Neuropathic plantar ulcers (PUs) or neuropathic arthropathies (NAs) are common and a source of considerable morbidity and high healthcare cost.1–3 At present, polyneuropathies, the associated diseases, and risk covariates in general medical cohorts are still inadequately defined. Studies of the diseases underlying PUs and NAs are needed because of the prevalence of these complications and the possibility that underlying diseases may be changing.4–7 Further, the ability to detect inherited polyneuropathies through the use of whole exome sequencing (WES) may identify an increasing number of such diseases.8
Early recognition and appropriate management of neuropathy are important because of the risk of injury to insensate feet. Although diabetes mellitus (DM) is one of the most common causes of peripheral neuropathy worldwide,9 it is not the cause of neuropathy in all patients with diabetes. Other causes should be actively excluded.9
The underlying mechanisms of major neuropathy syndromes are not well understood.2,9 Inherited polyneuropathies are diverse and often difficult to diagnose. In the past, reports have focused on the prevalence of neuropathic complications related to a single disease (hereditary sensory and autonomic neuropathies and DM).10–12 Studies of neuropathic complications of single-disease cohorts have provided insights about risk covariates and mechanisms of injury. In 1868, Charcot4 attributed NAs to loss of a trophic spinal cord center (posterior column demyelination) in tabes dorsalis. Subsequent experimental studies by Eloesser5 and Corbin and Hinsey6 provided alternative explanations. These authors performed surgical transection of posterior nerve roots innervating a single limb of cats, resulting in loss of protective sensation. The loss of protective sensation resulted in limb fractures, joint dislocations, arthropathies, and skin ulcers of the sensory-deprived limb. Confining the cats to cages delayed and/or decreased these lower extremity complications. The study showed the role of loss of protective sensation and physical activity in the pathogenesis of PUs and NAs.
Studies of known human disease have confirmed that sensory loss (especially small-fiber sensory loss typically seen in polyneuropathy) and injury are implicated in causing PUs and NAs.7 Study of inherited neuropathies has demonstrated that selective small (but not large) fiber sensory loss, the excessive use or abuse of limbs, and the lack of adequate protection from injury led to increased occurrence and severity of lower extremity complications.7,8,13,14 The loss of foot sensation, focal repetitive pressure injury because of foot deformity, or ill-fitting shoes are major risk covariates for lower extremity complications in DM.11,15–19 Surveillance of foot sensation, periodic foot care, and avoidance of excessive repetitive focal foot pressure injury are recommended.11,16,17,19 The aim of this study was to determine the risk covariates of PUs and NAs for patients seen in a wound clinic.
Study Setting, Design, and Ethical Conduct of Research
Mayo Clinic is a tertiary medical center. The Vascular Ulcer/Wound Healing Clinic is a specialized multidisciplinary facility to which patients with chronic wounds are referred. It is staffed by physicians, advanced practice providers, nurses, and clinical assistants from the departments of internal medicine, vascular medicine, and physical medicine and rehabilitation. Two of the authors provided comprehensive neurologic and neurophysiologic evaluations of wound clinic patients with clinical findings of neuropathy for a 3.5-year period.
The present study is a retrospective review of the electronic health record (EHR) data of 69 wound clinic patients with neuropathy, plantar neuropathic wounds, or NA who underwent a comprehensive neurologic evaluation during the period from January 17, 2007, to August 13, 2010. Patients with peripheral arterial disease (ie, patients with limb claudication, ischemic ulcers, or gangrene) were not included. Only the patients who provided written authorization for review of their medical record were included in this study. This study was approved by the institutional review board. In addition, the Biospecimens Committee approved the genetic studies.
Characterization of Lower Extremity Complications, Associated Disease, and Risk Covariates
At Mayo Clinic, the clinical medical observations and test results of all patients are entered into an EHR. From these data, information about disease, polyneuropathy, and risk covariates was abstracted, as well as information about potential risk factors such as body mass index (BMI), occupation (sedentary or physical), alcohol and tobacco use, diet, and other markers of metabolic disease.
The neurologic evaluation included estimated intake of calories and macronutrients by using the “Quick Check for Dietary Purposes” (a dietary questionnaire developed by Nutrition Scientific) and a questionnaire assessing daily physical activity and physical exercise program from childhood and later decades. A separate questionnaire assessed patients’ foot care over the preceding decades, including prior physical injuries (cuts requiring suturing, fractures, and sprains).
Quantification of Type and Severity of Polyneuropathy
The type, pattern, progression, and distribution of neuropathic signs; neurophysiologic test results; other findings (eg, distal sensorimotor polyneuropathy is largely confined to the feet and distal legs, is symmetrical, and is sensory predominant); and associated diseases were used to infer the clinical type and cause of the polyneuropathy.
Neuropathy signs, symptoms, and the Dyck/Rankin health score7 were obtained from Clinical Neuropathy Assessment forms.7,20 The Dyck/Rankin health score7 emphasizes dysfunction in activities of daily living. The neurologic assessment followed a recommended protocol of general medical and neuropathic evaluations. Only signs of unequivocal abnormality were recorded.10,21 Neuropathic signs were obtained from the Neuropathy Impairment Score (NIS).10,21 The NIS scores muscle weakness, reflex loss, and sensation abnormality in polyneuropathy as compared with healthy subjects. The NIS score has been extensively evaluated in diabetic sensorimotor polyneuropathy,22,23 chronic inflammatory demyelinating polyneuropathy,24 and transthyretin amyloidosis polyneuropathy.12
Nerve conduction studies with a Nicolet EDX Viking (Natus, Silverwater, New South Wales, Australia) were used to evaluate compound muscle action potential amplitudes of ulnar, fibular, and tibial nerves and sensory nerve action potential amplitudes of the sural nerve. Results were expressed as measured values, percentiles, and as points (ie, >5th percentile = 0, ≤5th to >1st = 1, and ≤1st = 2 points).25,26 Quantitative sensation tests (QSTs) of touch pressure, vibration, and heat at a pain level of 5 (of 1-10 severity) were performed with CASE IVC (WR Medical Electronics, Inc, Maplewood, Minnesota).
Distal polyneuropathy was further characterized as sensorimotor distal polyneuropathy or painful/painless sensory distal polyneuropathy. Sensorimotor distal polyneuropathy was determined by abnormality of nerve conduction (ie, ≤5th percentile of at least 2 points) of compound muscle action potential amplitudes of fibular or tibial nerves or sensory nerve action potential amplitudes of sural nerves. Small-fiber sensory distal polyneuropathy was present when nerve conduction was normal, but there was unequivocal involvement of small sensory nerve fibers as evidenced either by pain symptoms in Neuropathy Symptoms and Change score or as assessed by QST (of heat). In the heat pain test, the patient grades severity of pain as 0 when no pain is experienced and as a stimulus step level at which heat pain 5 of 1 to 10 pain severity is experienced.7 The Neuropathy Symptoms and Change score is designed to categorize and score neuropathic symptoms of weakness and/or sensation loss, sensation symptoms, autonomic symptoms, and impairments that may occur in peripheral neuropathy and then develop an overall numeric score.
Comparison of the Wound Clinic Cohort to the Rochester Diabetic Neuropathy Study Cohort
Abnormal values of neuropathic signs (NIS), symptoms (Neuropathy Symptoms and Change score), health scores, and other clinical measures (eg, injury and care of feet, type of work), nerve conduction, and QSTs were compared with baseline data of the Rochester Diabetic Neuropathy Study cohort.27,28 Results of the present study were compared with this previously studied cohort of patients from Olmsted County using standard statistical tests (Fisher exact test, Wilcoxon rank sum test).
Whole Exome Sequencing
Data analysis and WES were also available for 34 of the patients. A genomic technique, WES involves sequencing all of the protein-coding genes in a genome to test for genetic disorders. The test was applied using SureSelect All Exon Kit V3 (50 Mb; Agilent, Santa Clara, California) and HiSeq2000 (Illumina, San Diego, California) for 102 base pairs paired-end sequencing. Variant calls were carried out using an in-house–developed pipeline incorporating multiple large variant databases, as previously described.8 The average depth of coverage was 140×, and all exons in known genes for hereditary sensory and autonomic neuropathy were captured.
Characteristics of the Patient Cohort and Prevalence of Lower Extremity and Disease Complications
The cohort of 69 patients was mainly from Minnesota (39 [57%]) and was middle-aged or older adults (median age, 68 years [28–82 years]); all were white, with more men than women (2:1; Table 1).
Of these, PUs occurred in 32 (46%), NAs in 14 (20%), and both PUs and NAs in 23 (33%; Table 1). In 41 patients (75%), PUs were restricted to one side of the body, whereas NAs occurred unilaterally in 73% of cases. Further, PUs were typically situated in the anterior foot and commonly affected toes, plantar surfaces, or the edges of feet and toes. The NAs most commonly affected the midfoot, then the hindfoot, and last the forefoot (Figure).
Of the 69 patients, EHR data on the evaluation of polyneuropathy were sufficient in 61 to make quantitative judgments about polyneuropathy and associated diseases. Diabetes mellitus was observed in 45 patients; of these, 21 (47%) had sensorimotor distal polyneuropathy, 14 (31%) had small-fiber sensory distal polyneuropathy, and 2 (2%) did not have distal polyneuropathy (Table 1). The second most common group of polyneuropathies was chronic idiopathic axonal polyneuropathy (CIAP). Of this group, 15 patients had sensorimotor distal polyneuropathy, 5 had small-fiber sensory distal polyneuropathy, and 2 had no distal polyneuropathy. The two patients with inherited sensory and autonomic neuropathy had sensorimotor distal polyneuropathy (Table 1).
Comparison of Comorbidities in Patients With DM to Patients With CIAP
Patients in the DM group were significantly younger. As expected, glycated hemoglobin values were significantly higher in the DM group. Surprisingly, their plasma cholesterol and low-density lipoprotein lipids were significantly lower than in the CIAP group (Table 2). The ratio of sensorimotor distal polyneuropathy to small-fiber distal polyneuropathy did not differ between the disease groups. Also, most measures of type and severity of polyneuropathy did not differ significantly. Assessment of sensation loss determined by a neurologist using the NIS sensation was worse in the CIAP group, but this finding was not confirmed by QST. Alcohol use was higher in patients with CIAP. However, none were considered alcoholic (by the EHR). Sex, geographic referral sites, occupation, foot injuries, and smoking history did not differ between groups.
Comparison of the Wound Clinic Cohort to the Rochester Diabetic Neuropathy Study
The Rochester Diabetic Neuropathy Study cohort has patients without and with distal polyneuropathy. Of the nine dichotomous variables evaluated, six were significantly higher (worse) in the Wound Clinic cohort than in the Rochester Diabetic Neuropathy Study cohort (Table 3). The frequency of polyneuropathy, foot injury, alcohol use, and QST abnormality was significantly more frequent in the Wound Clinic cohort than in the Rochester Diabetic Neuropathy Study cohort.
Twelve of the 19 continuous covariates measured were significantly different between the two groups. Glycated hemoglobin and energy expenditure were significantly lower in the Wound Clinic cohort. All other significant measures were worse in the Wound Clinic cohort than in the Rochester Diabetic Neuropathy Study cohort. The increases in the Wound Clinic cohort included age, BMI, and various quantitative measures of polyneuropathy severity.
Comparison of Patients With Only Polyneuropathy in the Wound Clinic Cohort Versus the Rochester Diabetic Neuropathy Study Cohort
Considering dichotomous variables, manual labor (nonsedentary) as occupation, alcohol use, and sensation loss were notably more frequent in the Wound Clinic cohort than in the DM group (Table 4). Considering continuous variables, glycated hemoglobin was markedly lower in the Wound Clinic cohort, whereas all other measures (age, care of feet, physical activity, BMI, and measures of severity of polyneuropathy) were worse in the Wound Clinic cohort.
Findings of WES
Among the 34 WES samples evaluated, one patient had a novel mutation that is classified as damaging by both SIFT and Polyphen-2 in a known neuropathy causal gene, NGF. This mutation is a homozygous nonsynonymous mutation R121W. Another patient had a heterozygous novel mutation I98T in EGR2. The mutation is classified as damaging by both SIFT and Polyphen-2. The other 32 patients do not have any known or novel damaging mutations in known neuropathy genes. It is worth noting that each sample has approximately 50 to 100 private variants (nonsynonymous, splicing, or nonsense variants that have not been found in any public database and classified as damaging by SIFT and Polyphen-2).
The present study, especially in comparison with a cohort of patients with DM, confirms and adds to previous knowledge of the risk covariates for PUs and NAs. The major risk covariate for lower extremity complication can be summarized under the major headings of disease (DM, CIAP, and hereditary sensory and autonomic neuropathy, in decreasing order), sensation loss from distal polyneuropathy (both sensorimotor distal polyneuropathy and small-fiber sensory distal polyneuropathy), demographic and anthropomorphic variables (middle to old age, obesity, manual labor [nonsedentary] as occupation), and inadequate foot and medical care.
This study advances previous insights into lower extremity complications by simultaneously assessing both PUs and NAs. Study authors also assessed associated diseases in a cohort not restricted to a single disease, evaluated neuropathies using quantitative and referenced approaches, assessed risk covariates using questionnaires, and compared results with a population-based cohort of patients with DM.
Minorities were not represented in this sample because of the nature of the authors’ referral practice. In addition, known varieties of hereditary sensory and autonomic neuropathies and patients with NA may not have been referred to the wound clinic. Unknown varieties of hereditary sensory and autonomic neuropathy may still have gone undetected. Further, NAs (as compared with PUs) may have been underrepresented because they might have been referred to orthopedic surgery.
Despite these limitations, important insights have been gained. First, lower extremity PUs are associated with NAs in a much higher frequency than occurs by chance: in this series, approximately one-third of cases. Finding either PU or NA should lead to a careful search for the other.
A further insight is that the disease conditions underlying lower extremity complications have changed since the early 20th century (because of the reduction of syphilis and leprosy). The frequent association of DM was expected, but finding that about one-third of these patients had CIAP was unexpected. Characteristic features of patients with CIAP were their advanced age, obesity, and hyperlipidemia. In these patients, neuropathy might be attributed to the metabolic syndrome, but its exact characteristics and underlying mechanisms are not fully agreed on or understood.29
Because distal polyneuropathy is an important precursor of PU or NA, and healthcare providers evaluate patients who later develop these complications, healthcare providers can play a pivotal role in identifying patients who are at risk. With early identification, physicians, advanced practice providers, and other providers can help reduce high morbidity and healthcare costs. Not all foot complications can be prevented, but it is incumbent on healthcare providers to encourage weight loss as needed, carefully assess loss of sensation, instruct patients to protect their feet (avoid injury), and institute meticulous foot care.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
diabetes mellitus; diabetic foot; foot ulcer; home monitoring; neuropathic arthropathies; neuropathy; plantar ulcers; prevention; self-management; skin stress