Neuropathic and Ischemic Changes of the Foot in Brazilian Patients with Diabetes

   Diabetes mellitus is one of the most serious chronic diseases in the world, due to its high incidence and high levels of morbidity and mortality.^1,2 Defined as a chronic and degenerative disease that alters the individual's homeostasis, diabetes is characterized by disorders of carbohydrate, protein, and lipid metabolism that are secondary to a dysfunction or a lack of insulin production by the pancreas and/or to the decrease of its action upon the target tissues, causing chronic and acute complications.^3,4

   According to Smeltzer and Bare,⁵ 90% of all patients with diabetes are non-insulin-dependent, or type 2, while 5% to 10% are insulin-dependent, or type 1. A small percentage of patients has diabetes of a secondary type, or associated with other complications.

   Brazil is estimated to have 5 million people with diabetes; half of them are unaware of their condition and have not been diagnosed.^3,4,6 The prevalence of diabetes in the Brazilian population is similar for both men and women and increases with age. Brazilian study data show that the total prevalence of diabetes is 7.6%, ranging from 2% for people 30 to 39 years old, to 17.4% in the population ages 60 to 69 years.⁷

   Due to a variety of factors, including sedentary habits related to lifestyle changes associated with urbanization and modernization, poor diet and eating habits, and an increase in the population's life's expectancy,³ the prevalence of diabetes mellitus continues to increase in almost all parts of the world.

   Diabetes is one of the main causes of mortality in the northeastern and southern regions of Brazil and affects the social and economic order.^3,4 Foot ulcerations are one of its most serious chronic complications. Brazilian statistics reflect that 15% of people with diabetes are at risk of developing a foot ulcer.⁸ Diabetic foot ulcers are a major cause of hospitalization and frequently result in prolonged hospital stays, which are associated with high financial and psychological costs. The cost of treating a foot ulcer is quite often higher than the total annual cost for the person's metabolic control.⁹ Diabetes mellitus has become a major national health concern with a high incidence, prevalence, morbidity rate, and premature mortality, as well as high costs to control the disease and treat its complications.

The Diabetic Foot

   Neuropathy, ischemia, or a combination of these two conditions are the most important risk factors for the development of diabetic foot ulcers. Infection also can precipitate their development.^10,11 Not long ago, diabetic neuropathy was thought to be vascular in origin and caused by thickening of the walls of endoneural capillaries in the nerves until total occlusion occurred. More recently, diabetic neuropathy is thought to be metabolic in origin and related to an overstimulation of the polyol pathway in the neural tissue. Uncontrolled diabetes is associated with hyperglycemia; glucose builds up in the blood because insulin is not available or unable to provide entry into cells for conversion into energy. The glucose in the blood must be metabolized by the enzyme aldose reductase, resulting in sorbitol, a polyol. Subsequently, sorbitol accumulates in many tissues and causes damage in various ways. Excessive accumulation of sorbitol in the Schwann cells of the diabetic patient causes a toxic effect, resulting in a segmental dysmyelination and subsequent lower conduction speed in the peripheral nerves.

   At least 50% of patients with diabetes of long duration develop neurologic complications. Neuropathy is rarely diagnosed before the fifth year of the disease in patients with type 1 diabetes. Studies have shown that 8% of people with type 2 diabetes have neuropathy at the time of initial diagnosis while 40% have neuropathy after 20 years of living with the disease.¹²

   Clinical signs. On clinical exam, the neuropathic foot tends to be hot and dry due to a peripheral nerve dysfunction that is responsible for the characteristic auto-sympathectomy.¹⁰ The vibratory sense, Achilles reflex, and pain sensations diminish or disappear. Neuropathy also affects the motor nerves of the leg and foot, causing an inadequate muscular tonus in the foot, which leads to a weakening of the bone architecture (Charcot arthropathy). In critical cases, an elevated arch, displacement of plantar fat pads, and hammer toes may occur. Calluses may develop due to increased plantar pressures and from the toe rubbing against the inside of the shoes. Pressure from the superficial callus against bony prominences of the foot can create an underlying abscess, allowing infection to be more easily spread through the articular capsule and the metatarsal head, leading to osteomyelitis. The same pathological process that is associated with Charcot arthropathy may occur on the dorsum of the hammer toes, on the deformed and collapsed bones, and on the articulations.¹³

   Peripheral vascular disease or ischemia in patients with diabetes is related to the development of macrovascular arteriosclerosis - a consequence of the dysfunction of the lipidic metabolism caused by the disease especially when inadequately controlled. Vascular occlusion can progress rapidly and occurs on both sides. Patients with diabetes are more likely to have arteriosclerosis than people without diabetes due to multiple disease-related factors such as hyperlipidemia, hypertension, insulin resistance, hyperglycemia, and increases in plaque formation and coagulation.^14-16

   Clinical signs of the ischemic foot include thin or atrophied skin and loss of hair on the foot and ankles.¹⁰ The foot may feel very cold, the nails appear thickened, the dorsalis pedis and posterior tibial pulses reduced or absent, and intermittent claudication may be present. Frequently, fissures appear in the heel or in the prominent metatarsal heads associated with ischemia. Historically, ischemia in the absence of concurrent neuropathy is rarely seen in patients with diabetes. Recent studies indicate that in diabetic feet, approximately 50% present with clinical characteristics related to neuropathy and 50% to ischemia.^17-19 Patients with diabetes have a 15- to 46-fold higher risk of having a lower-extremity amputation than patients without the disease.²⁰

    Examining feet at risk. The risk for foot ulcerations in patients with diabetes is not always appreciated by healthcare professionals. A regular, thorough foot examination would greatly reduce the risk of foot ulcers because risk factors can be identified.²⁰ Palpation of the pulses and assessment of peripheral perfusion of the lower extremities are important aspects of a thorough examination. Despite the importance and simplicity of this examination, few patients have their feet examined regularly. In a study conducted at the University of California, only 6% of patients with diabetes reported that they had their feet examined once a year before a nursing program for foot care was established.²¹ Another study at the University Hospital of Sao Paulo showed that only 15% to 19% of patients with diabetes who visited a doctor had their feet examined. The same study showed a two-fold increase in probability for patients having their feet examined if they were wearing sandals instead of shoes with socks.²²

   A thorough examination of the foot is necessary to adequately assess the risk of foot ulceration and requires more than just simple observation and palpation of pulses. Assessment for loss of protective sensation in the foot is critical and may be performed using multiple techniques. However, the more sophisticated the evaluation technique and equipment, the less feasible it may be for a wide range of healthcare settings and populations to perform the assessments. Quantitative, reliable, and easy to perform methods for neurological evaluation are needed.

   Foot examination specifics. According to Nitrini²³ and the American Diabetes Association,²⁴ a comprehensive neurological exam involves motor, reflex, sensory, and autonomic considerations. The motor examination includes assessment of muscular strength, muscular tonus, and deep and superficial reflexes. The deep reflex examination assesses the Achilles reflex, which depends on the tibial nerve and is integrated in the segments L5 to S2. The reflex response depends on the vibration transmission, which, in hyper-reflex conditions, is sufficient to cause contraction.

   The sensory examination helps healthcare professionals identify specific patient complaints and assess disturbances in sensation frequently associated with diabetes or other neurological problems. A complete sensory examination includes assessment of the ability to perceive thermal, tactile, and pain sensation. Vibratory perception is a deep sensation, determined by using an electronic tuning fork placed on specific bones.^23,24 Thermal sensation can be assessed using two test tubes, one containing ice water and the other containing warm water. Tactile sensation can be assessed using a piece of cotton wool. Pain sensation used to be assessed with a disposable needle or pin. Most of these tests have been replaced by the Semmes-Weinstein monofilaments evaluation.

   Semmes-Weinstein evaluation. Ideally, six different monofilaments are used for a comprehensive evaluation of loss of protective sensation in the hands and feet.²⁵ Each monofilament is color-coded and bends at a different level of force (designated in grams of pressure). The inability to feel a particular monofilament as the tip is pressed until it bends against specific sites on the hands and feet is associated with specific types of sensory loss (see Table 1).

   According to the Brazilian Society for Diabetes,⁶ "detecting a decrease in the sensitivity for the orange (10-g) monofilament in more than four tested areas or in vibratory perception defines the patient with a high risk for ulcers." Therefore, Semmes-Weinstein monofilament testing can replace previous tests used to determine tactile sensation (with cotton wool), thermal perception (with test tubes), and pain sensation (with pins). The combination of the monofilament test with the vibratory perception threshold has been reported to yield 100%-sensitivity and a 77%-specificity to the evaluation of the diabetic neuropathy.²⁰

     Clinical, epidemiological, and biochemical evidence indicates that maintaining blood sugar and blood pressure levels close to normal may significantly reduce the onset and complications of diabetes, including the occurrence and severity of neuropathic and vascular complications on the diabetic foot.^15,26 However, maintaining adequate metabolic control is difficult in practice, especially in Brazil. Problems include poor patient compliance with treatment, leading to aggravation of complications; a lack of early diagnosis programs; and lack of routine patient assessment for the risk of developing complications, such as foot ulcerations.

Study Purpose and Methods

   A 1-day, multicenter descriptive study was conducted 1) to identify and describe the conditions that are indicators of foot neuropathy and ischemia in patients with type 2 diabetes, and 2) to examine the statistical correlations between the identified conditions and the individuals' age, sex, duration of diabetes, tobacco use, and length of time using insulin.

   This multicenter, descriptive study was carried out in a general private hospital, a philanthropic association for diabetic patients in Sao Paulo city (Sao Paulo, Brazil), and two outpatient care centers for diabetic patients in Sao Paulo city and Itabuna (Bahia, Brazil).

   The data were collected from 79 individuals with type 2 diabetes who were present at these healthcare facilities on the designated study day. Participants had to meet the following inclusion criteria:
   * age greater than 18 years
   * no diabetic ulcer
   * no amputation of the lower-extremity related to diabetes (neuropathic or ischemic alterations)
   * alert and able to answer the questions.

   After explaining the study and obtaining informed consent, patients were interviewed and had their feet examined. During the interview, patients were asked questions pertaining to demographics (name, age, race, sex); clinical history (duration of diabetes, type and duration of treatment); and risk factors (hypertension, current or previous tobacco use). The data were recorded and information confirmed or complemented, as necessary, through the patient's medical record.

    The foot exam was performed systematically by inspection and palpation, following the steps and items reported in the second part of the data collection tool.

   Foot exam procedure. After being positioned on the stretcher in a recumbent position, the patient exposed both feet. The feet were clinically evaluated for the presence of the following:
   1. local risk factors (dermatophytosis, onychomycosis, ingrown toenail, inadequate toenail cutting, edema, varices)
   2. ischemic changes (reduced capillary filling, blue toe syndrome, dorsalis pedis pulse, posterior tibial pulse, temperature, intermittent claudication, lack of hair)
   3. autonomic neuropathic changes (dry skin, fissures, Charcot arthropathy)
   4. motor neuropathic changes (claw toes, hammer toes, plantar arch and instep alterations, prominence of metatarsal heads or ball of the foot, calluses)
   5. sensory neuropathic changes (dysesthesia - burning, tingling, numbness, or cramps; paresthesia; hyperesthesia; sensory evaluations - monofilament testing, vibration perception).

   Sensory evaluation procedure. After visual inspection and palpation, the patient underwent somatosensory testing using the 10-g Semmes-Weinstein monofilament and a 128-Hz tuning fork. Before the tests were administered, the patient was asked to relax and concentrate with his/her eyes shut. Each test was preceded by a demonstration on the hand before it was performed on the foot. Monofilament testing was performed at 10 anatomical sites on the foot as previously established.^27,28 The patient identified the lack or presence of sensation at each of the sites. The vibratory perception, determined using an electronic tuning fork that vibrated at 128 Hz, was performed only on the big toe of each foot.

     Data analysis. The data were analyzed using inferential descriptive analysis. Statistical analyses included: confidence intervals of 95% to estimate (and compare) the real mean value of the quantitative variables and the real percentage of some interesting events of the study; the Kolmogorov-Smirnov normality test to test the normality hypothesis of the scores observed; the Spearman Correlation Coefficient and Pearson Linear Correlation to analyze correlation; and the chi-square test to analyze statistical association. The Fisher test and the Student t test were employed when more than 20% of the frequencies were inferior to five, considering the independent samples used in the comparison of the population. Correlations were significant at P less than 0.05. SPSS for Windows Release 10.01 - 1999 (SPSS Inc., Chicago, Ill.), the Minitab release 10.1 - 1994 (Minitab Inc., State College, Pa.), and the WinSTAT Statistics for Windows, 3.01 version - Release 1996, were used to analyze the data.

Results

   The majority of individuals in this sample population of 79 individuals were women (45, 57%). Ages ranged from 30 to 95 years, with an average age of 60.9 years (SD = 13.28). The average length of time elapsed since diagnosis of diabetes was 7.76 years (SD = 6.69), ranging from less than 1 year to 28 years since diagnosis. The average time of medicine use was 5.78 years (SD = 5.61) for the oral hypoglycemic and 6.18 years (SD = 18.28) for insulin users.

   Forty-three individuals (43, 54.4%) presented with hypertension. Eight (8, 10.1%) were current smokers with 10 to 40 years of tobacco use (22.4 years average, SD = 11.7), and 30 (38%) used to smoke in the past, signifying from 1 to 50 years of tobacco use (20 years average, SD = 14.2). It is important to note that 67.6% out of male patients were current or past smokers.
Onychomycosis was the most frequent risk factor (found in 60 patients, 76.92%), followed by inadequate toenail cutting (52 patients, 65.82%), dermatophytosis (38 patients, 49.35%), varices (32 patients, 41.03%), ingrown toenail (25 patients, 32.05%), and edema (17 patients, 21.79%) (see Table 2).

   Study of sensory neuropathic changes (see Table 3) indicates that 31 patients (42.47%) had cramps, 29 had numbness (39.73%), 31 (39.24%) lacked sensory perception to the monofilament, 26 (35.62%) experienced tingling, 16 had paresthesia (22.86%), 15 (19.99%) lacked vibratory perception to the tuning fork, 14 felt burning (19.44%) and six had hyperesthesia (10.34%) - diversely distributed among the sample population.

   Study of motor neuropathic changes (see Table 4), demonstrates that 48 patients (60.76%) had calluses, 32 (40.51%) had plantar arch and instep alterations, 28 (35.44%) had claw toes, 24 (30.38%) had prominence of metatarsal heads or ball of the foot, and 22 (27.85%) had hammer toes.

   The majority of patients presenting with autonomic neuropathic changes had skin dryness (69, 90.79%) and fissures (53, 81.54%) on the plantar, dorsal, and lateral feet (see Table 5). Charcot arthropathy was not detected in any examination.

   Ischemic changes (see Table 6) observed included 26 patients with hypothermia (34.21%), 26 with lack of hair (33.33%), 22 with blue toe syndrome (31.88%), 22 with lack of posterior tibial pulse (28.57%), 22 lacking dorsalis pedis pulse (27.85%), 15 with intermittent claudication (19.74%), and five with altered capillary filling (6.33).

  When analyzing the correlation between the quantitative and qualitative variables (see Table 7), positive and negative, strong to weak statistically significant correlations were identified. Onychomycosis, ingrown toenail, lack of hair, varices, claw toe, altered capillary filling, and lack of posterior tibial pulse were observed more frequently in older patients. On the other hand, patients with a shorter period of treatment tended to present more frequently with dermatophytosis and less frequently with cramping and varices. A correlation existed between length of time of insulin use and the presence of intermittent claudication and the loss of the vibratory perception to the tuning fork. A higher number of alterations including onychomycosis, edema, lack of hair, varices, altered capillary filling, intermittent claudication, burning, tingling, paresthesia, fissures, and loss of vibratory perception to the tuning fork was detected among patients who had a lack of sensory perception. Lack of sensory perception to the monofilament was statistically significant in older patients (r = 0.21, Spearman Correlation Coefficient test).

   Using the chi-square or the Student t test, men were more likely than women to exhibit reduced vibratory perception to the tuning fork (P less than 0.001), presence of calluses (P = 0.012), ingrown toenail (P = 0.012), and lack of posterior tibial pulse (P = 0.012). Significant differences between older and younger people were also observed. Older persons were more likely to exhibit a claw toe (P less than 0.001), lack of posterior tibial pulse (P = 0.039), ingrown toenail (P = 0.006), and varices (P less than 0.001).

Discussion

   The demographic characteristics of the 79 patients with diabetes who participated in this study are similar to the data collected by Malerbi and Franco⁷ within the Brazilian population - specifically, a similar distribution of men and women with diabetes, with an increasing number of people who are 60 years of age or older.

   Hypertension and current/previous tobacco use were observed in approximately 50% of the sample population. Diabetes mellitus is often associated with the presence of risk factors such hypertension, hyperlipidemia, increased age, tobacco use, and obesity - thereby, increasing the risk of mortality due to heart disease. Marsiglia,²⁹ in a study involving 550 diabetic and nondiabetic patients, observed that hypertension was more common among people with diabetes and was also considered a two-fold more common risk factor in type 2 patients older than age 40 with diabetes.

   Edmonds and Foster¹⁷ identified a number of local risk factors that lead to foot ulceration in the neuropathic and neuro-ischemic foot. In the current sample of people with diabetes, the majority were found to have onychomycosis, inadequate toenail cutting, dermatophytosis, ingrown toenail, varices, or edema. According to medical literature, nail pathology might be the most frequent dermatological alteration of the diabetic foot, with onychomycosis the most important nail concern for patients.¹⁷ Ingrown nails also are a common and painful problem. Edema is a major risk factor for foot ulceration, a common problem in elderly people, and a major complication of diabetic neuropathy.³⁰

   The neuropathic and ischemic changes detected most frequently in the sample population were cramps, numbness, lack of sensory perception to the 10-g monofilament, tingling, calluses, claw toe, dryness, fissures, hypothermia, lack of hair, and blue toe syndrome. Polyneuropathy is directly related to poor glycemic control and the duration of the diabetes.³¹ According to the Brazilian Health Authority, sensory neuropathy is present in 8% to 12% of type 2 diabetic patients at the time of the diagnosis and occurs in 50% to 60% of the patients after 20 to 25 years' duration of the disease.^12,31

   A significant negative correlation was found between length of time of previous or current tobacco use and the presence of dorsalis pedis and tibial pulses, indicating the arterial compromise of tobacco users. The American Diabetes Association²⁴ states that preventive strategies should include smoking reduction to diminish the risk of complications related to peripheral vascular diseases. Tobacco use may be a more relevant risk factor than hypertension. Mayfield et al³² report that a number of studies have shown an association between smoking and the increase of risk factors related to macrovascular disease, peripheral vascular disease, diabetic foot ulcers, or amputation. Smoking is one risk factor that must be more quickly reversed, since it increases the risk of developing microangiopathic, neuropathic, retinopathic, and vascular complications.³³ The severity of vasculopathy must be reinforced; it is not only directly related to glycemic control and duration of diabetes, but also to tobacco use, hypertension, hyperlipidemia, and central obesity^14,15,34 - factors that also aggravate polyneuropathy.³¹

   Callus formation, partly a result of increased plantar pressure, is common on the diabetic foot. According to Frykberg,³⁰ hyperkeratotic lesions (calluses) do not occur more frequently in patients with diabetes than in people without diabetes. Hyperkeratosis is a normal protective skin reaction to intermittent pressure and attrition; therefore, it can occur due to pressures from inadequately selected shoes, bony deformities, or altered biomechanics. Hyperglycemia causes collagen glycosylation, leading to less pliable skin, inflexibility, and stiff calluses, all of which contribute to the development of foot ulcers.¹⁰ The deformities are a result of high pressure in prominent areas. The body's response to this pressure is different in the neuropathic foot (hyperkeratosis, calluses and a tendency for ulceration) than in the neuro-ischemic foot (ulceration).¹⁷

   In this study, some neuropathic and ischemic changes, as well as some risk factors for their development, were found in older study participants. Abnormalities and risk factors observed included lack of sensitivity to the monofilament and claw toe (neuropathic changes), absence of posterior tibial pulse, reduced capillary filling and lack of hair (ischemic changes), and ingrown toenail, onychomycosis, and varices (risk factors). According to Kozak et al,¹³ the older the person with diabetes, the higher the chance of decreased sensitivity and peripheral circulation, along with a higher vulnerability to infections, especially when glycemic levels are poorly controlled.

   Despite the equal distribution of diabetes in men and women, the incidence of certain neuropathic and ischemic changes, as well as risk factors, was higher in men - specifically, lack of sensitivity to the tuning fork (sensory), presence of calluses (motor), the absence of the posterior tibial pulse alteration (ischemic), and ingrown toenails. According to a review by Mayfield et al,³² men with type 2 diabetes have a higher risk of ulceration and subsequent amputation. The mechanism of this increased risk has been investigated.

   In addition to statistically significant differences related to age and gender, study participants who had diabetes for a shorter time tended to have fewer cramps and varices and more dermatophytosis. These results are similar to recent studies that have shown that a shorter duration is related to a lower neuropathic and vascular compromise.^6,17,31

   These results show that vascular disease and peripheral neuropathy are present. Although the study has not indicated an association between vascular disease and peripheral neuropathy and a longer period of insulin use, longer periods of insulin use had a statistical correlation to the presence of intermittent claudication and lack of vibratory perception to the tuning fork.
Patients with reduced sensory perception to the monofilament were found to have the highest number of alterations, such as onychomycosis, edema, lack of hair, varices, altered capillary filling, intermittent claudication, burning, tingling, paresthesia, fissures, and lack of vibratory perception to the tuning fork. This finding confirms that lack of sensory perception to the monofilament is a serious indicator of neuropathic changes.

Conclusion

   Assessment of 79 patients with type 2 diabetes mellitus at specialized healthcare centers in the Sao Paulo area and Itabuna, Bahia revealed that most patients with type 2 diabetes have at least one risk factor for the development of foot ulcers. Onychomycosis was found in a great majority of the patients and was the most frequent risk factor for sensory neuropathic change. Calluses were the most frequent motor neuropathic change, and most patients experienced dryness and fissures as a result of autonomic neuropathic changes. One-third presented with hypothermia, lack of hair, blue toe syndrome, and posterior pulse with ischemic alterations. People who had diabetes for a shorter period of time reported less cramping and had fewer varices but more dermatophytosis; longer periods of insulin correlated with the presence of intermittent claudication and with the lack of vibratory perception to the tuning fork. People who had a lack of sensory perception to the 10-g monofilament had a higher number of neuropathic and ischemic changes, with motor, neuropathic, and ischemic changes of the foot observed more frequently in male patients and in older patients.

   Although not the purpose of the study, the authors also found that 80% of the participants had never had as detailed a foot examination by a healthcare professional as the one conducted at the time of the study. This may indicate a lack of information regarding the importance of a regular foot exam among healthcare professionals and patients. Additionally, patients reported that they had never been warned about the assessed foot changes or of the importance of a regular foot inspection.

   This study also included patients who had diabetes for less than 1 year, and the presence of risk factors for foot problems in this group suggests that efforts to detect and prevent complications are warranted in all patients with diabetes mellitus. The authors conclude that this exam, as a part of a comprehensive preventive program, can be the starting point for individual educational action based on objective and subjective clinical evidence. Logically, prevention of diabetic foot ulcers begins with recognition of the risk factors and possible complications. Prevention also can be facilitated by a more effective interaction between the patient and the healthcare professional, including better communication and increased patient commitment in seeking resolution of the problems. In addition to being easy and quick to perform, this systematic and regular foot inspection in patients with type 2 diabetes mellitus, when included in the regular procedures of the nursing program for foot care, can be a vital preventative measure. Finally, additional studies may validate these findings and perhaps reveal other important aspects related to appropriate foot care, such as wearing inadequate shoes, poor vision and limited mobility and flexibility.

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