The Foot in Diabetes - part 6 docx

At present, Dermagraft presents a new and exciting treatment for theindolent plantar neuropathic ulcer that has failed to respond toconventional treatment.GRANULOCYTE-COLONY STIMULATING

At present, Dermagraft presents a new and exciting treatment for theindolent plantar neuropathic ulcer that has failed to respond toconventional treatment.

GRANULOCYTE-COLONY STIMULATING FACTOR

(GCSF)Foot infection is common in patients with diabetes mellitus The incidenceand severity of such infections is greater in people with diabetes than in thenon-diabetic population The higher risk may be related to abnormalities inhost defence mechanisms, including defects in neutrophil function4,5.Effective neutrophil antimicrobial action depends on the generation ofseveral oxygen-derived free radicals These toxic metabolites, (e.g super-oxide anion) are formed during the respiratory (or oxidative) burst that isactivated after chemotaxis and phagocytosis De®ciencies in neutrophilchemotaxis, phagocytosis, superoxide production, respiratory burst activity,and intracellular killing have been described in association with diabetes.Granulocyte-colony stimulating factor (GCSF) is an endogenous haemo-poietic growth factor that induces terminal differentiation and release ofneutrophils from the bone marrow The recombinant form is used widely totreat chemotherapy-induced neutropenia Endogenous GCSF concentra-tions rise during bacterial sepsis in both neutropenic6and non-neutropenicstates7; these ®ndings suggest that GCSF may have a central role in theneutrophil response to infection8 In addition, GCSF improves function inboth normal and dysfunctional neutrophils9

Since diabetes represents an immunocompromised state secondary toneutrophil dysfunction, we investigated the effect of systemic recombinanthuman GCSF (®lgrastim) treatment in diabetic patients with foot infection.The aims of the study were to assess the effects of the GCSF on the clinicalresponse and to measure the generation of neutrophil superoxide inpatients and healthy controls10

Patients received either GCSF or a similar volume of placebo (salinesolution) GCSF or placebo was administered as a daily subcutaneousinjection for 7 days Glycaemic control was optimized with insulin in allparticipants, by means of a continuous intravenous infusion or a multiple-dose regimen Primary study objectives were time to resolution of infection(cellulitis), intravenous antibiotics requirements, and time to hospitaldischarge Secondary objectives were the need for surgery, effects ofGCSF on the generation of neutrophil superoxide, and the time taken forpathogens to be eliminated from the wound

Forty diabetic patients with foot infections were enrolled in a blind placebo-controlled study On admission, patients were randomlyassigned to GCSF therapy (n=20) or placebo (n=20) for 7 days There were

no signi®cant differences between the groups in clinical or demographiccharacteristics on entry to the study Both groups received similar antibioticand insulin treatment Neutrophils from the peripheral blood werestimulated with opsonized zymosan, and superoxide production wasmeasured by a spectrophotometric assay based on reduction of ferricyto-chrome c The maximum skin temperature within the area of cellulitis wasrecorded with an infra-red thermometer These readings were comparedwith those taken from the corresponding site on the non-infected foot Anydecisions about surgical debridement or amputation were based on clinicalsigns, including the presence of non-viable tissue, the development ofgangrene, abscess formation, and lack of improvement despite optimumantimicrobial therapy.

GCSF therapy was asociated with earlier eradication of pathogens frominfected ulcers [median 4 (range 2±10) vs 8 (2±79) days in the placebo group;p=0.02], quicker resolution of cellulitis [7 (5±20) vs 12 (5±93) days; p=0.03],shorter hospital stay [10 (7±31) vs 17.5 (9±100) days; p=0.02], shorterduration of intravenous antibiotic treatment [8.5 (5±30) vs 14.5 (8±63) days;p=0.02].There was a signi®cant reduction in the temperature differencebetween the infected and non-infected foot by day 7 in the GCSF-treatedgroup; by contrast, in the placebo group the reduction was not signi®cant

No GCSF-treated patient needed surgery, compared with four in theplacebo group Four patients had ulcers healed at day 7 in the GCSF group,compared with none in the placebo group ( p=0.09) After 7 days' treatment,neutrophil superoxide production was higher in the GCSF group than inthe placebo group [16.1 (4.2±24.2) vs 7.3 (2.1±11.5) nmol per 106neutrophils

in 30 minutes; p50.0001] GCSF therapy was generally well tolerated.Patients who received GCSF therapy had signi®cantly earlier eradication ofbacterial pathogens from wound swabs, quicker resolution of cellulitis,shorter hospital stays, and shorter duration of intravenous antibiotictreatment than placebo recipients Metabolic control did not differsigni®cantly between the groups

GCSF therapy was associated with the development of leukocytosis, duealmost entirely to an increase in neutrophil count Total white-cell andneutrophil counts increased signi®cantly after two doses of GCSF, and theincreases were maintained until day 7 There were also signi®cant increases inlymphocyte and monocyte populations in patients receiving GCSF All cellcounts returned to near-baseline values within 48 hours of the end oftreatment

CONCLUSIONThis study showed that in diabetic patients with foot infection, GCSFtreatment signi®cantly accelerated resolution of cellulitis, shortened

Dermagraft and Granulocyte-colony Stimulating Factor 183

hospital stay, and decreased antibiotic requirements Thus, GCSF may be animportant adjunct to conventional therapy Clinical improvements withGCSF were supported by a signi®cant decrease in foot temperaturedifference, and a shorter time to negative wound culture.

REFERENCES

1 Gentzkow G, Iwasaki S, Hershon K, Mengel M, Prendergast J, Ricotta J, Steed D,Lipkin S Use of Dermagraft, a cultured human dermis, to treat diabetic footulcer Diabet Care 1996; 19: 350±4

2 Naughton G, Mansbridge J, Gentzkow G A metabolically active humandermal replacement for the treatment of diabetic foot ulcers Arti®cal Organs1997; 21: 1203±10

3 York Health Economics Consortium Evaluation of the cost-effectiveness ofDermagraft in the treatment of diabetic foot ulcers in the UK University of York,1997

4 Sato N, Shimizu H, Shimomura Y, Mori M, Kobayashi I Myeloperoxidaseactivity and generation of active oxygen species in leukocytes from poorlycontrolled diabetic patients Diabet Care 1992; 15: 1050±2

5 Marphoffer W, Stein M, Maeser E, Frederlin K Impairment of nuclear leukocyte function and metabolic control of diabetes Diabet Care 1992;15: 256±60

polymorpho-6 Cebon J, Layton JE, Maher D, Morstyn G Endogenous haemopoietic growthfactors in neutropenia and infection Br JHaematol 1994; 86: 265±74

7 Selig C, Nothdurft W Cytokines and progenitor cells of granulocytopoiesis inperipheral blood of patients with bacterial infections Infect Immun 1995; 63: 104±9

8 Dale DC, Liles WC, Summer WR, Nelson S Granulocyte colony stimulatingfactor (GCSF): role and relationships in infectious diseases JInfect Dis 1995; 172:1061±75

9 Roilides E, Walsh TJ, Pizzo PA, Rubin M Granulocyte colony stimulatingfactor enhances the phagocytic and bactericidal activity of normal and defectiveneutrophils JInfect Dis 1991; 163: 579±83

10 Gough A, Clapperton M, Tolando N, Foster AVM, Philpott-Howard J, Edmonds

ME Randomised placebo-controlled trial of granulocyte-colony stimulatingfactor in diabetic foot infection Lancet 1997; 350: 855±9

14 New Treatments for

Diabetic Foot Ulcers

(c) Larval Therapy STEPHEN THOMAS

Princess of Wales Hospital, Bridgend, UK

HISTORY

In the treatment of infected or necrotic areas on the diabetic foot, as withmost types of chronic wounds, it is axiomatic that before the process ofhealing can begin, the affected areas must be thoroughly cleansed of alldevitalized tissue If surgical intervention is not an option, mostpractitioners use hydrogels to promote autolytic debridement1or resort tothe use of other agents of questionable value These include preparationscontaining povidone iodine and other lotions and potions containingsodium hypochlorite Enzymatic debriding agents such as those containingstreptodornase and streptokinase have also been used, although results ofclinical trials involving these preparations have been disappointing.Within the last few years, an alternative approach has been described thatinvolves the use of sterile maggots, larvae of the common greenbottle, toeffect wound debridement This is not a new technique but a revival of aprocedure that was widely used in the ®rst half of the century as atreatment for osteomyelitis and soft tissue infections

An early reference to the ability of maggots to cleanse wounds andprevent infection was made by Larrey, a military surgeon to Napoleon, whoreported that when these creatures accidentally developed in woundssustained in battle, they prevented the development of infection andaccelerated the process of wound healing2

The Foot in Diabetes, 3rd edn Edited by A J M Boulton, H Connor and P R Cavanagh.

& 2000 John Wiley & Sons, Ltd.

The Foot in Diabetes Third Edition.

Edited by A.J.M Boulton, H Connor, P.R Cavanagh

Copyright  2000 John Wiley & Sons, Inc ISBNs: 0-471-48974-3 (Hardback); 0-470-84639-9 (Electronic)

During the First World War, Baer, an American orthopaedic surgeon, alsoobserved the cleansing action of maggots in extensive traumatic injuries.Some 10 years later, when Clinical Professor of Orthopaedic Surgery at theJohns Hopkins Medical School, he remembered this experience and began

to use maggots to treat cases of intractable osteomyelitis He found that thewounds of many of his patients, which had failed to respond to all othertherapies, healed within 6 weeks with the continued application of thelarvae3 As a result of Baer's work, the clinical use of maggots becamecommonplace in the USA during the 1930s4 and remained so for about adecade until the development of antibiotics offered an easier and moreaesthetically acceptable form of treatment for serious wound infections

In recent years, however, multiresistant strains of bacteria such asStaphylococcus aureus (MRSA) have evolved The clinical problems caused

by these organisms, combined with a general recognition that conventionaldebriding agents are of limited ef®cacy in the management of problem orpotentially limb-threatening wounds such as those on the diabetic foot,have caused some practitioners to revert to the use of maggots, often withimpressive results

The revival of larval therapy began in the USA in 1983 when Sherman et

al5used maggots for treating pressure ulcers in persons who had sufferedspinal cord injuries This was followed by further reports of the use of larvaltherapy in podiatry6 and recurrent venous ulceration7

In the UK, sterile larvae under the brand name of LarvE are produced inthe Biosurgical Research Unit in South Wales8 Over a 4 year period, about

10 000 containers of sterile larvae have been supplied by this unit to about

700 centres, mainly in the UK, but also in Sweden, Germany and Belgium Asigni®cant proportion of these larvae has been used in the treatment ofwounds associated with diabetes These vary in size from small neuropathiculcers to more serious infected wounds involving one or more toes9,10 aswell as wounds such as leg ulcers and pressure sores8,9,11±13

A particularly graphic account of the use of larvae in the management ofdiabetic patients with extensive ulceration of the feet was published byRayman et al14 These initial reports of the value of larval therapy are nowbeing tested in randomized controlled trials to compare larvae withconventional treatments in the management of different types of necroticwounds

Treatment times vary according to the severity of the wound and thenumber of larvae applied A small wound may only require one applicationlasting 3 days, but for more extensive wounds containing large amounts ofnecrotic tissue additional treatments may be required Experience suggeststhat the continued application of larvae to a chronic or indolent woundfollowing complete debridement will help to prevent further infection andmay actually promote healing Although larvae are generally applied to

cleanse wounds in order to promote healing, they have also been used toimprove the quality of life for terminally ill patients, for whom healing isnot a realistic option In such situations it has been reported that they mayeliminate odour and reduce wound-related pain One paper describes howlarvae used in this way removed extensive amounts of necrotic tissue,including the toes, from a terminally ill gentleman with diabetes15.

FLIES USED IN LARVAL THERAPYThe maggots used clinically are the larvae of Lucilia sericata a member of thefamily Calliphoridae, also classi®ed as higher Diptera (Muscamorpha)16.The adult insects are a metallic coppery green colour, hence the commonname, ``greenbottles'' They are facultative parasites, able to develop both

on carrion and live hosts In some animals such as sheep, greenbottle larvaeproduce serious woundsÐa condition known as sheep-strikeÐbut inhuman hosts the larval enzymes appear able only to attack dead or necrotictissue

The life cycle of the insect involves four stages; the egg, the larval form,the pupa (in its puparium) and the adult Adult ¯ies lay their eggs directlyonto a food source and these hatch within about 18±24 hours, according totemperature, into larvae 1±2 mm long These larvae immediately begin tofeed using a combination of mouth hooks and proteolytic secretions andexcretions If conditions are favourable, the larvae grow rapidly, moultingtwice before reaching maturity The full-grown larvae, some 8±10 mm long,stop feeding and search for a dry place to pupate and complete the life cyclewith the emergence of a new adult ¯y

Sterile larvae for clinical use are collected in the laboratory from eggs theouter surface of which have treated to remove the very high numbers ofbacteria that are normally present The absence of micro-organisms on thesenewly hatched larvae is subsequently con®rmed by a sterility test

MODE OF ACTION OF STERILE LARVAE

Maggots remove dead tissue by means of complex mechanisms whichinvolve both physical activity and the production of a broad spectrum ofpowerful enzymes that break down dead tissue to a semi-liquid form,which is then ingested by the larvae Young et al17showed that the range ofmolecules secreted by larvae is complex and dynamic, changing quitedramatically over a short time frame of a few days The majority of theseagents belong to the serine class of proteases and some are developmentallyregulated

In order to maximize the ef®ciency of their extra-corporeal digestiveprocess, larvae tend to congregate into groups, feeding in the head-downposition, concentrating initially on small defects or holes in the tissue.

In human wounds it is believed that the enzymes produced by Luciliasericata are inactivated by enzyme inhibitors in healthy tissue which are notpresent in necrotic tissue or slough Some evidence for this hypothesiscomes from the observation that if a signi®cant quantity of larval enzymesare allowed to escape from the area of the wound and spread onto thesurrounding skin, they can cause severe excoriation, eventually penetratingright through the keratinized epidermal layer Once the enzymes breach theepidermis, however, no further damage occurs9 It is therefore assumed thatthe enzymes are inactivated at this point by proteolytic enzyme inhibitors inthe dermis

The mechanisms by which larvae prevent or combat infection are alsocomplex Pavillard, in 195718, demonstrated that secretions of larvae of theblack blow¯y contained an antibiotic agent that, when partially puri®edand injected into mice, protected them from the lethal effects ofintraperitoneal injection with a suspension of Type 1 pneumococci It hasbeen shown in studies conducted in the author's laboratory that activelyfeeding larvae produce a marked increase in the pH of their localenvironment, which is suf®cient to prevent the growth of some pathogenicGram-positive bacteria Furthermore, it has been shown that other bacteriawhich are not susceptible to pH changes within the wound are ingested byfeeding larvae and killed as they pass through the insects' gut19

The early literature contained numerous references to the fact thatmaggots appeared to stimulate the production of granulation tissue3,20,21,and this effect has also been noted in more modern studies There are anumber of possible explanations for this observed effect Prete22 demon-strated the existence of intrinsic ®broblast growth-stimulating factors in thehaemolymph and alimentary secretions of maggots which may have somestimulatory effects in vivo It may also be that the presence of the larvae, ortheir metabolites, stimulates cytokine production by macrophage cellswhich initiate or potentiate the in¯ammatory response within the woundand thus enhance the ability of the body to resist the development ofinfection and initiate healing

LARVAE: METHOD OF USEVarious techniques have been described for retaining larvae in a wound7,12

In the main these rely upon the use of a piece of sterile net anchored to asuitable substrate applied to the area surrounding the wound to form asimple enclosure A simple absorbent pad completes the dressing system.The adhesive substrate, which may consist of a hydrocolloid dressing, a

zinc paste bandage or some other suitable alternative, ful®ls threeimportant functions It provides a sound base for the net, protects theskin from the potent proteolytic enzymes produced by the larvae, andprevents any tickling sensation caused by the larvae wandering over theintact skin surrounding the area of the wound If larvae are applied to orbetween the toes, it is prudent to protect the areas between the adjacent toeswith small amount of alginate ®bre to absorb any excess secretions.The outer absorbent dressing can be changed as often as required and,because the net is partially transparent, the activity of the larvae can bedetermined without removing the primary dressing As a rule of thumb,about 10 larvae/cm2 should be introduced into a small wound (a circularwound 35 mm in diameter has an approximate area of 10 cm2 and couldtherefore be treated with about 100 larvae) The fully grown larvae aregenerally removed from the wound after 2±3 days.

Studies have shown that larvae are unaffected by the concurrentadministration of systemic antibiotics23 but residues of hydrogel dressingswithin the wound may have an adverse effect upon their development24.Unpublished studies have shown that larvae appear to be unaffected by X-rays and therefore do not need to be removed if a patient requires such aninvestigation

CONCLUSIONSLarvae are living chemical factories that produce a complex mixture ofbiologically active molecules, many of which have yet to be fullycharacterized Long-term clinical experience with maggots in wounds hasbeen extremely positive and the wealth of recorded observationsconcerning the ability of these creatures to debride wounds and stimulatehealing are gradually beginning to be substantiated by structured clinicalinvestigations It has also been shown that the use of larvae produces awound bed that is very suitable for grafting

Whilst some patients ®nd the use of larvae unacceptable, generally there

is much less resistance to this form of treatment than might have beenexpected Some medical and nursing staff initially ®nd the idea distasteful

or consider that it represents an outmoded or unacceptable form of therapy,but once they have seen the bene®ts of larval therapy at ®rst hand manybecome enthusiastic converts

Although larval therapy has been used for all types of chronic wounds,the technique is of particular value in the treatment of the diabetic foot Thelarvae are frequently able to remove all traces of necrotic tissue andeliminate wound infections in a fraction of the time taken by conventionaltherapies The procedure may often be carried out in the patient's own

home, thus reducing or eliminating the need for hospitalization, withimportant implications for overall treatment costs.

At the present time larval therapy is regarded by some as a treatment of

``last resort'' For this reason it is only offered to patients when all otheroptions have been exhausted and when some form of amputation isconsidered inevitable If the technique were to be applied at an earlier stage,

it might prevent relatively small isolated areas of infection extending tothreaten a foot or even an entire limb

11 Thomas S A wriggling remedy Chem Ind 1998; 17: 665±712

12 Thomas S, Jones M, Andrews M The use of larval therapy in woundmanagement J Wound Care 1998; 7: 521±4

13 Thomas S, Jones M, Shutler S, Andrews A Wound care All you need to knowabout maggots Nursing Times 1996; 92: 63±6, 68, 70 passim

14 Rayman A, Stans®eld G, Woolard T, Mackie A, Rayman G Use of larvae in thetreatment of the diabetic necrotic foot Diabet Foot 1998; 1: 7±13

15 Evans H A treatment of last resort Nursing Times 1997; 93

16 Crosskey RW Introduction to the Diptera In Lane RP, Crosskey RW (eds),Medical Insects and Arachnids London: Chapman & Hall, 1995

17 Young AR, Mesusen NT, Bowles VM Characterisation of ES products involved

in wound initiation by Lucilia cuprina larvae Int J Parasitol 1996; 26: 245±52

18 Pavillard ER, Wright EA An antibiotic from maggots Nature 1957; 180:916±17

19 Robinson W, Norwood VH Destruction of pyogenic bacteria in the alimentarytract of surgical maggots implanted in infected wounds J Lab Clin Med 1934;19:581±6

20 Fine A, Alexander H Maggot therapyÐtechnique and clinical application JBone Joint Surg 1934; 16: 572±82.

21 Buchman J, Blair JE Maggots and their use in the treatment of chronicosteomyelitis Surg Gynecol Obstet 1932; 55: 177±90

22 Prete P Growth effects of Phaenicia sericata larval extracts on ®broblasts:mechanism for wound healing by maggot therapy Life Sci 1997; 60: 505±10

23 Sherman RA, Wyle FA, Thrupp L Effects of seven antibiotics on the growthand development of Phaenicia sericata (Diptera: Calliphoridae) larvae J MedEntomol 1995; 32: 646±9

24 Thomas S, Andrews A The effect of hydrogel dressings upon the growth oflarvae of Lucilia sericata J Wound Care 1999; 8: 75±7

15 The Role of Radiology in the Assessment and Treatment

of the Diabetic Foot

JOHN F DYET, DUNCAN F ETTLES and

ANTHONY A NICHOLSON

Hull and East Yorkshire Hospitals NHS Trust, Hull, UK

Radiology has an important role in the diagnosis of the underlying bonyabnormalities encountered in the diabetic foot Whilst plain ®lm radio-graphy will demonstrate the basic bone pathology, newer modalities such

as magnetic resonance imaging (MRI) add a further dimension by beingable to detect dynamic changes The interventional radiologist is able to useendovascular techniques to improve the blood supply to the diabetic foot,which is often affected by ischaemia

PATHOGENESISRadiological manifestations in diabetic foot disease result from acombination of neuropathy, infection and vascular disease, all of whichare present to a greater or lesser extent in diabetic foot problems Thedisease affects all parts of the diabetic foot, including skin, soft tissues,muscles, blood vessels and bones It is the neuropathy which is thefoundation upon which the other aspects of the diabetic foot aresuperimposed

The severity of the bone disease in the absence of osteomyelitis is due tothe neuropathy1 It is generally believed that loss of sensation allowsrepeated minor trauma The patient continues to weight bear, so leading toThe Foot in Diabetes, 3rd edn Edited by A J M Boulton, H Connor and P R Cavanagh.

& 2000 John Wiley & Sons, Ltd.

The Foot in Diabetes Third Edition.

Edited by A.J.M Boulton, H Connor, P.R Cavanagh

Copyright  2000 John Wiley & Sons, Inc ISBNs: 0-471-48974-3 (Hardback); 0-470-84639-9 (Electronic)

progressive joint destruction This is accelerated by sympathetic tion of small blood vessels causing hyperaemia, which in turn causesincreased osteoclastic activity with bone resorption, thus weakening thebone structure2.

denerva-Atheromatous vascular disease is approximately four times morecommon in diabetic patients than in the non-diabetic population3and thepattern of vascular disease is also different In non-diabetic patients, disease

in the femoral and popliteal arteries is most common, followed by disease

in the aorto-iliac segment In patients with diabetes, multiple stenoses andocclusions in the popliteal and tibial arteries occur most frequently, withrelative sparing of the vessels around the ankle and foot4,5 Anothercharacteristic of diabetic vascular disease is MoÈnckeberg's medialcalci®cation, which is found in the intermediate-sized vessels and isthought to be caused by autonomic denervation The affected artery hasbeen likened to a lead pipe which is non-compressible (Figure 15.1)

DIABETIC OSTEOPATHY AND NEUROARTHOPATHY

``Diabetic osteopathy'' is the term commonly used to describe the bonechanges in the neuropathic foot that are usually associated with jointdestruction (neuro-arthropathy) Bone changes associated with primaryneuro-arthropathy are most common in the phalanges and metatarsals,although the tarsal bones and ankles may also be involved Whilst it is theolder age group (60+) who are most commonly affected, the youngerpatient is not immune6

Figure 15.1 Calci®cation in the anterior tibial artery at the ankle

The early radiographic signs are those of soft tissue swelling with jointeffusion This may be followed by mild subluxation and peri-articularfractures (Figure 15.2a) As the process worsens, subluxation and frankosteoclastic destruction predominate (Figure 15.2b) Attempts at healingwith periosteal new bone formation may cause the bones to have a scleroticappearance (Figure 15.3) Eventually the peri-articular surfaces becomecompletely resorbed due to excessive osteoclastic activity, and the resultingappearance has been described variously as a pencil-like deformity, suckedcandy, and wax running down a burnt candle (Figures 15.2b and 15.3).Resorptive changes predominate in the metatarsals and phalanges, whereas

in the tarsal bones and ankle the changes are mainly destructive Thedestruction causes a deranged and unstable joint (Figures 15.3 and 15.4).Synonyms for the process include neuro-osteoarthropathy and Charcotjoint7

INFECTIONSoft tissue infection is always a possibility where ulceration and ®ssuringare found in the diabetic foot Direct spread of infection to the adjacent bone(Figure 15.5) and/or joint may occur, leading to osteomyelitis and septic

Role of Radiology in Assessment and Treatment 195

Figure 15.2 Bony changes as a result of diabetic neuroarthopathy (a) There arefractures at both ends of the shaft of the proximal phalanx of the fourth toe There ispartial erosion of the distal phalanges of the fourth and ®fth toes (b) The middle anddistal phalanges of the fourth toe have been amputated The proximal phalanx nowshows the classical ``sucked candy'' appearance

arthritis Plain ®lm radiography is poor at differentiating betweenneuropathic changes and neuropathy plus osteomyelitis Both processescause bone resorption with cartilage and joint destruction The presence ofinfection may lead to more abundant periosteal reaction and also moremarked soft tissue swelling8 Other factors that may help in diagnosis arethe fact that changes may be localized to one site and an adjacent soft tissueulcer may be visible (Figure 15.6).

Because of the dif®culty of diagnosing osteomyelitis on plain ®lmradiography, other techniques have been employed Bone scintigraphy,using the isotope99mTc-MDP, has been useful in helping to differentiate theearly changes of osteomyelitis from uncomplicated neuropathic changes9

Figure 15.3 Diabetic neuroarthopathy There is destruction of most of thephalanges The heads of the second and third metatarsals are also destroyed Theupper ends of their shafts are sclerotic, and the appearance on the second metatarsal

is like wax running down a candle The ®rst metatarsophalangeal joint isdisorganized (the so-called Charcot joint)

However, in their article, Yuh et al2 found that due to lack of spatialresolution and the coexistent neuropathy, scintigraphy proved less thanreliable In their series of 29 patients in whom pathological specimens hadbeen obtained, only MRI accurately diagnosed the presence or absence ofinfection in all cases Scintigraphy proved to give a high false-positive ratefor the presence of infection The MRI studies showed a normal bonemarrow signal in the absence of infection but a high signal intensity inosteomyelitis (Figure 15.7) However, studies with leucocyte scans usingindium (111In oxyquinoline) were also shown to be superior to bonescintigraphy and radiology, with a sensitivity of 89%10.

MAGNETIC RESONANCE IMAGINGEarly and accurate diagnosis of infection or neuropathy is the key tosuccessful management of the diabetic foot In addition, it is essentialthat developing angiopathy be treated early in order to avoid ischaemia.This requires high quality imaging of the arterial supply to the leg andfoot Spin echo MRI combined with 2D time-of-¯ight sequences can

Role of Radiology in Assessment and Treatment 197

Figure 15.4 Diabetic neuroarthopathy involving the second to ®fth tarso-metatarsaljoints

provide all this information The time-of-¯ight sequences look at blood

¯ow rather than blood vessels Thus, blood ¯owing in both arteries andveins is imaged Because this would be confusing, a system of saturationbands is used in order that the blood returning to the heart (i.e venous

Figure 15.5 Infection in diabetic neuropathy (a) A soft tissue ulcer can be seen andthere is erosion of the adjacent bone There is no periosteal reaction (b) One monthlater, the erosion is much more extensive, suggesting infection, but there is still noperiosteal reaction

Figure 15.6 Infection in diabetic neuropathy (a) There is an obvious soft tissueulcer but the underlying bone is not obviously infected (b) The ulcer has now healedbut marked periosteal thickening of the underlying bone indicates that it wasinfected

blood) is presaturated, such that on exposure to the radiofrequency pulses,

no return signal is produced As discussed above, distinguishingosteomyelitis and neuro-arthropathy frequently presents a clinical andradiological challenge in diabetic patients In osteomyelitis, signal intensitychanges in the bone marrow (low signal on T1- and high signal on T2-weighted images (Figure 15.7), associated occasionally with cortical lesionsand often with soft tissue abnormalities Decreased signal in bone,regardless of pulse sequence or no signal change, is the characteristic ofchronic neuro-arthropathy However, patients with acutely evolvingneuropathy can have signal intensity changes in the marrow, which can

be a source of diagnostic error The use of contrast agents such asgadolinium dimeglumine has not been shown to be helpful in distinguishingbetween osteomyelitis and neuro-arthropathy11 Although the later stages ofosteomyelitis may produce a soft tissue mass, this is not seen in the ®rstweek Similarly, cortical changes can take 7±10 days to become visible onplain radiographs, and although seen earlier by MRI, do not help acutely.Despite this potential pitfall, the diagnostic sensitivity, speci®city andaccuracy of MRI has been shown to be 88%, 100% and 95% respectively12.This compares with plain radiography (22%, 94% and 70%), technetiumbone scanning (50%, 50% and 50%) and labelled white cell studies (33%,60% and 58%) from the same study In addition, MRI accurately delineates

Role of Radiology in Assessment and Treatment 199

Figure 15.7 Magnetic resonance imaging in infection A transverse image takenthrough the heads of the metatarsals The head of the ®fth metatarsal gives a veryhigh-intensity signal, indicating infection

the limits of the infection, reducing the incidence of recurrent infection postsurgery This makes MRI extremely cost effective13.

Magnetic resonance angiography is a useful non-invasive tool in theassessment of foot vessel run-off, especially when there are proximalarterial occlusions limiting the diagnostic value of angiography (Figure15.8) The use of warm water baths to vasodilate the arterial run off to thefeet further enhances the diagnostic quality of the images14 However,unlike plain radiographs, MRI gives no clue about arterial calci®cation,which is important to the surgeon, although less so to the vascularradiologist In the future it is likely that magnetic resonance protonspectroscopy will provide information about the microvasculature of thediabetic foot

Figure 15.8 Magnetic resonance (MR) angiography Time-of-¯ight MR imagesshowing a distal peroneal artery that was not visible on digital subtractionangiography