Wound Repair and Regeneration

P E RS P E C T I V E A R TI C L E

Venous ulcers: A reappraisal analyzing the effects of neuropathy, muscle involvement, and range of motion upon gait and calf muscle function
Michael I. Shiman, BS1; Barbara Pieper, PhD2; Thomas N. Templin, PhD2; Thomas J. Birk, PhD, MPT3; Asha R. Patel, BS1; Robert S. Kirsner, MD, PhD1,4
1. Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, 2. College of Nursing, Wayne State University, Detroit, Michigan, 3. Department of Health Care Sciences, Wayne State University, Detroit, Michigan, and 4. Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida

Reprint requests: Robert S. Kirsner, MD, PhD, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, PO Box 016250 (R250), Miami, FL 33136. Tel: 11 305 243 4472; Fax: 11 305 243 6191; Email: RKirsner@med.miami.edu Manuscript received: August 24, 2008 Accepted in nal form: December 1, 2008 DOI:10.1111/j.1524-475X.2009.00468.x

ABSTRACT Chronic venous insufciency is a complex disease that can result in severe sequelae including venous ulceration. Though the exact progression from chronic venous insufciency to venous ulcer remains unclear, the high cost and burden of this disease on patients and society is quite clear. Sustained ambulatory venous pressures or venous hypertension plays an integral role in the development of venous ulceration and involves the failure of the calf muscle pump system. Standard of care involves compression therapy to assist the calf muscle pump. However, several cofactors may contribute to or exacerbate this disease and understanding their impact may provide insight into new treatment modalities. Nerve involvement, which may result in neuropathic pain and muscle dysfunction, alterations in mobility and a decrease in range of motion may lead to gait alterations all affecting calf muscle pump function. In this paper, we analyze these cofactors and discuss possible treatment options to target them. Physicians treating this disease should be aware of the numerous factors involved in its development. Exploring new treatment options may 1 day lessen the burden and suffering caused by venous insufciency.

Chronic venous insufciency is a common disorder that has a signicant impact on quality of life and healthcare costs in our society.1 Representative of this, approximately 7 million Americans suffer from chronic venous insufciency at an average cost of $40,000 over a lifetime.1 One consequence, and among the most important, is the formation of a venous leg ulceration.2 While the exact pathophysiologic mechanisms that lead from venous disease to venous ulcers are not entirely known; several hypotheses have been developed. Theories have been proposed that attribute factors including pericapillary brin cuff formation leading to poor oxygen and nutrient exchange, trapping of growth factors within this cuff, and white blood cell plugging of capillaries.35 Integral to all hypotheses and to this process is the development of venous hypertension, or more accurately sustained ambulatory venous pressure.6 Attempts to reverse venous hypertension have been targeted in the treatment and prevention of venous ulcers.7 The chronic nature of this disease, signicant burden it places on society, and emerging data, leads to a reassessment of several cofactors that may play a role in the progression from venous hypertension to venous leg ulceration (Figure 1). This paper will review nerve and muscle disturbances, mobility or range of motion changes, and gait alterations in patients with venous disease which may alter calf muscle pump function and contribute to the pathogenesis of venous ulcers. Understanding the roles of these cofactors in venous leg ulceration may have implications for the treatment of this disease.
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EPIDEMIOLOGY AND COSTS OF CHRONIC VENOUS INSUFFICIENCY

The signicant impact of chronic venous insufciency is evident in both its prevalence of clinical manifestations and chronic nature of disease. The estimated prevalence of mild varicose veins for males and females is thought to be 40 and 31%, respectively.8 Overall in Western countries, the estimated prevalence of venous ulcers is 1% for both men and women.8 Several studies have shown the chronic and recurrent character of venous ulcers.9,10 Patients often had persistent ulcers, as it was found that 35% of patients with leg ulcers had a problem of ulceration for more than 5 years and 50% had their lesions for over 1 year.9,10 While failure to receive optimal care may in part explain nonhealing ulcers, even those patients receiving the standard of care may have persistent ulcers.11 Additionally, many ulcers recur and the high recurrence rate causes treatment and nancial burdens on the health care system.12 By example, one study found that 20% of patients with venous leg ulceration suffered from 10 or more episodes of ulceration.9 When compared with other common causes of ulcers such as arterial and neuropathic ulcers, venous ulcers are known to be more common and have a higher recurrence rate.10,13 For example, up to 72% of patients with venous ulcers have recurrences compared with 45% in nonvenous ulcers.10
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Figure 1. Interactions in the development of venous leg ulceration.

The nancial burden of venous ulcers is evident in high cost and loss of productivity in the workforce.14 In 2004, skin ulcers and wounds were estimated to incur 9.7 billion dollars in direct and 2.2 billion dollars in indirect costs.15 A study done by Olin et al.16 highlighted the costs incurred in inpatient and outpatient treatment of patients with venous stasis ulcers. The average total medical cost per patient was $9,685, with a median cost of $3,036. This study accounted for hospitalizations, home healthcare, and home dressing changes which accounted for 25, 48, and 21% of total costs, respectively.16 These costs underestimate the true burden of venous ulcers as factors including time missed from work, forced early retirement, loss of independent functional status, and suffering were not taken into account. Additionally, inationary changes make current care of venous ulcers more expensive. Combining the estimated cost per patient and the prevalence of this disease, the total cost was estimated to be 1% of the total healthcare budget in Western European countries.17

MUSCLE PUMP FUNCTION AND AMBULATORY VENOUS HYPERTENSION

Despite ongoing study and debate regarding the mechanisms by which venous ulceration occurs, a key aspect of progression from chronic venous insufciency to venous ulcer formation is ambulatory venous hypertension.18,19 In order to return blood to the heart via the venous system, several factors must work together: a central pump, a peripheral venous pump, a pressure gradient, and competent veins and/or venous valves.19 A normal physiological response causes a decrease in pressure of veins in the lower leg during activity of the peripheral calf muscle pump. By denition, sustained ambulatory venous pressure or venous hypertension is the failure to reduce these venous pressures during exercise.18,19 The lower extremity venous system is composed of a deep, supercial, and communicating venous system. Calf muscle contraction functions to propel venous blood from the supercial to the deep venous system via the communicating or perforator veins.6 During ambulation, the ve148

nous pressure in the deep and supercial venous system decreases from approximately 100 mmHg at rest to about 30 mmHg during contraction.18,19 Despite a pressure gradient during contraction created by increased venous pressures in the thigh veins and decreased pressures in the leg veins, retrograde blood ow is precluded by competent one-way valves in the veins.18 Functioning valves prevent the retrograde ow of blood to the supercial venous system. These one-way bicuspid valves reopen as the pressure in the deep venous system decreases as blood empties into the heart.6 The localization of the reux in either the supercial or deep veins was less signicant than the actual volume of the reux.18 Attributing venous hypertension to one or two causative factors would be an oversimplication of this complex disease. The multifactorial pathogenesis of chronic venous insufciency should be noted. Raju et al.20 studied 373 limbs with ambulatory venous hypertension to identify the etiology. They concluded that contributing components were: poor calf muscle pump, reux, increased arterial inow, reduced venous capacitance, poor ejection fraction, and a combination of the above.20 Thus, treatment of this condition should also be multifactorial.

CURRENT TREATMENTS AND PROGNOSIS

The mainstay of treatment for a venous ulcer is graduated compression with multilayer bandages.21,22 The concept of compression wraps has been appreciated for centuries, dating back to Hippocrates in ancient Greece.1 The goal of this therapy is to provide a pressure gradient that increases from the ankle upwards.1 Additionally, continued use of compression stockings after an ulcer has healed is associated with a decreased risk of recurrence.23 A systematic review by Borges et al.21 concluded that consistent use of graduated compression with a multilayer system should be the rst choice for treatment of noncomplicated venous ulcers and is reliable and cost effective in a majority of patients. Additionally, other compression methods, including the Unna boot, short-stretch bandages, and compression stockings, have been shown in randomizedc 2009 by the Wound Healing Society Wound Rep Reg (2009) 17 147152

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controlled trials to be effective as treatment options for properly selected patients.24,25 As adjuvants to compression therapy, several medications, i.e., aspirin, pentoxifylline, daon, and sulodexide have demonstrated their effectiveness in trials.7,22,26 Varied levels of evidence support surgical techniques which have been employed such as autologous skin grafting, living skin equivalents, debridement, and venous surgery.27 31 Among these treatments, the best evidence exists for bilayered living skin equivalents.7,32 Potential treatments, e.g., granulocyte-macrophage colony stimulating factor and keratinocyte growth factor-2, have been either found to be inconvenient or ineffective.33,34 Gohel et al.35 compared compression therapy alone to compression plus venous surgery. Their randomized-controlled trial found surgical correction of supercial venous reux in addition to compression did not improve ulcer-healing rates. However, surgery did reduce the recurrence rate and increase ulcer free time. Some patients appear more likely to respond to compression therapy. Understanding the prognostic factors in venous ulcers is important to identify patients who may benet from additional and alternative therapies. Among a number of studies, Margolis et al.36 described a two point scoring system based on wound size (> 5 cm2) and wound duration (> 6 months) to predict healing after 24 weeks of compression. Their research showed that 93% of patients healed when having none of their criteria, while only 13% of patients healed when having both of their criteria. Phillips et al.37 analyzed the results of a large multicenter venous ulcer trial and concluded that baseline ulcer size and duration are signicant prognostic indicators. They noted that an ulcer which is slow to heal after 3 weeks of optimal therapy has a poor prognosis as well.37 Another predictive tool is a scoring system developed by Falanga et al.38 which evaluates characteristics of the wound bed score and was shown to have validity in predicting complete wound closure. This scoring system takes into account the following: the healing edges, presence of eschar, greatest wound depth/granulation tissue, amount of exudate, edema, periwound dermatitis, periwound callus and brosis, and a pink/red wound bed. A diagnostic test shown to reliably predict prognosis of venous ulcers by assessing muscle pump function is air plethysmographic exam.39 It is suggested, but not known, whether improvement in calf muscle function leads to better results in air plethysmographic exam.39 Patients with poor prognostic characteristics may nd benet in alternative therapies, in conjunction with the current standard of care.

NEUROPATHY
Local tissue destruction in chronic venous insufciency develops in conjunction with damage to peripheral nerves which has been demonstrated in both clinical and immunohistochemical studies.40,41 Nerve involvement may be an underappreciated cofactor in chronic venous insufciency with possible implications for treatment of venous ulcers. Reinhardt et al.40 performed a neurological study on 30 patients with chronic venous insufciency and compared the results to healthy controls. All patients with conditions predisposing to peripheral neuropathy were exc 2009 by the Wound Healing Society Wound Rep Reg (2009) 17 147152

cluded from the study. They found that patients with chronic venous insufciency had a prolongation of distal motor latency, a reduced vibration threshold, and diminished warmth and cold perception. Their conclusion based on these clinical ndings was that patients with chronic venous insufciency had disturbances in A-a bers, A-b bers, A-d bers, and thermoafferent-C bers.40 Biopsy specimens from the nerves of patients with chronic venous insufciency conrmed neuropathic changes and revealed denervation.42 In 2004, Guest et al.41 used immunohistochemistry to conrm the presence of peripheral neuropathy in patients with venous ulcers. These researchers performed punch biopsies adjacent to venous ulcers in patients with healing ulcers, nonhealing ulcers, and control patients with varicose veins. Antibodies were used to study the distribution of nerve bers in the epidermis and papillary dermis. Compared with controls, patients with healing ulcers had a decreased number of nerve bers in the dermis. Patients with nonhealing ulcers had a decreased number of nerve bers in the epidermis, and both groups had shorter nerve bers in the epidermis. These ndings conclude that the initial development of venous ulcers may be inuenced by reduced dermal and epidermal innervations. Also, chronic ulcers may be inuenced by a decrease in epidermal nerve bers, which may be important in the healing process.41 In 2007, Ogrin et al.43 studied the changes in the neurovasculature of chronic venous ulcers in patients treated with four-layer compression bandaging. They found that after therapy, patients improved their electrical cutaneous perception thresholds. In addition to a panoply of other functions, nerves also serve as a source of growth factors which appear to be important in healing. For example, the topical application of nerve growth factor to pressure ulcers has been shown to improve healing rates.44,45 Landi et al.45 revealed in a double-blind, placebo-controlled trial that patients who received daily application of a solution of nerve growth factor had a statistically signicant improved rate of healing compared with controls. Tuveri et al.46 treated chronic vasculitic leg ulcers with nerve growth factor and observed rapid healing in patients with rheumatoid arthritis. Less striking improvements were observed in patients with systemic sclerosis. While the effect of nerve growth factor on venous ulcers has not been studied, it is likely that its effect is not limited to pressure ulcers alone. This may lead to new treatment options. While the pain of venous ulcers has long been ignored, pain is now known to be a signicant problem.47,48 Based on a questionnaire, 64% of patients believed to have ulcers with a purely venous etiology reported having severe pain.47 A multicenter cross-sectional study in 2007 revealed that leg ulcers are very painful. There is also a direct correlation between ulcer duration and size to pain and quality of life.49 Dworkin et al.50 studied venous ulcers in injection drug users and concluded that pain is present in this group. Pain was associated with a poor coping ability and a decreased quality of life.50,51 In another study of the same cohort, pain was one of the symptoms with the most profound impact on quality of life.52 Much of this pain may be neuropathic in origin and often medications such as amitriptyline, gabapentin, and
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pregabalin among others are useful in dealing with this pain.5355 Nerve involvement is an understudied cofactor in venous ulcers. Further studies are needed to elucidate the role of nerve involvement and to identify potential targets for therapy. Treating the neuropathic pain or using nerve growth factor, e.g., in patients with venous leg ulcers may have therapeutic effects.

GAIT ABNORMALITIES
Few studies have been performed to identify the relationship between chronic venous insufciency and gait alterations. Pieper et al.64 used the Tinetti Balance and Gait tests to assess the effects of chronic venous insufciency on walking. In this study, patients who injected drugs into the lower extremities and therefore were known to be at high risk for venous disease, were found to have lower balance and gait scores than those drug abusers that either did not inject drugs or injected into their arms only.60,64 Patients with venous ulcers may also have an abnormal walking motion. Newland et al.65 evaluated the gait of patients with venous disease. Using pedal pressure measurements to identify differences compared with controls, foot pressures were measured as a surrogate method to study gait. Patients with chronic venous insufciency were observed to have lower total foot pressures. The distribution of pressure was also altered, with chronic venous insufciency patients having higher midfoot and lower big toe pressures.65 Additionally, patients with venous ulcers have also been shown to take fewer steps per week compared with controls.66

MOBILITY AND RANGE OF MOTION

Mobility and range of motion are affected in patients with venous ulcers.56,57 Therefore, attributing calf muscle pump failure solely to abnormalities in venous function may be a false assumption. This association was investigated by Dix et al.57 as they measured range of ankle movement using goniometry. Results showed that in all grades of venous insufciency, from varicose veins to venous ulcers, there was an association with signicantly reduced range of ankle motion. As the severity of venous hypertension increased, the range of ankle motion decreased.57 Back et al.58 showed that an increased number of patients with venous ulcers had impaired dorsiexion, which is thought to be required for normal function of the calf muscle pump. Pieper et al.59 studied the relationship between ankle mobility, chronic venous disorders, and injection drug injury. Injury from injecting drugs into the lower extremity showed a negative effect on ankle mobility. In another study, Pieper et al.60 recognized chronic venous disease as a complication of injecting drugs into the lower extremities. Studying the damage caused by injecting drugs on veins, nerves, and muscles can serve as a model to better understand the complex nature of venous ulcers. Targeting muscle pump function in patients with chronic venous insufciency with exercise is one approach that may enhance current treatment options. Yang et al.61 demonstrated that patients with chronic venous disease and a history of venous ulcer had reduced function of the calf muscle itself. Muscle strength measured as peak torque/body weight and muscle endurance measured as total work were both found to be decreased in this study. They suggested that the primary problem leading to calf muscle impairment may be the poor calf muscle itself, rather than chronic venous insufciency.61 A randomized, prospective trial done by Padberg et al.62 studied the implication of a supervised exercise program in patients with venous ulcers. After a 6-month calf muscle exercise program, hemodynamic performance was improved. Calf pump function improved based on measurements of ejection fraction, residual volume fraction, and strength. The benets were maintained for at least 3 months after termination of the exercise.62 Margolis et al.63 analyzed the relationship between venous leg ulcers and concomitant medical conditions. They found a statistically signicant association in their patients between having osteoarthritis and a recent onset of a venous leg ulcer. This relationship may be linked through changes in mobility and range of motion, and benet may be obtained from treating the osteoarthritis. These studies shed light on the potential of physical exercise or rehabilitation to improve the muscle pump system and be used as an adjunct to current treatment options for patients with chronic venous insufciency and venous ulcers.
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CLINICAL IMPLICATIONS
Clinicians and researchers should be aware of the multifactorial pathogenesis of chronic venous insufciency in order to denitively diagnose and manage this disease and its sequelae. Understanding that neuropathy, neuropathic pain, decreased mobility, or gait changes may be present, may assist clinicians in diagnosing the underlying venous insufciency. Neuropathic pain may be managed with medications aimed at alleviating it such as amitriptyline, gabapentin, or pregabalin. Further studies assessing nerve growth factor in patients with venous ulceration are needed to test the efcacy of this treatment. Recommending physical therapy to teach and supervise calf muscle exercises to improve the calf muscle pump and treating concomitant osteoarthritis and other conditions limiting ankle mobility are important modalities of treatment. Identifying gait changes in patients with chronic venous insufciency is essential in understanding mobility issues and the risk of falls. Ambulatory changes in patients with venous ulcers need to be further studied along with physical rehabilitation and gait training to supplement current treatment of venous ulcers. These approaches can potentially improve healing rates or help decrease recurrences in patients affected by venous ulcerations (Table 1). In conclusion, advances in the understanding of the pathophysiology of venous ulcerations have led to the appreciation that venous ulcers should not be simplied solely as a pathology of blood vessels. This disease should be regarded as a multifaceted, complex syndrome involving all aspects of the calf muscle pump. Relevant and emerging research suggests that changes in nerve and muscle function and range of motion may affect gait and ambulation either causal in disease formation or leading to an exacerbation or progression of disease symptomatology. Based on the signicant prevalence of this disease, as well as its considerable health and economic burden on society, we believe a new, multifactorial approach to treatment should be evaluated. Additional studies of the
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Table 1. Potential treatment options for cofactors involved in the formation of venous leg ulceration 13. Cofactors Neuropathy Pain related to neuropathy Impaired ankle range of motion Potential treatment options Nerve growth factor Amitriptyline Gabapentin Pregabalin Calf muscle exercises Physical therapy evaluation and treatment plan Treatment of osteoarthritis and other joint limiting conditions Gait training exercises 14.

15.

Gait abnormalities

16.

neuropathic changes, ankle mobility, muscle alterations, and gait abnormalities may provide clues to new treatment modalities. Studies using pain control, nerve growth factors, exercise, and gait training are potential options for future research. Further studies to assess these parameters and to clarify the causeeffect relationship of many of these factors will help elucidate the pathophysiologic development of venous ulcers, and potentially alternative treatments.

17.

18. 19.

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