Foot Problems in Diabetes

Jonathan E. Shaw, Andrew J.M. Boulton

Department of Medicine, Manchester Royal Infirmary, Manchester, UK

Introduction

The diabetic foot can present with a variety of problems, but the most important clinically are ulceration, amputation and Charcot neuroarthropathy. These will be the focus of this chapter. Many diabetic complications have a great impact on the foot and it is therefore not surprising that diabetic foot problems account for more hospital inpatient days than any other diabetic problems. Diabetic neuropathy and peripheral vascular disease are the main aetiological factors in foot ulceration and may act alone, together or in combination with other factors such as microvascular disease, biomechanical abnormalities, limited joint mobility and increased susceptibility to infection. A thorough understanding of the contributory factors that lead to foot ulceration and amputation is essential for successful treatment of established pathology. Perhaps more importantly, as the role of education and appropriate footwear in preventing ulceration and amputation is now established, accurate identification of high-risk patients on whom these services can be focused is vital.

Peripheral Vascular Disease

Atherosclerotic vascular disease is probably present (at least in a subclinical form) in all patients with long-duration diabetes. Like other forms of macrovascular disease, peripheral vascular disease (PVD) is more common in diabetes. Using clinical techniques of palpation of foot pulses, the Framingham Study found a 25-50% excess of PVD in people with diabetes, but using Doppler pressures, PVD can be found in up to 3 times as many diabetic as nondiabetic people.

The distribution of vascular disease in the lower limb is thought to be different in diabetes, with more frequent involvement of vessels below the knee. This is somewhat similar to the distal pattern of disease that is often seen in the coronary circulation, and may partly explain the fact that PVD is frequently asymptomatic in people with diabetes, and may present with is-chaemic foot ulceration or gangrene, with no previous claudication. Distal disease may allow a reasonable blood supply to be maintained to the large muscles involved in walking, whilst critically impairing the supply to the skin of the feet. Co-existent neuropathy and exercise limitation due to other diseases may also mask the symptoms of PVD. Thus, regular screening by physical examination is necessary to identify people with PVD.

Although PVD is more prevalent amongst the diabetic population, once established it does not progress any more rapidly than does PVD in the nondiabetic population. Furthermore, its treatment should follow similar lines. Exercise can improve claudication distances, and revascularization procedures are frequently successful, although may require a more distal anastomosis.

In the pathogenesis of diabetic foot ulcers, ischaemia is a major factor in a third to a half of all cases, and approximately 50% of amputations can be attributed to ischaemia. In a prospective study of type 2 diabetes, PVD (measured by Doppler techniques) nearly doubled the risk of developing a foot ulcer - an effect that was independent of a wide range of other risk factors.

Diabetic Neuropathy

Somatic Neuropathy

Chronic sensorimotor peripheral neuropathy is one of the commonest long-term complications of diabetes affecting at least a third of older diabetic patients in the UK according to a large study of hospital outpatients. Its onset is insidious and data suggest that only about a third of patients with objective evidence of neuropathy actually have neuropathic symptoms. Thus progression to the insensitive foot at high risk of ulceration can occur without the patient being aware of any disorder. Identification of the neuropathic foot at risk of ulceration therefore relies on careful examination.

Typically, the sensory defect predominates, but a motor component is often present, and its distal nature leads to small muscle wasting in the foot with a consequent imbalance of flexor and extensor muscles resulting in clawing of the toes and prominence of the metatarsal heads, which then become potential sites of ulceration.

Peripheral somatic neuropathy has been clearly associated with foot ulceration in several cross-sectional and prospective studies. The risk of ulcera-

tion attributable to neuropathy ranges between 2- and 10- fold, and is independent of the presence of PVD. Sensory neuropathy is most easily determined by measuring vibration perception thresholds (using a bio- or neurothesi-ometer), pressure perception thresholds (using monofilaments) or by clinical examination. These methods have been validated in their ability to predict ulceration.

Autonomic Neuropathy

Sympathetic dysfunction affecting the lower limbs leads to reduced sweating and results in dry skin that is prone to crack and fissure. It also increases blood flow (in the absence of large vessel PVD) with arteriovenous shunting leading to the warm foot. The insensitive foot is therefore often warm resulting in a false sense of security, as the patient perceives that because the circulation is intact, the risk is minimal.

Other Risk Factors for Foot Ulcers

Biomechanical Aspects

The neuropathic foot does not ulcerate spontaneously. It is the combination of neuropathy and trauma that results in tissue breakdown. The trauma required to ulcerate the neuropathic foot can take several different forms. Sometimes it is a single event such as standing on a nail, but more frequently it occurs as repeated minor trauma such as unperceived shoe rubbing to the toes or increased pressure beneath the metatarsal heads during walking. A number of studies have clearly demonstrated that dynamic plantar foot pressures are elevated in diabetic neuropathy and especially in patients with a history of plantar ulceration. More importantly, a prospective study has shown that elevated plantar pressures are predictive of ulceration, with 17% of patients with high foot pressures developing plantar ulcers during a 30-month follow-up period, whilst no plantar ulcers developed in patients with normal pressures. The presence of callus (produced in response to pressure) may exacerbate the problem both by acting as a foreign body and by increasing plantar pressures. Amongst those with diabetic neuropathy, the presence of callus is a strong and important predictor of subsequent ulceration at the site of the callus. The simple removal of the callus significantly reduces foot pressures, and presumably, therefore, also reduces the risk of ulceration.

Most studies on foot pressure have simply looked at the highest instantaneous pressure measured during a single foot step. However, evidence from in vitro studies indicates that the rate of increase of applied pressure is more important than the peak pressure achieved in causing cellular damage. If this could be confirmed in vivo, it would have important implications for the design of pressure-relieving orthoses which may need to control the rate of descent of the forefoot (increased in the 'footslap' caused by motor neuropathy), as much as redistribute load and lower the peak pressure.

The main cause of increased pressure is thought to be the alteration in foot shape resulting in prominent metatarsal heads. Atrophy of the intrinsic muscles of the foot (predominantly plantar flexors of the toes) alters the flexor/ extensor balance at the metatarso-phalangeal joints and causes clawing of the toes, and prominence of the metatarsal heads.

A further contributing factor to elevated plantar pressure is limited joint mobility. Glycosylation of collagen results in thickening and cross-linking of collagen bundles. This is manifested clinically as thick, tight, waxy skin and restriction of joint movement. Limited joint mobility of the subtalar joint alters the mechanics of walking and is strongly associated with high plantar pressure.

Other Long-Term Complications

Patients with retinopathy and nephropathy have been shown to have an increased risk of foot ulceration and amputation. The pathogenic mechanisms by which other complications lead to ulceration and amputation are not entirely clear, but visual impairment makes it more difficult for patients to identify a lesion at an early stage, and tissue repair is slow in nephropathy, because of oedema, the frequent co-existence of macrovascular disease and immunological abnormalities. Thus, such patients must always be regarded as being at high risk.

Previous Foot Ulceration

Several studies have confirmed foot ulceration is more common in those patients with a past history of ulceration or amputation and in patients with a poor social background.

Diabetes Control

Poor glycaemic control as measured by HbA1c, fasting and even a single random blood glucose is a strong risk factor for subsequent amputation. Chronic hyperglycaemia increases the risk of developing complications such as neuropathy, and impairs the wound healing capacity, thus setting the scene for ulceration and amputation.

Ethnicity

Lower extremity amputation rates have been shown to be high amongst several groups of American Indians and may be as much as 4 times greater than in the general US diabetic population. Amputation rates also appear to be higher amongst Black than Europid people with diabetes. Studies in the UK have shown lower incidences of amputation and foot ulceration in the Asian than the White population. The reasons for different amputation rates among different ethnic groups are unclear. Access to health care (ranging from detection and early treatment of diabetes to availability of specialized foot services) is likely to be important, but biological variation between ethnic groups may also play a role.

Cardiovascular Factors

Evidence would suggest that hypertension is probably a moderately important risk factor for amputation, but neither lipid abnormalities nor surprisingly smoking predict amputation.

Behavioural/Psychological Factors

Despite the fact that causal pathways to ulceration are well recognized (predominantly involving neuropathy and PVD), and many high-risk patients receive education on footcare, ulceration remains common. It has been suggested that denial of risk is the main reason for this and indeed extreme denial has been reported in some foot ulcer patients. However, in our own prospective study of psychological factors in foot ulceration, measures of denial have failed to predict ulceration. In contrast, neuropathic patients developing ulcers showed a more negative attitude to the feet, and their belief in the efficacy of advice (as provided in footcare education) was lower than that of patients who did not develop ulcers.

Wound Healing

Slow wound healing and increased susceptibility to infection increase the problems of foot ulceration and may predispose to amputation. A number of inherent immunological abnormalities have been documented in diabetes and these may explain the increased infection rates that are seen in postoperative wounds of diabetic patients. Amongst other abnormalaties, neutrophil function is impaired, with abnormalities of adherence, chemotaxis, phagocytosis and killing ability, and these may be partly due to ascorbic acid transport defects.

Microcirculation and Endothelial Dysfunction

Diabetes is associated with microcirculatory abnormalities, which are accentuated in the presence of long-term complications, including diabetic neuropathy. Typically, in the neuropathic foot, resting skin blood flow is elevated, but there is a marked blunting of the hyperaemic reserve, and of the postural vasoconstriction that should reduce limb blood flow on standing. The vasodila-

Table 1. Foot ulcer risk factors and relevant measurement techniques; all people with diabetes should be screened for these risk factors annually

Risk factor Screening method Abnormal result indicating increased risk of foot ulceration

Neuropathy Vibration perception threshold1 Pressure perception threshold1

Clinical examination1

Peripheral vascular disease Clinical examination Doppler pressures1

Previous foot lesion

Self-report1

Greater than 25 V at the great toe

Insensitivity to a 10-gram monofilament on the plantar surface of the foot Absent ankle reflexes or sensory loss

Less than 2/4 palpable foot/ankle pulses Systolic ankle pressure less than 90% of brachial pressure

Previous ulcer or amputation

1 Screening methods that have been shown to predict subsequent foot ulceration.

tory response is mediated by both endothelium-dependent and endothelium-independent mechanisms, both of which appear to be impaired in neuropathy. Whilst the direct causal connection between these abnormalities and foot ulceration is attractive, since a failure to respond appropriately to tissue injury could lead to chronic ulceration, the possible association is as yet untested.

Another related factor which may be important in the development of ulceration is capillary fragility. Recent work has shown the presence of micro-haemorrhages in the feet of neuropathic patients with a history of ulceration. As haemorrhage into callus commonly precedes ulceration, this may be an important finding.

Management of Ulcers

The first principle of foot ulcer management is prevention. Regular screening for the presence of risk factors (table 1) requires only very simple skills, and when combined with education (table 2) about footcare for those identified as being at risk, the likelihood of foot ulceration can be significantly reduced.

The management of diabetic foot ulcers relies on relief of pressure, debride-ment of necrotic tissue, aggressive treatment of infection when present and restoration of normal circulation if PVD is present. All people presenting with foot ulcers should have an examination of the peripheral sensation and

Table 2. Principles of footcare education

Target the level of information to the needs of the patient. Those not at risk require only general advice about foot hygiene and footwear

Make positive rather than negative recommendations Do inspect the feet daily

Do report any problems immediately - even if painless Do buy shoes with a square toe box and laces

Do inspect the inside of shoes for foreign objects every day before putting them on Do attend a fully trained podiatrist regularly Do cut your nails straight across and not rounded

Do keep your feet away from heat (fires, radiators, hot water bottles) and check the bath water with your hand or elbow Do always wear something on your feet to protect them and never walk barefoot

Repeat the advice at regular intervals and check for compliance

Disseminate the advice to other family members and other health-care professionals involved in the care of the patient circulation to classify the ulcer as neuropathic, neuroischaemic or ischaemic. Most neuropathic ulcers are due to repetitive pressure either from tight-fitting shoes (on the dorsum of the toes) or from walking (over the metatarsal heads). Pressure must be relieved in order to heal the ulcer. Poorly-fitting shoes need to be replaced by shoes with a better fit, while pressure on the plantar surface of the foot usually requires some form of walking cast (such as a total contact cast) to redistribute the load away from the ulcer. If there is any clinical evidence of PVD, Doppler pressures must be measured to determine if angiography is required. If revascularization is possible (by surgery or angioplasty), it should be performed, both to aid healing and to prevent recurrence.

An infected diabetic foot ulcer can lead to limb loss in a matter of days, but by no means are all ulcers infected, although bacterial colonization is almost universal. The distinction between colonization and infection can be difficult and is not usually aided by microbiological investigations. Clinical signs are the most reliable indicators of infection. Evidence of systemic upset (e.g. fever, leukocytosis) is usually absent and signs of local inflammation and the presence of pus usually confirm the diagnosis. Infections are usually polymicrobial, and so broad-spectrum antibiotics (such as clindamycin, or amoxycillin combined with clavulanic acid) are required. Osteomyelitis should be suspected in any nonhealing ulcer, and in all ulcers in which it is possible to 'probe to bone'. While it is often apparent on plain X-rays, CT, MRI or isotope scanning may be needed for the diagnosis.

Recent studies have opened up the possibility of manipulating the wound environment in order to accelerate healing. These interventions have sprung from a clearer understanding of the complex processes that underlie normal and delayed wound healing, much of which is orchestrated by growth factors. A topically applied 'bioengineered human dermis' which consists of neonatal dermal fibroblasts cultured on a bioabsorbable mesh is thought to promote healing by the production of growth factors and of matrix elements such as collagen and fibronectin. Evidence suggests that healing rates of neuropathic ulcers can be significantly improved with this material, although this conclusion relied on a post-hoc analysis, which excluded a number of subjects who were judged to have received a product of low metabolic activity. The direct application of growth factors to foot ulcers is another area of rapid progress. The underlying assumption is that chronic diabetic foot ulcers are slow to heal, at least in part because of a failure to produce adequate amounts of growth factors. Platelet-derived growth factor has now been shown to improve the ulcer healing rate from 35 to 50% at 20 weeks, but a small pilot study of fibroblast growth factor found no benefit.

During the American Civil War, maggot-infested wounds were noted to be cleaner and to heal better than other wounds. This observation has recently been applied therapeutically to a variety of other wounds, and anecdotal reports suggest a beneficial effect in diabetic foot ulcers. The larvae selectively ingest necrotic slough leaving healthy tissue alone, and possibly also produce substances that directly stimulate wound healing.

Hyperbaric oxygen therapy increases tissue oxygenation, inhibits anaerobic microorganisms and promotes macrophage activity. It is therefore a candidate for treatment of diabetic foot ulcers. In a small trial of limb-threatening (predominantly ischaemic) diabetic foot lesions, a significant reduction in the rate of major amputations was seen in the group randomized to receive hyperbaric oxygen. This finding needs to be reproduced in larger trials before this expensive therapy can be recommended for widespread use.

The surgical management of foot ulcers is usually limited to amputation and the debridement of infected and necrotic tissue, but it may have a role to play in directly facilitating wound closure. A small study has described better 6-month healing and recurrence rates when noninfected ulcers were excised and closed surgically than when treated conventionally.

Charcot Neuroarthropathy

A Charcot joint is characterized by the simultaneous presence of bone and joint destruction, fragmentation and remodelling. Diabetes is the commonest cause of the Charcot foot and most patients have a dense neuropathy, but good circulation. Early animal experiments suggested that walking on an insensitive limb could lead to joint destruction. Excessive and repetitive stress to bones leads to microfractures, which render the bone more brittle and could lead to bone and joint destruction. However, the degree of bone destruction often seen in the absence of major injury has suggested an underlying bone abnormality. Diabetic neuropathy leads to an increase in bone blood flow, which may promote osteoclastic activity and bone resorption. Indeed, a small study has demonstrated increased serum markers of osteoclastic action in patients with acute Charcot that was not accompanied by a concomitant increase in markers of osteoblastic activity. Furthermore, lower limb bone mineral density has been found to be lower in patients with a Charcot foot, when compared to neuropathic controls. A full understanding of the pathological process leading to the often dramatic and progressive destruction seen in this condition has not yet been arrived at, and as it is rare and usually presents late, the opportunities for further studies are limited.

In the early acute stages, when bone turnover is high, treatment involves rest and immobilization of the foot (usually with a total contact cast) in an attempt to reduce the metabolic activity within the bone. There is now some evidence that bisphosphonate drugs given during this acute phase may shorten the duration of the acute phase presumably by reducing the bone turnover directly, and hence slowing down the process which weakens the bone and renders it susceptible to further fracture and fragmentation.

Whenever unilateral swelling of the foot is present in someone with diabetic neuropathy, Charcot neuroarthropathy must be considered. Plain X-ray is usually adequate to make or exclude the diagnosis, and while the radiological appearances can be similar to those of osteomyelitis, in the absence of a source of infection (such as an overlying ulcer), neuroarthropathy is nearly always the cause.

Conclusion

Although the roles of peripheral neuropathy and peripheral vascular disease are now well established as the main aetiological factors in diabetic foot ulceration, there is much work to be done in both the way in which ulcers develop and the interactions of the main risk factors with each other and with all the other risk factors discussed in this chapter. However, this complexity should not deter the clinician, as it is now very clear that simple clinical tests will identify patients at risk of ulceration and amputation, and appropriate, but simple education about footcare can greatly reduce the likelihood of developing diabetic foot problems. Foot ulcers can be difficult to heal, but treatment is likely to be successful in the vast majority of cases when pressure is removed, callus and necrotic tissue debrided, infection controlled, and a good circulation is maintained.

Suggested Reading

Boulton AJM, Connor H, Cavanagh PR (eds): The Foot in Diabetes, ed 2. Chichester, Wiley, 1994. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994;331:854-860. Schapper NC, Bakker K (eds): The diabetic foot. Diabet Med 1996;13(suppl 1):1-64. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: An overview. Diabetes 1997;46(suppl 2): 58-61.

Dr J. Shaw, Department of Medicine (M7), Manchester Royal Infirmary, Manchester M13 9WL (UK)

Tel. +44 161 276 4452, Fax +44 161 274 4740, [email protected]

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 218-228

Chapter XVI

Diabetes Sustenance

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