Neurology International 2009; volume 1:e7

Amyloid myopathy:a diagnostic challengeHeli Tuomaala,1,2 Mikko Kärppä,1Hannu Tuominen,3 Anne M. Remes,1,2

1Department of Neurology, University ofOulu, 2Clinical Research Center, OuluUniversity Hospital, 3Department ofPathology, University of Oulu, Oulu,Finland

Abstract

Amyloid myopathy (AM) is a rare manifesta-tion of primary systemic amyloidosis (AL).Like inflammatory myopathies, it presentswith proximal muscle weakness and anincreased creatine kinase level. We describe acase of AL with severe, rapidly progressivemyopathy as the initial symptom. The clinicalmanifestation and muscle biopsy were sugges-tive of inclusion body myositis. AM was notsuspected until amyloidosis was seen in thegastric mucosal biopsy. The muscle biopsy wasthen re-examined more specifically, and Congored staining eventually showed vascular andinterstitial amyloid accumulation, which led toa diagnosis of AM. The present case illustratesthe fact that the clinical picture of AM canmimic that of inclusion body myositis.

Introduction

Primary systemic amyloidosis (AL) is a raredisease. Its typical presentations are nephroticsyndrome, cardiomyopathy, peripheral neu-ropathy and hepatomegaly.1,2 One uncommonmanifestation is amyloid myopathy (AM), thesymptoms of which are usually non-specific,typically including progressive proximal weak-ness with an increased creatine kinase (CK)level, macroglossia and muscle pseudohyper-trophy.3,4,5 Muscle weakness is atypical as theinitial symptom of the disease.1,6 The diagnosisof AM is usually overlooked and it is often mis-diagnosed as inflammatory myopathy, evenwhen a muscle biopsy is available.7 When sus-pecting AM, Congo red staining and animmunohistochemistry or immunofluoresenceassay should be performed. Furthermore, theuse of MRI for evaluating neuromuscular dis-orders and inflammatory myopathies hasbecome increasingly common, especially incases of polymyositis.8,9 We present here a caseof AL with severe and rapidly progressivemyopathy as the initial symptom.

Clinical summary

The patient was a 65-year-old man with ahistory of hypertension and obesity (weight144 kg) who presented with proximal muscleweakness in the legs and a 35 kg weight loss.No familial occurrence of muscle diseases wasreported. At the first clinical examination aftertwo years of experiencing fatigue, the patientshowed slight proximal muscle weakness cor-responding to 4/5 on the Medical ResearchCouncil (MRC) scale and minor weakening ofthe tendon reflexes but was able to walk with-out support. Muscle weakness progressedwithin six months, however, forcing thepatient to use a walking aid. He then had grade3 symptoms on the MRC scale in the shouldergirdle and bilaterally in the thigh muscles, withgrade 4 in the distal hand and leg musclegroups. In addition, the new findings includedmild dysphagia, macroglossia and an absenceof tendon reflexes. No muscle atrophy wasestablished and sensory functions were intact.The results of brain MRI and a cerebrospinalfluid analysis were normal. Laboratory findings included elevated serum

creatine kinase (CK) and serum aldolase lev-els (Table 1). Liver function tests were abnor-mal, but MCV was slightly elevated. Serumtransferrine, protein electrophoresis andimmunofixation findings were normal, whilstserum ferritine was elevated. The plasma albu-min level was low, and marked proteinuria wasobserved. An electromyography (EMG)revealed proximal fibrillation and motor unitpotentials of short duration, low amplitude anda polyphasic character and insertional activity.The myopathy specific EMG findings arousedsuspicions of inclusion body myositis andpolymyositis. The patient had arrhythmicepisodes of supraventricular tachycardia(SVT), and a chest X-ray film showed cardiacdilatation. Echocardiography revealed markedleft ventricular hypertrophy. The ejection frac-tion was 55%, and the myocardium was slight-ly abnormal, indicating muscle disease. Muscle magnetic resonance imaging (MRI)

was performed with T1, short tau inversionrecovery (STIR) and T2 FAT SAT axial projec-tions (Figure 1). Axial T2 fat suppression mag-netic resonance imaging of the thighs showeda mildly increased signal intensity in the pos-terior muscles, while coronal T2 fat suppres-sion magnetic imaging showed a coarse retic-ular pattern in the subcutaneous fat of thelower extremities. A left vastus lateralis mus-cle biopsy showed mainly non-specificchanges, but there was some evidence sugges-tive of inclusion body myositis. An abdominalultrasonography showed the presence of aslightly clear liver. The abdominal CT resultswere normal. The provisional diagnosis at thisstage was considered to be inclusion body

myositis. A gastroscopy was performed onaccount of elevated liver enzymes and a suspi-cion of celiac disease, and biopsies from theduodenum, antrum and corpus revealed dif-fuse mucosal, submucosal and vascular amy-loid accumulation. The histological findingsconformed to primary amyloidosis. Immuno-fixation of serum and urine also revealed aminimal amount of lambda light chains. Theamount of plasma cells in a bone marrow biop-sy was normal. In view of the gastric biopsyfindings and the diagnosis of primary amyloi-dosis, the muscle biopsy was re-examinedmore specifically. Congo red staining eventual-ly showed vascular and extracellular amyloidaccumulation, which led to a diagnosis of AM.Despite the gastrointestinal changes, thepatient did not have any clinical symptoms ofthis.After the IBM diagnosis, the patient was

treated with prednisone 100 mg/day for twomonths and then at a decreasing dosage forthree months. Since the muscle weakness hadmarkedly progressed in spite of this pred-nisone medication, the treatment was stoppedafter five months. Immunoglobulin 0.4 mg/kgi.v. was given for five days, leading to a minorimprovement in muscle strength, so that the

Correspondence: Anne M. RemesDepartment of Neurology, University of Oulu,Box 5000, FIN-90014 Oulu, FinlandE-mail: anne.remes@oulu.fi

Key words: amyloid myopathy, amyloidosis, congored, magnetic resonance imaging, myopathy

Acknowledgments: this work was supportedfinancially in part by grants from the FinnishMedical Foundation (AMR) and the Päivikki andSakari Sohlberg Foundation (AMR).

Contributions: HT participated in designing thestudy and drafted the manuscript, MK participat-ed in examining the patient, designing the studyand revising the manuscript, and HT carried outthe neuropathological examinations and helpedto revise the manuscript. AMR participated indesigning and coordinating the study and helpedto draft the manuscript. All the authors have readand approved the final manuscript.

Conflict of interest: the authors reported no poten-tial conflicts of interests.

Received for publication: 26 February 2009.Revision received: 8 June 2009.Accepted for publication: 11 June 2009.

This work is licensed under a Creative CommonsAttribution 3.0 License (by-nc 3.0)

©Copyright H. Tuomaala et al., 2009Licensee PAGEPress, ItalyNeurology International 2009; 1:e7doi:10.4081/ni.2009.e7

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treatment was repeated three times monthly.oral melphalan and prednisone treatment wasalso started after the diagnosis of amyloidmyopathy, the total target dose of melphalanbeing 740 mg, while prednisone was given 100mg p.o. once a day for four days. Only a minorresponse to the medication was seen as far asthe progression of muscle weakness and othersymptoms during one year of follow-up wasconcerned. The patient died of pneumonia atthe age of 69 years. No autopsy was performed.

Pathological findings

The first examination of the left vastus lat-eralis muscle biopsy showed changes sug-gesting neurogenic atrophy, regeneration andsome rimmed vacuoles. NADH-Tr andtrichrome staining results were normal, butSDH-COX staining revealed some COX-nega-tive fibers. No MCH-class I upregulation wasseen on the muscle membranes nor any fibernecrosis. Although the muscle biopsy findingswere mainly non-specific, there was some evi-dence suggestive of inclusion body myositis. A gastroscopy was performed later on

account of elevated liver enzymes and a suspi-cion of celiac disease, and duodenum, antrumand corpus biopsies revealed diffuse mucosal,submucosal and vascular amyloid accumula-

tion which was resistant to potassium per-manganate digestion. An immunohistochemi-cal assay was negative for amyloid A, but theaccumulation was positive for lambda lightchain staining. The histological findings con-formed to primary amyloidosis. The numberof plasma cells in a bone marrow biopsy wasnormal. In view of the gastric biopsy findingsand the diagnosis of primary amyloidosis, themuscle biopsy was examined again morespecifically. Congo red staining eventuallyshowed vascular and extracellular amyloidaccumulation, which led to a diagnosis of AM(Figure 2). An immunohistochemical assayfor amyloid A was negative, and kappa andlambda light chain stainings were inconclu-sive.

Discussion

The first recognised patient presenting withamyloid involvement in muscle, the conditionknown as AM, was reported by Lubarsch in1929,10 and it has now been reported in three ofthe largest series that myopathy is rarely causedby amyloidosis.1,4,6,7 The symptoms of AM are usu-ally non-specific, including progressive proximalweakness with an elevated creatine kinase level,macroglossia and muscle pseudohypertrophy asthe typical features.3,4,5 We described a case of ALwith severe, rapidly progressive myopathy as theinitial symptom. The patient had suffered frommild muscle weakness for 2.5 years, followed by arapid progression of the condition and the onset

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Table 1. Abnormal laboratory test findings.

Laboratory test Laboratory values Reference values

S-CK (U/L) 1900-2200 40-280 (for men)S-aldolase (U/L) 18 <5 E-MCV (fL) 100-106 82-98 P-albumin (g/L) 24-35 36-45 U-protein (mg/L) 2100 <200 S- ferritine (ug/L) 797 20-250 P-ALAT (U/L) 90-196 10-70P-GT (U/L) 242-1284 15-115

Figure 1. (a) Axial T2 fat suppression mag-netic resonance imaging of the patient’sthighs. Mildly increased signal intensity isvisible in the posterior muscles. (b) CoronalT2 fat suppression magnetic imaging showa coarse reticular pattern in the subcuta-neous fat of the lower extremities.

Figure 2. (a) Biopsy of the vastus lateralis muscle shows the vascular wall and an intersti-tial accumulation of amyloid (Congo red), (b) expression of neonatal myosin in atroph-ic cells (myosin heavy chain neonatal immunoperoxidase staining, original magnificationx 20), (c) a COX-negative fiber (succinate dehydrogenase – cytochrome oxidase doublestaining) and (d) a duodenal mucosal biopsy containing amyloid (Congo red). Scale bar100 µm (figure a-c), 200 µm (figure d).

of other clinical symptoms such as dysphagia andmacroglossia. Visceral manifestations of AL,including cardiomyopathy, nephropathy and gi-changes, were also observed. Weakness of kneeextensors with absent knee reflexes was promi-nent in the early course of the disease suggest-ing the diagnosis of IBM although distal involve-ment in the hands was observed later.Although amyloid myopathy is a well-

described disorder, it is often overlooked, for tworeasons: first, it is rarely observed clinically, andsecond, a broad span of differential diagnoses isneeded. It is usually misdiagnosed as inflamma-tory myopathy, even given a muscle biopsy, asseen here and reported by others. Three cases ofAM mimicking polymyositis have been reportedlately, all showing similarities in clinical, neuro-physiological and muscle biopsy findings whenstained only with hematoxylin-eosin. In all threecases, the original muscle biopsy samples wereanalyzed retrospectively with Congo red staining,which led to a proper diagnosis of AM.6,11,12

Furthermore, Spuler et al. found that the routineuse of Congo red-stained sections increased thefrequency of a diagnosis of AM 10-fold. The pres-ent case illustrates the difficulty of differentiat-ing AM from inflammatory myopathies: the firstsuspected diagnosis was inclusion body myositis.The presence of neonatal myosin in some fibersreflects the immaturity/regenerative activity ofthe muscle and is a sign of a pathological state inthe muscle. COX-negative fibers are a commonfinding in IBM, but non-specific, as they areoften seen in the muscle of aged people. AM wasnot suspected until amyloidosis was seen in thegastric mucosal biopsy. Congo red staining even-tually showed vascular and extracellular amyloidaccumulations in the original muscle biopsy sec-tions, which led to a diagnosis of AM. The use ofMRI for the evaluation of inflammatorymyopathies and neuromuscular disorders hasbecome increasingly common, especially incases of polymyositis,8,9 and its usefulness for

diagnosing AM has also been described.11 Hull etal. reported a case of a patient with the occur-rence of abnormal subcutaneous fat in MRI andincreased T2 signal intensity and minimal signalintensity alternation in the muscles, and estab-lished that these findings coupled with minimalmuscular involvement constituted a uniqueguide to a proper diagnosis of primary AM. Thisis consistent with the previous MRI findings in 2patients described by Metzler et al. In particular ahypointense reticular appearance for the subcu-taneous fat in MRI distinguishes AM from manyother neuromuscular conditions.12,13 Further-more, in the case of the patient described by Hullet al., MRI also revealed decreased T1 signalingin the bone marrow, suggesting hematologicmalignancies. In the present case the muscleMRI revealed evidence suggestive of atrophy andoedema in the muscles of the hips, thighs andcalves. Nevertheless, as noticed after thepatient’s death, the MRI had been performedwithout using a muscle-specific protocol, so thatthe finding remained inconclusive. In summary,we have reported here on a well-described case ofthe rarely occurring disease AM. This casedemonstrates that AM can masquerade as IBM,which is known to be a more common disorder.The inflammatory myopathies are increasinglybeing evaluated using MRI, which can be of prac-tical significance in differentiating AM fromother muscle diseases, targeting affected mus-cles for biopsy and assessing disease activity.12 Inaddition, MRI is of use when performed with anappropriate muscle-specific protocol. To clarifythe etiological diagnosis of myopathy, however,Congo red staining and immunohistochemicaltesting should be performed.

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