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Home , Diabetic foot, Diabetic foot ulcer

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Neuropathy and foot How to reduce the incidence of foot ment of the following can identify high ulceration and risk patients6 who need to be under regular review by a community or hos- Improve the control of blood and problems in diabetes pital podiatrist: cardiovascular risk factors. Prospective peripheral vascular disease studies in type 11 and type 2 diabetes2 • (impalpable pulses or reduced SG Gilbey MD FRCP, Consultant Physician, have confirmed the importance of blood ankle/brachial plexus systolic blood Leeds Teaching Hospitals, Leeds glucose control. The United Kingdom pressure index) Prospective Diabetes Study showed that: neuropathy (assessment of light Clin Med 2004;4:318–23 a 1% reduction in haemoglobin A1c • • touch using a 10 g neurofilament from any baseline level reduced the fibre (Fig 1), and Introduction risk of amputation or death from peripheral vascular disease by 43%,3 foot deformity. The cardiovascular system (considered in • and Patients with foot disease benefit from another article in this series) bears the attending a clinic where brunt of diabetic complications. The there is a 16% decrease in • podiatrists, orthotic shoe fitters and dia- kidney, another important target organ, amputation or death from vascular betologists work together and have access is susceptible to both microvascular disease for every 1 mmHg reduction 4 to vascular and orthopaedic surgeons. and macrovascular disease. This article in systolic blood pressure. concentrates both on neuropathy as a In the Heart Protection Study,5 cause of multisystem disease in diabetes random allocation to simvastatin Who needs urgent referral or and on diabetic foot disease as a condi- reduced vascular events (coronary admission? events, strokes, revascularisation) in dia- tion where prompt, appropriate action Any patients with foot ulceration should betic patients by 22% (p <0.0001) with a by a non-diabetologist can prevent major be referred for assessment (Table 2) and morbidity. marginally significant reduction in the much smaller number of patients devel- The diabetic foot oping peripheral macrovascular compli- cations (arterial , angioplasty, Epidemiology amputation or foot ulcers). Foot ulcers occur in 5–10% of the dia- betic population, with an annual inci- Improve the organisation of foot care for dence of 2–3% and a 3% lifetime risk of all patients with diabetes and define t amputation. Neuropathy and peripheral hose at risk of foot ulceration (Table 1). All vascular disease both contribute to foot diabetic patients should have their feet disease. Diabetic patients undergoing examined at least once a year and be amputation have a one-year mortality of given simple advice on foot care, 11–41%. footwear and prevention. Assess-

Table 1. Risk factors for diabetic foot ulceration.

Risk factor Clinical features

Neuropathy: • sensory Reduced light touch sensation Reduced temperature sensation • motor Small muscle wasting leading to foot deformity/high foot pressure • autonomic Reduced sweating Dry Altered small vessel regulation Peripheral vascular disease Diabetic pattern of distal atherosclerosis Other risk factors Smoking Hyperlipidaemia Hypertension Poor vision Poor foot care Old age Fig 1. A 10 g monofilament for testing sensation.

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Table 2. Assessment of a . Key Points Site, size and depth of ulcer Clinical observation Evidence of cellulitis, spreading , Clinical observation The life time risk of amputation for a X-ray diabetic patient is 3% MRI Evidence of neuropathy and deformity Clinical observation Long-term control of blood glucose Sensory testing and blood pressure has been ?Autonomic function shown to reduce the risk of macro- and microvascular diabetic Evidence of vascular insufficiency Clinical observation complications in type 1 and type 2 Ankle/brachial blood pressure index (abnormal diabetes if <0.8; may be obscured by vascular calcification) All diabetic patients should have Angiography (MR angiography if regular foot review and foot care contraindicated) advice

MRI = magnetic resonance imaging. Diabetic foot clinics reduce the risk of ulceration leading to amputation

Table 3. Leeds policy for diabetic foot ulceration (courtesy of Dr C Amery). The acute Charcot foot needs urgent admission and immobilisation If clinical suspicion of infection Swab all ulcers (deep as possible) (erythema, raised CRP) Bone scrapings if possible Current therapy for diabetic painful Outpatients Amoxycillin + flucloxacillin neuropathy is disappointingly Clindamycin if penicillin allergy ineffective If osteomyelitis suspected Clindamycin + ciprofloxacin (12 weeks) (admit acute cases) Symptomatic diabetic autonomic Inpatients iv benzylpenicillin + flucloxacillin (+ metronidazole if neuropathy is rare significant infection) iv clindamycin + oral ciprofloxacin if penicillin allergy KEY WORDS: amputation, Charcot foot, If osteomyelitis suspected iv flucloxacillin, oral ciprofloxacin + metronidazole diabetes, foot disease, neuropathy, iv clindamycin + oral ciprofloxacin if penicillin allergy peripheral vascular disease Review antibiotic choice with swab result

CRP = C-reactive protein; iv = intravenous. thetic neuropathy, may lead to a hyper- vascular response to local trauma, local bone resorption and osteopenia, setting intervention in a foot clinic. Urgent up a vicious circle of local fracture and • inflammation.8 This in turn results in referral is indicated by markers of signif- surgery//skin flap to • foot deformities and a high risk of ulcer- icant infection (local erythema, pain, enable healing systemic unwellness), increasing size or ation. • osteotomy to relieve high pressure The acute Charcot foot (Fig 3) presents depth of ulcer. Hospital admission is areas, and indicated for: with pain and swelling. Failure to diag- revascularisation/amputation. nose this will result in persistent weight administration of intravenous • • bearing by the patient and a cycle of con- antibiotics for severe ulceration and tinuing bone damage. The main differ- infection including osteomyelitis The Charcot foot ential diagnosis is infection. Patients in (Table 3) The Charcot foot occurs in patients with whom clinical and radiological examina- • urgent investigations (X-ray, a relatively long duration of diabetes tion leave the diagnosis in doubt may magnetic resonance imaging), (type 1 or type 2) and poor diabetes con- have to be treated with antibiotics angiography) with a view to trol. In one series of 1,000 diabetic ‘blindly’. Any patient who appears to be intervention (Fig 2(a) and (b)): local patients, 26% were at risk of foot ulcera- developing a Charcot foot should be debridement/ foot surgery, tion and 0.4% had a Charcot foot.7 referred urgently, with hospital admis- angioplasty, vascular reconstruction, Patients usually have severe peripheral sion indicated if the index of suspicion is amputation. sensory neuropathy in the presence of reasonably high. Intervention for foot ulceration good peripheral circulation. The patho- Treatment (Table 4) involves immobil- includes: physiology of the acute Charcot foot is isation for a period of weeks, with subse- • local treatment (degranulation, unclear. Abnormal local vascular quent use of full contact casts and Walker removal of dead tissue, application responses, similar to those in reflex sym- boots to reduce pressure on the foot. of maggots) pathetic dystrophy and due to sympa- Because of the apparent role of

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a Fig 2. Diabetic foot ulcer: (a) the foot shows the typical ‘claw foot’ deformity with prominent metatarsal heads secondary to neuropathy and small muscle wasting; (b) the angiogram shows diffuse, distal arterial disease with no prospect for reconstruction.

osteopenia and fracture, bisphospho- nates have been used to ‘stabilise’ bone turnover and accelerate recovery from the acute phase. One placebo-controlled study showed that a single dose of pamidronate could reduce pain and local inflammation but did not alter the nat- ural history of the neuroarthropathic process.9 The chronic Charcot foot is painless, deformed and vulnerable to repeated ulceration. Increasingly, orthopaedic b intervention (including surgery) is used to reduce both deformity and pressure areas.

Diabetic neuropathy

A simple classification of diabetic neu- ropathy is summarised in Table 5. There is a multifactorial aetiology. Prolonged hyperglycaemia leads to local metabolic changes, all of which may contribute to neuropathy: • sorbitol accumulation • myoinositol depletion10 • of local tissue, and • local damage to small vessels within the nerve bundle (microvascular disease).11 Experimental attempts to reverse metabolic changes and improve clinical disease using aldose reductase inhibitors have been unsuccessful. The only treat- ment for which there is unequivocal evi- dence of benefit for nerve function and some evidence of benefit for neuropathic symptoms is improved diabetic control.

Peripheral sensory neuropathy

Sensory neuropathy in diabetes is irre- versible and symmetrical (‘glove and

Fig 3. An acute Charcot foot. The right foot is swollen and painful, requiring immobilisation and relief of weight bearing.

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Table 4. The Charcot foot.

Phase Symptoms Findings Management

Acute phase Pain Raised CRP Immobilisation/off-loading Swelling Erythema Analgesia Fractures/joint subluxation Glucose control Increased bony disorganisation Increased blood flow Osteopenia Chronic phase Foot deformity Chronic bony changes Foot care advice Analgesia Increased foot pressures Bespoke footwear Increased ulcer risk Regular podiatric review Increased risk contralateralCharcot Surgery to relieve pressure areas (selected cases)

CRP = C-reactive protein. stocking’). It preferentially affects small the disruption to quality of life. Chronic made clinically and with nerve conduc- fibres mediating pain and temperature, pain may persist for years. tion studies. Management includes particularly in the early phase. Longer The variety of treatments available improved diabetes control and analgesia. nerves are especially vulnerable – hence (Table 6) indicates how difficult diabetic The usual natural history is gradual reso- the predilection for neuropathy in the pain is to treat.13 Patients need to be lution over 6–18 months. The major dif- diabetic foot, which is in turn the made aware of the difficulty of treat- ferential diagnosis is a spinal problem anatomical site most vulnerable to ment. A combined approach with a pain causing nerve root compression. mechanical damage. Clinical symptoms specialist service may be helpful. Mononeuropathies can affect thoracic of neuropathy have been found in up to nerve roots (thoracic radiculopathy) and 12 50% of diabetic patients and up to 11% Motor neuropathy and cranial nerves. have chronic pain. Patients with type 2 mononeuropathies The pathophysiology of motor neu- diabetes may present with established ropathy and mononeuropathies in sensory neuropathy, presumably due to Diabetic amyotrophy (or proximal motor diabetes is unclear but most likely a prolonged period of undiagnosed neuropathy) is a predominantly motor ischaemic. The natural history is resolu- diabetes. neuropathy causing pain, weakness and tion with time. Management is sympto- atrophy affecting the pelvic girdle and matic with optimisation of diabetic Painful neuropathy thigh musculature. The diagnosis can be control.

Symptomatic neuropathy can be an acute presenting feature of diabetes Table 5. A classification of diabetic neuropathies. (‘hyperglycaemic’ neuropathy, usually Chronic symmetric Distal sensory (may have chronic painful symptoms) self-limiting) or follow a period of Sensorimotor (associated with mild motor weakness) rapid improvement of diabetic control Autonomic for reasons that remain unclear. ‘Diabetic Acute/reversible Acute painful neuropathy (often associated with weight loss) neuropathic cachexia’ is a syndrome of Diabetic amyotrophy (painful neuropathy with muscle severe painful neuropathy associated wasting) with depression, anorexia and weight Acute focal neuropathy (eg cranial, radiculopathy) loss, with gradual resolution over a Compression neuropathies Ulnar, median nerves (ulnar, median nerves) period of months. Neuropathic pain ranges from mild discomfort to severe, distressing, unre- Table 6. Treatment of confirmed painful . lenting symptoms, including: burning First-line Improve diabetic control • Tricyclic antidepressants (particularly if sleep disturbance) shooting, lancinating • Substitute gabapentin if tricyclics unsuccessful ‘walking on marbles’ • Second-line Alternative anti-epileptic agents (carbamazepine, phenytoin) • paraesthesia/hyperaesthesia Antiarrhythmic agents (eg intravenous lignocaine) • aching/cramping, and Topical treatments (capsaicin, Op-site) • nocturnal exacerbation/contact Topical nitrates (under investigation) dysaesthesia (allodynia). Narcotic analgesics Transcutaneous electrical nerve stimulation Loss of sleep due to nocturnal symp- Sympathectomy toms is a major problem and exacerbates

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Nerve entrapment syndromes of any risk of sudden death thought to be attrib- of over 30 mmHg on standing, with type are more common in diabetic than utable to cardiac arrhythmias.14 symptoms. It may take 2–3 minutes for non-diabetic people for reasons that the blood pressure drop to manifest remain unclear. itself. Clinical features of autonomic neuropathy and their Autonomic neuropathy management (Tables 7 and 8) Gastroparesis Symptomatic autonomic neuropathy is Cardiovascular autonomic Abnormalities of gastric function are rare in diabetic patients. It is so often dysfunction found in 30–50% of patients with accompanied by overt somatic neuro- long-standing diabetes.15 Symptomatic pathy that the absence of peripheral Patients with established diabetic auto- gastroparesis with recurrent vomiting neuropathy should prompt a search for nomic neuropathy have a fixed, increased can be intractable. Hyperglycaemia has a another cause for symptoms eg adreno- heart rate due to loss of vagal tone and major influence on gastric emptying so a cortical insufficiency in diabetic patients cardiovascular reflexes. This is the basis presenting with postural hypotension of most simple measurements of auto- and vomiting. On the other hand, subtle nomic function in diabetes. a autonomic dysfunction may play a significant part in the pathophysiology of Postural hypotension cardiovascular complications of diabetes. An extreme example is diabetic patients Postural hypotension, a late feature of with symptomatic autonomic neu- diabetic autonomic neuropathy, is ropathy who have a small but significant defined as a fall in systolic blood pressure

Table 7. Clinical features of diabetic autonomic neuropathy.

System Clinical features

Cardiovascular Fixed unresponsive heart rate Symptomatic postural hypotension (postural fall of systolic BP >30 mmHg Neuropathic oedema Cardiorespiratory arrest Gastrointestinal Diarrhoea/constipation Gastroparesis Gustatory sweating Genitourinary Bladder paresis Erectile dysfunction (multifactorial) Retrograde ejaculation b

Table 8. Clinical management of autonomic neuropathic symptoms.

Symptoms Clinical management

Postural hypotension Mineralocorticoids Sympathomimetic agents (ephedrine, midodrine) Partial beta-agonists (pindolol) Prostaglandin synthetase inhibitors Octreotide (constricts splanchnic bed) Desmopressin acetate Gastroparesis Correct hyperglycaemia Domperidone Metoclopramide Erythromycin Percutaneous jejunostomy if required for nutrition Surgery rarely useful Diabetic diarrhoea Exclude other causes (coeliac disease, metformin, pancreatic insufficiency) Conventional antidiarrhoeal agents Tetracyclines (presumed bacterial overgrowth) Fig 4. Delayed gastric emptying – Clonidine diabetic gastroparesis. Symptoms Octreotide improved dramatically with improved diabetic control.

322 Clinical Medicine Vol 4 No 4 July/August 2004 CME Diabetes priority is to optimise glycaemic control. easily quantified and correlate well with 11 Tesfaye S, Malik R, Harris N, Jakubowski JJ Investigations confirm grossly delayed other tests such as peripheral sweating et al. Arterio-venous shunting and prolifer- gastric emptying (Fig 4). abnormalities. Postural hypotension is ating new vessels in acute painful neuro- pathy of rapid glycaemic control ( easily measured but it is a late feature of neuritis). Diabetologia 1996;39:329–35. Diabetic diarrhoea and constipation symptomatic neuropathy (see above). 12 Veves A, Manes C, Murray HJ, Young MJ, Boulton AJ. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Patients with symptomatic autonomic Conflict of interest neuropathy can present dramatically Care 1993;16:1187–9. 13 Spruce MC, Potter J, Coppini DV. The with profuse watery diarrhoea including None. pathogenesis and management of painful faecal incontinence. This is often inter- diabetic neuropathy: a review. Diabet Med spersed with prolonged episodes of con- 2003;20:88–98. stipation. Other causes of diarrhoea need References 14 Ewing DJ, Campbell IW, Clarke BF. to be excluded, including: Mortality in diabetic autonomic neuro- 1 The Diabetes Control and Complications pathy. Lancet 1976;i:601–3. • pancreatic pathology Trial Research Group. The effect of intensive 15 Horowitz M, O’Donovan D, Jones KL, • coeliac disease (2–6% prevalence in treatment of diabetes on the development Feinle C et al. Gastric emptying in diabetes: type 1 diabetes16), and and progression of long-term complications clinical significance and treatment. Review. in insulin-dependent diabetes mellitus. N Diabet Med 2002;19:177–94. • metformin therapy. Engl J Med 1993;329:977–86. 16 Holmes GK. Coeliac disease and Type 1 dia- Treatment is with antidiarrhoeal 2 Intensive blood-glucose control with betes mellitus – the case for screening. agents and, in some patients, short sulphonylureas or insulin compared with Review. Diabet Med 2001;18:169–77. conventional treatment and risk of compli- courses of antibiotics (eg tetracycline) cations in patients with which can relieve diarrhoea by treating (UKPDS 33). UK Prospective Diabetes bacterial overgrowth. Study (UKPDS) Group. Lancet 1998;352: 837–53. 3 Stratton IM, Adler AI, Neil HA, Matthews Bladder symptoms DR et al. Association of glycaemia with macrovascular and microvascular complica- Bladder symptoms include impaired tions of type 2 diabetes (UKPDS 35): bladder sensation, inability to void urine prospective observational study. BMJ and a sense of inadequate bladder 2000;321:405–12. 4 Adler AI, Stratton IM, Neil HA, Yudkin JS et emptying. Investigations show an al. Association of systolic blood pressure increased residual urine volume post- with microvascular and microvascular com- micturition. Treatment is by behavioural plications of type 2 diabetes (UKPDS 36): and pharmacological techniques to prospective observational study. BMJ improve bladder emptying and, if neces- 2000;321:412–9. 5 Collins R, Armitage J, Parish S, Sleigh P et sary, self-catheterisation to reduce the al. MRC/BHF Heart Protection Study of risk of infection. cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361: Erectile dysfunction 2005–16. 6 Kumar S, Fernando DJ, Veves A, Knowles Causes of erectile dysfunction include EA et al. Semmes-Weinstein monofila- autonomic dysfunction and vascular ments: a simple, effective and inexpensive disease. Treatment has been revolu- screening device for identifying diabetic tionised by phosphodiesterase inhibitors patients at risk of foot ulceration. Diabetes Res Clin Pract 1991;13:63–7. such as sildenafil, reducing the need for a 7 Klenerman L. The Charcot joint in diabetes. panoply of alternative treatments. Review. Diabet Med 1996;13(Suppl 1): S52–4. 8 Jeffcoate W, Lima J, Nobrega L. The Charcot When should autonomic function foot. Review. Diabet Med 2000;17:253–8. tests be arranged? 9 Jude EB, Selby PL, Burgess J, Lilleystone P et al. Bisphosphonates in the treatment of The main value of autonomic function Charcot neuroarthropathy: a double-blind tests is to confirm that a patient with randomised controlled trial. Diabetologia somatic neuropathy who is suspected 2001;11:2032–7. of autonomic symptoms does have 10 Greene D, Lattimer SA, Sima AA. Sorbitol, phosphoinositides, and sodium-potassium- abnormal autonomic function. Most ATPase in the pathogenesis of diabetic com- tests are based on parasympathetic plications. Review. N Engl J Med 1987;316: cardiovascular reflexes because these are 599–606.

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