MASTERCLASS

An unexpected cause of muscle pain in diabetes

L Silberstein, K E Britton, F P Marsh, M J Raftery, D D’Cruz

AbstractDiabetic muscle infarction is a rarecondition which may present to a rheuma-tologist. It was first reported in 1965. Twoillustrative cases are described here andthe mechanisms of pathogenesis dis-cussed. Analysis of the published data,results of the muscle biopsies, and atechnetium-99m sestamibi scan suggestthat the condition, which occurs against abackground of diabetic microangiopathy,can be triggered by an ischaemic eventand causes extensive muscle necrosisthrough hypoxia-reperfusion injury andcompartment syndrome.(Ann Rheum Dis 2001;60:310–312)

Diabetic muscle infarction is a rare cause ofacute severe muscle pain in patients withdiabetes mellitus. The diVerential diagnosisincludes focal or systemic myositis, localisedabscess, haematoma, deep venous thrombosis,osteomyelitis, and a muscle tumour (sarcomaor lymphoma). We describe two illustrativepatients and discuss the investigations and pos-sible pathogenesis of this condition.

Case 1A 46 year old West Indian woman with a 14year history of type II diabetes mellituscomplicated by diabetic nephropathy and pro-liferative retinopathy presented to a localhospital with a painful swollen left leg after aninsulin injection into the left femoral canalarea. Deep venous thrombosis was excluded byDoppler ultrasound, and a computed tomogra-phy (CT) scan showed swelling of the left vas-tus medialis muscle. The erythrocyte sedimen-tation rate (ESR) was raised at 130 mm/1st h,antineutrophil cytoplasmic antibodies(ANCA), antinuclear antibodies (ANA), andrheumatoid factor were negative. Muscle bi-opsy showed chronic inflammation. She re-ceived treatment with steroids and antituber-culous drugs, but did not improve. Six weekslater she was transferred to this hospital forfurther assessment.

Clinically she was afebrile and markedlyoverloaded with fluid. There was swelling andtenderness of the left vastus medialis compart-ment and proximal weakness of the left leg.Investigations showed no neutrophilia, creatinekinase (CK) 202 IU/l (reference range 0–170IU/l), ESR 97 mm/1st h, and albumin 16 g/l. Arenal biopsy confirmed diabetic nephropathy.

She was given intravenous albumin and diuret-ics. Although no specific treatment for theswelling of the leg was prescribed, the symp-toms gradually improved. She did, however,develop contractures in the thigh musclesrequiring physiotherapy. At the time of dis-charge she could walk with a stick.

She presented again five months later with aone week history of painful swelling of theopposite thigh. On this occasion, there were noprecipitating factors. The medial compartmentof the right thigh was markedly swollen. Therewas no neutrophilia or CK rise. A CT scanshowed generalised swelling of the anterior andmedial groups of muscle and connective tissuefrom the pelvis distally.

The patient underwent surgical debridementof the mass. The sartorius muscle was necroticand was excised. Swollen but viable muscles inthe adductor and quadriceps compartmentswere noted. Histological examination showedwidespread necrosis. The vessels had lumenalstenosis and calcification consistent with long-standing diabetes.

In view of the worsening renal failure,peritoneal dialysis was started. She remainedwell for the next four years, but her conditionlater deteriorated and she died from a compli-cation of peritoneal dialysis.

Case 2A 55 year old Afro-Caribbean man with a 24year history of type II diabetes complicated byperipheral neuropathy, proliferative retinopa-thy, and nephropathy requiring continuousambulatory peritoneal dialysis (CAPD) pre-sented to his local hospital with a tender swell-ing on his left upper lateral thigh. Serial bloodand fungal cultures, cryoglobulins, ANA, anti-dsDNA, and ANCA were all negative. A biopsyshowed striated muscle exhibiting infarctionand infiltration by neutrophils. The arteriesshowed lumenal thrombosis and organisation,and small arterioles showed fibrinoid necrosis.Stains for bacteria and fungi were negative.The patient was given fusidic acid andflucloxacillin and gradually improved.

Two months later he re-presented with pain-ful well defined swelling in the left thigh. Creactive protein (CRP) on admission was 60mg/l (reference range 0–10 mg/l) and rose to105 mg/l one week later. He was given intra-venous flucloxacillin and ciprofloxacin for fourweeks, but failed to improve and the entiremass was excised. Histological findings were

Ann Rheum Dis 2001;60:310–312310

St Bartholomew’s andthe Royal LondonSchool of Medicineand Dentistry, London,UKL SilbersteinK E BrittonF P MarshM J RafteryD D’Cruz

Correspondence to:Dr D D’Cruz, The LupusResearch Unit, The RayneInstitute, St Thomas’sHospital, Lambeth PalaceRoad, London SE1 7EH,UK

Accepted 20 October 2000

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similar to the previous biopsy, but arteriolarfibrinoid necrosis was more marked.

Ten months later the patient was admittedwith pain and swelling of the opposite thigh,which had developed over a few weeks. Onexamination he had a large discrete swelling onthe lateral aspect of the right thigh which waswarm and exquisitely tender. He had a mildneutrophilia, markedly raised CRP of 132 mg/l,but normal CK. A plain x ray examination ofthe right hip was normal, apart from wide-spread vascular calcification. Doppler ultra-sound showed no evidence of a deep veinthrombosis. A magnetic resonance imaging(MRI) scan of the thighs showed an area ofincreased signal density in the right vastus lat-eralis compartment consistent with oedema ofthe muscle (fig 1). He was treated with intra-venous antibiotics and analgesia. His symp-toms gradually improved, he no longer re-quired opiates, and could walk with a stick. Atechnetium (Tc) labelled bone scan performed

two weeks after discharge showed increasedblood flow to the aVected area of the musclewith slightly increased tracer uptake in the softtissues and normal uptake in the skeletalsystem.

The patient was readmitted a month laterwith worsening pain in the right thigh. SerialCK measurements remained normal. He wasgiven a small dose of steroids and his conditionimproved. A 99mTc-sestamibi scan showedincreased vascularity at the lesion in the rightthigh, seen on the bone scan, and the presenceof living muscle (fig 2).

Over the next three months he was admittedseveral times with infection of the fascial spacesof the hand and CAPD peritonitis; he diedfrom the complications of diabetes.

DiscussionDiabetic muscle infarction is a rare complica-tion of diabetes, which should be suspected inany diabetic subject with atypical severemuscular pain. It was first described in 1965 byAngerall and Stener as a “tumoriform focalmuscular degeneration”1 and since then hasbeen reported in a total of 86 patients.1–33 Sixtyfive patients had type I diabetes, 19 patientshad type II diabetes, and in two patients thetype was not specified. The male/female ratiowas almost equal (44/42), with an age range of19–81 years. Most patients had longstandingdiabetes and extensive end-organ damage dueto microvascular disease.

The condition presents as an atraumaticswelling of the limb, commonly the thigh. Theonset of pain is usually gradual, but can besudden. The swelling is exquisitely tender. Itresolves within a few weeks, but frequentlyrecurs. The white cell count and the level ofCK are normal or slightly raised. Musclebiopsy typically shows large confluent areas ofmuscle necrosis and oedema.2 The best imag-ing results are with T2 weighted MRI scans,which have a fairly characteristic, but non-specific appearance showing the absence of adiscrete mass and increased signal within theaVected muscle.3

The diVerential diagnosis includes a muscletumour (sarcoma or lymphoma), localisedabscess, haematoma, focal or systemic myosi-tis, deep venous thrombosis, and osteomyelitis.The management should include bed rest,analgesia, tight metabolic control, and physio-therapy.2 4

Various mechanisms of pathogenesis havebeen proposed. Earlier reports focused on dia-betic microangiopathy, atheromatosis,1 andembolisation of atheromatous material fromulcerated aortic plaques as the causes of muscleinfarction.5 In the presence of diabetic micro-vascular disease, a thromboembolic event ismore likely to lead to infarction because ofimpaired collateral circulation.6 However, laterreports showed that only a minority of caseshad a vascular occlusion which would corre-spond to the extent of muscle necrosis. Theabove concept was therefore modified, suggest-ing that an initial ischaemic event itself does

Figure 1 T2 weighted magnetic resonance image. Anincreased signal density in the right vastus lateralis musclecan be seen.

Figure 2 Dynamic 99mTc-sestamibi scan. Increased traceruptake at the site of the lesion in the right thigh is seen.

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not cause infarction but leads to it by produc-ing muscle oedema which increases the pres-sure within a fascial compartment and causesfurther ischaemia.7

We suggest that hypoxia-reperfusion injurymay have an important role in the pathogenesisof diabetic muscle infarction. The likelysequence of events leading to muscle necrosis isas follows. Compartment syndrome, precipi-tated by a small thrombotic/embolic event orintramuscular insulin injection, produces is-chaemic muscle damage. This leads to a potentinflammatory response, hyperaemia, and reper-fusion with generation of reactive oxygenspecies causing further muscle damage, bothdirectly and through worsening of the com-partment syndrome due to muscle oedema.Thus there is a “vicious circle” which eventu-ally results in extensive muscle necrosis. It is ofnote that a Tc labelled bone scan in case 2confirmed the presence of hyperaemia, whichwas consistent with the findings of other inves-tigators.8 9 Although a 99mTc-sestamibi scanshowed the presence of a living muscle at thesite of the injury, it is possible that the “viciouscircle” was disrupted and the images weretaken before significant muscle necrosis hadoccurred. Interestingly, Jawed et al have shownthat cyclical hypoxia-reperfusion injury isresponsible for synovial damage in chronicinflammatory arthropathies as they are charac-terised by a rise in the intra-articular pressureabove the capillary perfusion pressure.10

The clinical features of our two patientsclosely resemble those of previously reportedcases. Both of them had longstanding diabeteswith retinopathy, neuropathy, and nephropathyrequiring CAPD. They both presented withtender recurrent swelling aVecting the musclesof the legs and improved with supportive treat-ment, though steroids may have contributed tothe recovery in the second patient. Thediagnosis was confirmed by a muscle biopsy,except for the last recurrence of the disease inthe second patient, when the procedure wasnot performed in view of the similar clinicalpresentation and characteristic MRI findings.

Diabetic muscle infarction is a rare conditionthat has become more frequently recognised inthe past few years. It should be suspected in apatient with a longstanding diabetes whopresents with a painful swollen limb. MRI is thebest imaging modality, but early core-needle oropen muscle biopsy at first presentation isessential to establish the diagnosis.

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