PERSPECTIVE ARTICLE

Venous ulcers: A reappraisal analyzing the effects ofneuropathy, muscle involvement, and range of motion upongait 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 final form: December 1, 2008

DOI:10.1111/j.1524-475X.2009.00468.x

ABSTRACT

Chronic venous insufficiency is a complex disease that can result in severe sequelaeincluding venous ulceration. Though the exact progression from chronic venous in-sufficiency to venous ulcer remains unclear, the high cost and burden of this diseaseon patients and society is quite clear. Sustained ambulatory venous pressures or ve-nous hypertension plays an integral role in the development of venous ulceration andinvolves the failure of the calf muscle pump system. Standard of care involves com-pression therapy to assist the calf muscle pump. However, several cofactors maycontribute to or exacerbate this disease and understanding their impact may provideinsight into new treatment modalities. Nerve involvement, which may result in neu-ropathic pain andmuscle dysfunction, alterations inmobility and a decrease in rangeof motionmay lead to gait alterations all affecting calf muscle pump function. In thispaper, we analyze these cofactors and discuss possible treatment options to targetthem. Physicians treating this disease should be aware of the numerous factors in-volved in its development. Exploring new treatment options may 1 day lessen theburden and suffering caused by venous insufficiency.

Chronic venous insufficiency is a common disorder that hasa significant impact on quality of life and healthcare costs inour society.1 Representative of this, approximately 7 millionAmericans suffer from chronic venous insufficiency at anaverage cost of $40,000 over a lifetime.1 One consequence,and among the most important, is the formation of a venousleg ulceration.2 While the exact pathophysiologic mecha-nisms that lead from venous disease to venous ulcers are notentirely known; several hypotheses have been developed.Theories have been proposed that attribute factors includingpericapillary fibrin cuff formation leading to poor oxygenand nutrient exchange, trapping of growth factors withinthis cuff, and white blood cell plugging of capillaries.3–5 In-tegral to all hypotheses and to this process is the develop-ment of venous hypertension, or more accurately sustainedambulatory venous pressure.6 Attempts to reverse venoushypertension have been targeted in the treatment and pre-vention of venous ulcers.7 The chronic nature of this disease,significant burden it places on society, and emerging data,leads to a reassessment of several cofactors that may play arole in the progression from venous hypertension to venousleg ulceration (Figure 1). This paper will review nerve andmuscle disturbances, mobility or range of motion changes,and gait alterations in patients with venous disease whichmay alter calf muscle pump function and contribute to thepathogenesis of venous ulcers. Understanding the roles ofthese cofactors in venous leg ulceration may have implica-tions for the treatment of this disease.

EPIDEMIOLOGYAND COSTS OF CHRONICVENOUS INSUFFICIENCY

The significant impact of chronic venous insufficiency isevident in both its prevalence of clinical manifestationsand chronic nature of disease. The estimated prevalence ofmild varicose veins for males and females is thought to be40 and 31%, respectively.8 Overall in Western countries,the estimated prevalence of venous ulcers is 1% for bothmen and women.8

Several studies have shown the chronic and recurrentcharacter of venous ulcers.9,10 Patients often had persistentulcers, as it was found that 35% of patients with leg ulcershad a problem of ulceration for more than 5 years and50% had their lesions for over 1 year.9,10 While failure toreceive optimal care may in part explain nonhealing ulcers,even those patients receiving the standard of care mayhave persistent ulcers.11 Additionally, many ulcers recurand the high recurrence rate causes treatment and financialburdens on the health care system.12 By example, one studyfound that 20% of patients with venous leg ulcerationsuffered from 10 or more episodes of ulceration.9

When compared with other common causes of ulcers suchas arterial and neuropathic ulcers, venous ulcers areknown to be more common and have a higher recurrencerate.10,13 For example, up to 72% of patients with venousulcers have recurrences compared with 45% in nonvenousulcers.10

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Wound Repair and Regeneration

The financial burden of venous ulcers is evident in highcost and loss of productivity in the workforce.14 In 2004,skin ulcers and wounds were estimated to incur 9.7 billiondollars in direct and 2.2 billion dollars in indirect costs.15 Astudy done by Olin et al.16 highlighted the costs incurred ininpatient and outpatient treatment of patients with venousstasis ulcers. The average total medical cost per patientwas $9,685, with a median cost of $3,036. This study ac-counted for hospitalizations, home healthcare, and homedressing changes which accounted for 25, 48, and 21% oftotal costs, respectively.16 These costs underestimate thetrue burden of venous ulcers as factors including timemissed from work, forced early retirement, loss of inde-pendent functional status, and suffering were not takeninto account. Additionally, inflationary changes make cur-rent care of venous ulcers more expensive. Combining theestimated cost per patient and the prevalence of this dis-ease, the total cost was estimated to be 1% of the totalhealthcare budget in Western European countries.17

MUSCLE PUMP FUNCTION ANDAMBULATORY VENOUS HYPERTENSION

Despite ongoing study and debate regarding the mecha-nisms by which venous ulceration occurs, a key aspect ofprogression from chronic venous insufficiency to venousulcer formation is ambulatory venous hypertension.18,19 Inorder to return blood to the heart via the venous system,several factors must work together: a central pump, a pe-ripheral venous pump, a pressure gradient, and competentveins and/or venous valves.19 A normal physiological re-sponse causes a decrease in pressure of veins in the lowerleg during activity of the peripheral calf muscle pump. Bydefinition, sustained ambulatory venous pressure or ve-nous hypertension is the failure to reduce these venouspressures during exercise.18,19

The lower extremity venous system is composed of adeep, superficial, and communicating venous system. Calfmuscle contraction functions to propel venous blood fromthe superficial to the deep venous system via the commu-nicating or perforator veins.6 During ambulation, the ve-

nous pressure in the deep and superficial venous systemdecreases from approximately 100mmHg at rest to about30mmHg during contraction.18,19 Despite a pressure gra-dient during contraction created by increased venous pres-sures in the thigh veins and decreased pressures in the legveins, retrograde blood flow is precluded by competentone-way valves in the veins.18

Functioning valves prevent the retrograde flow of bloodto the superficial venous system. These one-way bicuspidvalves reopen as the pressure in the deep venous systemdecreases as blood empties into the heart.6 The localiza-tion of the reflux in either the superficial or deep veins wasless significant than the actual volume of the reflux.18

Attributing venous hypertension to one or two causa-tive factors would be an oversimplification of this complexdisease. The multifactorial pathogenesis of chronic venousinsufficiency should be noted. Raju et al.20 studied 373limbs with ambulatory venous hypertension to identify theetiology. They concluded that contributing componentswere: poor calf muscle pump, reflux, increased arterial in-flow, reduced venous capacitance, poor ejection fraction,and a combination of the above.20 Thus, treatment of thiscondition should also be multifactorial.

CURRENT TREATMENTS AND PROGNOSIS

The mainstay of treatment for a venous ulcer is graduatedcompression with multilayer bandages.21,22 The concept ofcompression wraps has been appreciated for centuries,dating back to Hippocrates in ancient Greece.1 The goalof this therapy is to provide a pressure gradient that in-creases from the ankle upwards.1 Additionally, continueduse of compression stockings after an ulcer has healed isassociated with a decreased risk of recurrence.23 A system-atic review by Borges et al.21 concluded that consistent useof graduated compression with a multilayer system shouldbe the first choice for treatment of noncomplicated venousulcers and is reliable and cost effective in a majority ofpatients. Additionally, other compression methods, in-cluding the Unna boot, short-stretch bandages, and com-pression stockings, have been shown in randomized-

Figure 1. Interactions in the development

of venous leg ulceration.

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Factors affecting venous ulcers and calf muscle function Shiman et al.

controlled trials to be effective as treatment options forproperly selected patients.24,25

As adjuvants to compression therapy, several medica-tions, i.e., aspirin, pentoxifylline, daflon, and sulodexidehave demonstrated their effectiveness in trials.7,22,26 Var-ied levels of evidence support surgical techniques whichhave been employed such as autologous skin grafting, liv-ing skin equivalents, debridement, and venous surgery.27–31 Among these treatments, the best evidence exists forbilayered living skin equivalents.7,32 Potential treatments,e.g., granulocyte-macrophage colony stimulating factorand keratinocyte growth factor-2, have been either foundto be inconvenient or ineffective.33,34 Gohel et al.35 com-pared compression therapy alone to compression plus ve-nous surgery. Their randomized-controlled trial foundsurgical correction of superficial venous reflux in additionto compression did not improve ulcer-healing rates. How-ever, surgery did reduce the recurrence rate and increaseulcer free time.

Some patients appear more likely to respond to com-pression therapy. Understanding the prognostic factors invenous ulcers is important to identify patients who maybenefit from additional and alternative therapies. Amonga number of studies, Margolis et al.36 described a twopoint scoring system based on wound size (> 5 cm2) andwound duration (> 6 months) to predict healing after 24weeks of compression. Their research showed that 93% ofpatients healed when having none of their criteria, whileonly 13% of patients healed when having both of their cri-teria. Phillips et al.37 analyzed the results of a large multi-center venous ulcer trial and concluded that baseline ulcersize and duration are significant prognostic indicators.They noted that an ulcer which is slow to heal after 3weeks of optimal therapy has a poor prognosis as well.37

Another predictive tool is a scoring system developed byFalanga et al.38 which evaluates characteristics of thewound bed score and was shown to have validity in pre-dicting complete wound closure. This scoring system takesinto account the following: the healing edges, presence ofeschar, greatest wound depth/granulation tissue, amountof exudate, edema, periwound dermatitis, periwound cal-lus and fibrosis, and a pink/red wound bed.

A diagnostic test shown to reliably predict prognosis ofvenous ulcers by assessing muscle pump function is airplethysmographic exam.39 It is suggested, but not known,whether improvement in calf muscle function leads to bet-ter results in air plethysmographic exam.39 Patients withpoor prognostic characteristics may find benefit in alter-native therapies, in conjunction with the current standardof care.

NEUROPATHY

Local tissue destruction in chronic venous insufficiencydevelops in conjunction with damage to peripheral nerveswhich has been demonstrated in both clinical andimmunohistochemical studies.40,41 Nerve involvementmay be an underappreciated cofactor in chronic venousinsufficiency with possible implications for treatment ofvenous ulcers. Reinhardt et al.40 performed a neurologicalstudy on 30 patients with chronic venous insufficiency andcompared the results to healthy controls. All patients withconditions predisposing to peripheral neuropathy were ex-

cluded from the study. They found that patients withchronic venous insufficiency had a prolongation of distalmotor latency, a reduced vibration threshold, and dimin-ished warmth and cold perception. Their conclusion basedon these clinical findings was that patients with chronicvenous insufficiency had disturbances in A-a fibers, A-bfibers, A-d fibers, and thermoafferent-C fibers.40 Biopsyspecimens from the nerves of patients with chronic venousinsufficiency confirmed neuropathic changes and revealeddenervation.42

In 2004, Guest et al.41 used immunohistochemistry toconfirm the presence of peripheral neuropathy in patientswith venous ulcers. These researchers performed punch bi-opsies adjacent to venous ulcers in patients with healingulcers, nonhealing ulcers, and control patients with vari-cose veins. Antibodies were used to study the distributionof nerve fibers in the epidermis and papillary dermis. Com-pared with controls, patients with healing ulcers had a de-creased number of nerve fibers in the dermis. Patients withnonhealing ulcers had a decreased number of nerve fibersin the epidermis, and both groups had shorter nerve fibersin the epidermis. These findings conclude that the initialdevelopment of venous ulcers may be influenced by re-duced dermal and epidermal innervations. Also, chroniculcers may be influenced by a decrease in epidermal nervefibers, which may be important in the healing process.41

In 2007, Ogrin et al.43 studied the changes in the ne-urovasculature of chronic venous ulcers in patients treatedwith four-layer compression bandaging. They found thatafter therapy, patients improved their electrical cutaneousperception thresholds.

In addition to a panoply of other functions, nerves alsoserve as a source of growth factors which appear to be im-portant in healing. For example, the topical application ofnerve growth factor to pressure ulcers has been shown toimprove healing rates.44,45 Landi et al.45 revealed in a dou-ble-blind, placebo-controlled trial that patients who re-ceived daily application of a solution of nerve growthfactor had a statistically significant improved rate of heal-ing compared with controls. Tuveri et al.46 treated chronicvasculitic leg ulcers with nerve growth factor and observedrapid healing in patients with rheumatoid arthritis. Lessstriking improvements were observed in patients with sys-temic sclerosis. While the effect of nerve growth factor onvenous ulcers has not been studied, it is likely that its effectis not limited to pressure ulcers alone. This may lead tonew treatment options.

While the pain of venous ulcers has long been ignored,pain is now known to be a significant problem.47,48 Basedon a questionnaire, 64% of patients believed to have ulcerswith a purely venous etiology reported having severepain.47 A multicenter cross-sectional study in 2007 re-vealed that leg ulcers are very painful. There is also a di-rect correlation between ulcer duration and size to painand quality of life.49

Dworkin et al.50 studied venous ulcers in injection drugusers and concluded that pain is present in this group. Painwas associated with a poor coping ability and a decreasedquality of life.50,51 In another study of the same cohort,pain was one of the symptoms with the most profound im-pact on quality of life.52

Much of this pain may be neuropathic in origin and of-ten medications such as amitriptyline, gabapentin, and

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pregabalin among others are useful in dealing with thispain.53–55 Nerve involvement is an understudied cofactorin venous ulcers. Further studies are needed to elucidatethe role of nerve involvement and to identify potential tar-gets for therapy. Treating the neuropathic pain or usingnerve growth factor, e.g., in patients with venous leg ulcersmay have therapeutic effects.

MOBILITYAND RANGE OF MOTION

Mobility and range of motion are affected in patients withvenous ulcers.56,57 Therefore, attributing calf muscle pumpfailure solely to abnormalities in venous function may be afalse assumption. This association was investigated byDix et al.57 as they measured range of ankle movement us-ing goniometry. Results showed that in all grades of ve-nous insufficiency, from varicose veins to venous ulcers,there was an association with significantly reduced rangeof ankle motion. As the severity of venous hypertensionincreased, the range of ankle motion decreased.57 Backet al.58 showed that an increased number of patients withvenous ulcers had impaired dorsiflexion, which is thought tobe required for normal function of the calf muscle pump.

Pieper et al.59 studied the relationship between anklemobility, chronic venous disorders, and injection drug in-jury. Injury from injecting drugs into the lower extremityshowed a negative effect on ankle mobility. In anotherstudy, Pieper et al.60 recognized chronic venous disease asa complication of injecting drugs into the lower extremi-ties. Studying the damage caused by injecting drugs onveins, nerves, and muscles can serve as a model to betterunderstand the complex nature of venous ulcers.

Targeting muscle pump function in patients withchronic venous insufficiency with exercise is one approachthat may enhance current treatment options. Yang et al.61

demonstrated that patients with chronic venous diseaseand a history of venous ulcer had reduced function of thecalf muscle itself. Muscle strength measured as peaktorque/body weight and muscle endurance measured astotal work were both found to be decreased in this study.They suggested that the primary problem leading to calfmuscle impairment may be the poor calf muscle itself,rather than chronic venous insufficiency.61 A randomized,prospective trial done by Padberg et al.62 studied the im-plication of a supervised exercise program in patients withvenous ulcers. After a 6-month calf muscle exercise pro-gram, hemodynamic performance was improved. Calfpump function improved based on measurements of ejec-tion fraction, residual volume fraction, and strength. Thebenefits were maintained for at least 3 months after termi-nation of the exercise.62

Margolis et al.63 analyzed the relationship between ve-nous leg ulcers and concomitant medical conditions. Theyfound a statistically significant association in their patientsbetween having osteoarthritis and a recent onset of a ve-nous leg ulcer. This relationship may be linked throughchanges in mobility and range of motion, and benefit maybe obtained from treating the osteoarthritis. These studiesshed light on the potential of physical exercise or rehabil-itation to improve the muscle pump system and be used asan adjunct to current treatment options for patients withchronic venous insufficiency and venous ulcers.

GAIT ABNORMALITIES

Few studies have been performed to identify the relation-ship between chronic venous insufficiency and gait altera-tions. Pieper et al.64 used the Tinetti Balance and Gait teststo assess the effects of chronic venous insufficiency onwalking. In this study, patients who injected drugs into thelower extremities and therefore were known to be at highrisk for venous disease, were found to have lower balanceand gait scores than those drug abusers that either did notinject drugs or injected into their arms only.60,64

Patients with venous ulcers may also have an abnormalwalking motion. Newland et al.65 evaluated the gait of pa-tients with venous disease. Using pedal pressure measure-ments to identify differences compared with controls, footpressures were measured as a surrogate method to studygait. Patients with chronic venous insufficiency were ob-served to have lower total foot pressures. The distributionof pressure was also altered, with chronic venous insuffi-ciency patients having higher midfoot and lower big toepressures.65 Additionally, patients with venous ulcers havealso been shown to take fewer steps per week comparedwith controls.66

CLINICAL IMPLICATIONS

Clinicians and researchers should be aware of the multi-factorial pathogenesis of chronic venous insufficiency inorder to definitively diagnose and manage this disease andits sequelae. Understanding that neuropathy, neuropathicpain, decreased mobility, or gait changes may be present,may assist clinicians in diagnosing the underlying venousinsufficiency. Neuropathic pain may be managed withmedications aimed at alleviating it such as amitriptyline,gabapentin, or pregabalin. Further studies assessing nervegrowth factor in patients with venous ulceration areneeded to test the efficacy of this treatment. Recommend-ing physical therapy to teach and supervise calf muscle ex-ercises to improve the calf muscle pump and treatingconcomitant osteoarthritis and other conditions limitingankle mobility are important modalities of treatment.Identifying gait changes in patients with chronic venousinsufficiency is essential in understanding mobility issuesand the risk of falls. Ambulatory changes in patients withvenous ulcers need to be further studied along with phys-ical rehabilitation and gait training to supplement currenttreatment of venous ulcers. These approaches can poten-tially improve healing rates or help decrease recurrences inpatients affected by venous ulcerations (Table 1).

In conclusion, advances in the understanding of thepathophysiology of venous ulcerations have led to the ap-preciation that venous ulcers should not be simplifiedsolely as a pathology of blood vessels. This disease shouldbe regarded as a multifaceted, complex syndrome involv-ing all aspects of the calf muscle pump. Relevant andemerging research suggests that changes in nerve and mus-cle function and range of motion may affect gait and am-bulation either causal in disease formation or leading to anexacerbation or progression of disease symptomatology.

Based on the significant prevalence of this disease, aswell as its considerable health and economic burden onsociety, we believe a new, multifactorial approach to treat-ment should be evaluated. Additional studies of the

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neuropathic changes, ankle mobility, muscle alterations,and gait abnormalities may provide clues to new treatmentmodalities. Studies using pain control, nerve growth fac-tors, exercise, and gait training are potential options forfuture research. Further studies to assess these parametersand to clarify the cause–effect relationship of many ofthese factors will help elucidate the pathophysiologic de-velopment of venous ulcers, and potentially alternativetreatments.

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Table 1. Potential treatment options for cofactors involved in

the formation of venous leg ulceration

Cofactors Potential treatment options

Neuropathy Nerve growth factor

Pain related to

neuropathy

Amitriptyline

Gabapentin

Pregabalin

Impaired ankle

range of motion

Calf muscle exercises

Physical therapy evaluation and treatment

plan

Treatment of osteoarthritis and other joint

limiting conditions

Gait abnormalities Gait training exercises

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