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1 March 2025

Investigation into a Predominant Laterality for the Development of Lower-Extremity Neuropathic Ulceration and Amputation

and
University Health Lakewood Medical Center, 7900 Lee Summit Rd, Kansas City, MO 64139
J. Am. Podiatr. Med. Assoc.2025, 115(2), 22223;https://doi.org/10.7547/22-223
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Abstract

Background: The incidence of neuropathic pedal ulceration is on the rise, especially as rates of type 2 diabetes continue to increase. Currently, there is limited research into the laterality for the development of lower-extremity neuropathic ulceration or a predominant side for amputation. However, identifying whether a predominant laterality exists could allow for better preventive measures to help mitigate risk and decrease the significant quality of life and health-care costs associated with lower-extremity ulceration and amputation. We sought to determine whether a predominant laterality exists for the development of lower-extremity neuropathic ulceration and amputation. Methods: Patient data from the authors’ primary health-care facility were retrospectively reviewed to determine the laterality of the initial presenting lower-extremity neuropathic ulcerations as well as the laterality of the initial lower-extremity amputations experienced during their care, if any. Results: A total of 136 patients were included in the study, with 61% of the initial ulcerations presenting on the right and 39% on the left, which was statistically significant. Of the 70 patients who went on to require amputation during their care, 67% experienced right-sided amputation and 33% experienced left-sided amputation, which was also statistically significant. Conclusions: The right lower extremity likely shows a predominance for the development of neuropathic ulceration and likewise is at a higher risk for advancing to lower-extremity amputation
As the incidence of diabetes continues to rise, so does the prevalence of peripheral neuropathy, and along with it the development of neuropathic foot ulceration. Approximately 50% of adults with diabetes will develop peripheral neuropathy, and of those, up to 25% to 50% will then go on to ulcerate [1]. Diabetic foot ulceration care is estimated to cost the health-care system upward of $1.38 billion per year [2]. Even more, diabetes accounts for approximately 83% of all of the major lower-limb amputations in the United States, and, alarmingly, the 5-year mortality rate after a lower-limb amputation is approximately 50%, which is significantly higher than that of prostate cancer, breast cancer, and Hodgkin lymphoma [1,3]. It is difficult to define this epidemic as anything short of a public health crisis, and the need for further research into the development of neuropathy, ulceration, infection, and amputation with a goal of developing better preventive care is arguably higher than ever.
Investigation into the prevalence of asymmetry in the development of lower-extremity neuropathic ulceration and amputation is fairly limited. The first two studies to evaluate for this potential phenomenon were published in 1999. The first, by Evans et al [4], who evaluated specifically for laterality in lower-limb amputation, found that of 25 patients with lower-limb neuropathic ulceration, 24 (96%) were to the right lower extremity, with 18 of those (75%) being right handed [4]. Although arguably the sample size of this study limits the confidence in the results, a second study in 1999 by Coxon and Gallen [5] also looked into the laterality of lower-limb amputation. They found that of 219 diabetic patients with unilateral amputation, 179 (81.7%) were on the right and 40 (18.3%) were on the left [5]. This sparked a direct response by Abbott et al [6], who stated that they did not find a predominant laterality after retrospectively reviewing 190 diabetic patients with lower-extremity amputation. Specifically, they reported that 79 amputations were on the right, 78 were on the left, 14 were bilateral, and 19 were unspecified [6]. Likewise, a more recent study by Demetriou et al [7] in 2019 investigated for possible asymmetry in the development of both neuropathic and neuroischemic ulceration. Among 63 patients with neuropathic ulcers, they found no predominant laterality (32 right and 31 left) [7].
When evaluating the limited existing research and combining the patients from the studies by Coxon and Gallen [5] and Evans et al [4], this totals 244 in support of a laterality predominance. In contrast, the patients from the studies by Abbott et al [6] and Demetriou et al [7], which found no predominance, totaled 253. Undoubtedly, this is an area that requires further research because there is no clear evidence of whether a predominant laterality exists. There is research precedent, however, to the asymmetry of lower-extremity biomechanics, which at least lends credence to the possibility of the asymmetrical development of injury within or without the context of ulceration development. A study by Polk et al [8] in 2017 that evaluated for asymmetry in biomechanics during ambulation found that the dominant limb generated a higher asymmetry in terms of mediolateral peak ground reaction forces, concluding that limb dominance was a better predictor of asymmetrical biomechanics than other factors. Interestingly, a study by Vagenas and Hoshizaki [9], who also evaluated for and identified consistent functional asymmetry in lower limbs in long-distance runners, found that upper-extremity limb dominance was independent of the lower-extremity asymmetry findings. Furthermore, Nagano et al [10] performed a study evaluating for changes in foot-ground clearance in the context of treadmill and overground walking for younger individuals (mean age, 22.5 years) compared with older individuals (mean age, 73.8 years). They found that regardless of age, the nondominant limb showed greater minimum foot-ground clearance and first maximum clearance, hypothesizing that the nondominant limb functions more as a stabilizer, whereas the dominant limb provides the primary role of forward progression during gait [10]. This lends credibility to the idea that a dominant limb may experience higher microtrauma as the primary progressive limb when walking.
The implication of these biomechanical research findings, in addition to the inconclusive results of current research on a predominant laterality for neuropathic ulceration development, is that further investigation is reasonably warranted and could result in the development of superior custom off-loading footwear, which remains the gold standard for prevention of neuropathic ulceration.
The purpose of his study was to evaluate for a predominant laterality in the initial development of lower-extremity neuropathic ulceration as well as to see whether such a predominant laterality also exists with initial pedal amputation.

Methods

A research proposal for a retrospective review was submitted to the University of Missouri Institutional Review Board for approval, and exemption status was obtained. Data from patients treated between January 1, 2011, and April 30, 2022, were then retrospectively reviewed to determine the laterality of pedal neuropathic ulceration at initial presentation to University Health Lakewood Medical Center (Kansas City, Missouri) as well as the initial laterality of any amputation experienced at the same health-care facility. The laterality of the initial ulceration as well as the laterality of any initial amputation was then documented and totaled for all of the patients.
All of the patients presenting to University Health Lakewood Medical Center for evaluation or treatment of pedal neuropathic ulceration were included. Patients experiencing an initial lower-extremity amputation related to infection from neuropathic ulceration during treatment at this facility were included. These initial amputations for amputation-naive patients were included regardless of whether the amputation was a result of infection from the initial ulceration. All of the included patients had a documented intact vascular status via physical examination, advanced imaging, or both.
Patients presenting with a traumatic or other etiology of ulceration outside of neuropathic were excluded. Patients with development of ulceration related to ischemia regardless of their neuropathic status were excluded. Patients with a history of lower-extremity amputation at initial presentation were also excluded.
Two-sample proportions z-tests were conducted to examine the equality of the percentages. In addition, a statistical software program (SAS, Version 9.4; SAS Institute Inc, Cary, North Carolina) was used for statistical analysis and to obtain P values. Statistical significance was set at P < .05.

Results

Of 136 patients included, 132 were diagnosed as having diabetic peripheral neuropathy, two with alcoholic neuropathy, and two with idiopathic neuropathy. Forty-three of the patients were female (31.6%) and 93 were male (68.4%). Two of the patients (1.5%) presented initially with both right and left foot wounds, 82 (60.3%) with initial ulceration on the right foot, and 52 (38.2%) with initial ulcer on the left foot. This was significant at P < .0001.
Seventy patients (51.5%) also experienced a lower-extremity amputation related to neuropathic foot infections during treatment. Of those, 47 (67.1%) were on the right and 23 (32.9%) were on the left. This was also significant at P < .0001.
In addition, eight of the patients either had or developed Charcot’s arthropathy during their treatment: six (75%) developed Charcot’s arthropathy on the same side as their initial ulceration and two (25%) on the opposite side of their initial ulceration. From the data set, there were only three patients with Charcot’s arthropathy who experienced amputation: two matched their initial ulceration laterality and one did not.

Discussion

There was a higher incidence of right foot ulceration (61%) at initial presentation compared with the left (39%). However, the incidence of amputation related to neuropathic infection significantly favored the right lower extremity at 67% compared with 33% on the left. There is a significant amount of research that certainly supports the occurrence of subtle asymmetry in lower-extremity ambulation and biomechanics, which may partially account for these results [11–13]. This is exhibited in a study by Promsri et al [14], who looked into the specific lower-extremity biomechanics of downhill skiers and found that injuries were related to consistent asymmetry in sensorimotor control. Likewise, Sernert et al [15] found in their evaluation of knee laxity measurements in the context of predicting anterior cruciate ligament injury that the right knee showed significantly more laxity than the left in both healthy patients and those with a history of anterior cruciate ligament injury. Furthermore, Helme et al [16] found in their systematic review that functional asymmetry in the lower extremities was a risk factor for injury across multiple sports.
Although there is no consensus on a superior method of determining the laterality of lower-extremity dominance, there is widespread agreement that a dominance exists among the lower extremities [17]. This especially becomes important in the context of lower-extremity ambulation mechanics, with the dominant limb serving as the primary progressor and the nondominant limb serving as the primary stabilizer. Although there is limited research on the effect of asymmetrical pedal microinjury related to neuropathy, there is a reasonable amount of evidence that shows that there is asymmetry when it comes to lower-extremity injury in nonneuropathic settings, especially in the context of the knee and anterior cruciate ligamentous injury [18–22]. It is reasonable to assume, therefore, that there is at least the potential for increased injury to the dominant leg. In addition, we hypothesize that the duration of ulceration for the dominant foot may be longer given the potential for higher repetitive microtrauma as the primary progressor. This would then leave the right open to infection for longer periods and may subsequently increase the risk of amputation; however, further study is needed.
When evaluating the implications of a predominant laterality for the development of neuropathic ulceration, it is important to further consider the contribution of shoes in treatment strategies. It has been well-established that areas of elevated pedal pressure increase the risk of the development of ulceration, and off-loading via prefabricated or custom shoes and orthoses remains the prophylactic gold standard [23–28]. In that vein, a 2020 study by Wang and Graham [29] investigated ambulation mechanics with varying shoe weights and found that shoes with higher mass caused an increase in the peak vertical ground reaction forces during ambulation. In 2011, Niu and Wang [30] did a study to evaluate the effectiveness of limb laterality on foot and ankle kinematics during ambulation also with varying weights of shoes, but they were increased or decreased in equal increments on both the right and left. What they found was that wearing heavier shoes caused the peak impact force to occur earlier during ambulation and that this early occurrence of the peak impact force increased pedal soft-tissue tension and increased the risk of joint injury. They, therefore, concluded that in the nondominant leg, the risk of injury may be affected by shoe weight. However, this phenomenon was found only in the nondominant leg, and the peak impact time of the dominant leg was not affected by the weight of the shoe. They hypothesized that this was because the increased strength and flexibility of the dominant leg resulted in better dynamic control [30]. Although both of these studies were performed in healthy nonneuropathic patients, the implications suggest that dominant and nondominant limbs respond differently to alterations in shoes. This suggests that there may be some benefit to intentionally creating asymmetrically accommodating shoes and orthoses based on a patient’s leg dominance or nondominance to account for their difference in roles during ambulation mechanics.
Furthermore, although this was not specifically investigated in the present study, there were eight patients who either had or developed Charcot’s arthropathy during their treatment. Notably, 75% of those matched the laterality of their initial presenting ulceration, and only 25% developed Charcot’s arthropathy on the contralateral side. Although the full pathophysiology of lower-extremity Charcot’s arthropathy remains unclear, it is clear that a progressive development of neuropathy contributes to an increase in microtrauma. This is then further complicated by hyperemia causing monocyte and osteoclast enrichment and overall initial bony resorption with breakdown of bone [31–35]. Currently, there are no published studies evaluating whether there is a predominant laterality for the development of Charcot’s arthropathy; however, given what is known about its pathophysiology, it would be reasonable to assume that there may also be a predilection for its development in the dominant limb. At a minimum, this is certainly supported by our preliminary results. Clearly, there is significant need for further study to delve further into the implications not only of the presence of a predominant laterality for Charcot’s arthropathy but for the consequences and potential for better prophylaxis given the resulting predominance of right-sided neuropathic ulceration and right-sided amputation.
There were several potential weaknesses of this study. The first weakness was the small sample size of 136 patients. Although this sample size was slightly larger than two of the four existing studies on this topic, the results of the paired z-test assume a standard normal distribution, which may result in a misleadingly high statistical significance. In addition, if a patient had a history of ulceration healing or treatment before presentation at our facility, then initial laterality at presentation to us may not represent the actual laterality of initial ulceration experienced by the patient. However, given that this potential is arguably the same for every patient and that initial presentation to our health-care facility represents a snapshot in time with equal chance of a matching or nonmatching laterality for initial presentation, we do not believe that confidence is lost in the results of this investigation. Future studies with higher sample sizes may be more powerful not only for gaining confidence in the statistical significance but also if at initial presentation an investigation was performed to determine whether the patient had a history of pedal ulceration.
In addition, because this was a retrospective analysis, no investigation into determining the patients’ dominant lower extremity was performed. However, if such an investigation were to be added to the study, it does have the potential to either strengthen or weaken the results. Although we hypothesize that the resultant predominance of right-sided initial ulceration and initial amputation is a result of the repetitive microtrauma inflicted on what we assume to be the dominant leg, it is possible that in some of these instances, the dominant leg is actually on the left, which may weaken the results in support of the hypothesis. In that vein, however, it is similarly possible that the patients presenting with initial left-sided ulcerations and resultant left-sided amputations could also have a dominant left leg, which would strengthen the results of this study. Clearly, further research is warranted.

Conclusions

There is a higher incidence of neuropathic ulceration development to the right foot compared with the left. Likewise, right-sided lower-extremity amputation related to neuropathic foot infection is significantly more prevalent. With this understanding, the development of dominance-specific shoes and orthotic devices could potentially have a significantly positive effect on minimizing the development of these neuropathic ulcerations and amputations.

Financial Disclosure

None reported.

Conflicts of Interest

None reported.

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