypertension, gender and BMI, Author distributed these variables with respect to height quartiles. Author found that height was an independent variable in causation of PIN. The present study showed significant association between smoking and development of PIN which was similar to a recent meta-analysis. 39 Smoking was found to cause microvascular complications that may be the cause for PIN. Alcohol consumption was also significantly associated with PIN, which is similar to the findings of a recent meta-analysis conducted by Julian et al, the cause is postulated to be nutritional deficiency. 40 Present study was a cross-sectional study and the sample size was not representative of the entire population. The duration of diabetes and hypertension specified in the study is not a true reflection of the duration of the illness. Since this was a cross-sectional study, authors were incapable of concluding the association between modifiable risk factors and development of PIN as a cause-effect association. Authors used the monofilament test to determine the presence of PIN, while this has decent sensitivity and specificity; nerve conduction studies have better accuracy.

CONCLUSION
Height is one of the independent risk factors for development of peripheral insensate neuropathy. Diabetes and hypertension are also found to be important independent risk factors. Body height will help heath care providers in identifying individuals who will require intensive neurological screening. We recommend individuals with height more than 171.5cm in males and 162.5cm in females to be screened annually for development of peripheral insensate neuropathy after the age of 30 years regardless of risk factors.