Br Heart J 1988;59:486-90

Cardiomyopathy in the Kearns-Sayre syndromeK S CHANNER, J L CHANNER, M J CAMPBELL, J RUSSELL REES

From the Departments of Cardiology, Histopathology, and Neurology, Bristol Royal Infirmary, Bristol

SUMMARY The Kearns-Sayre syndrome is a mitochondrial myopathy characterised by ptosis,chronic progressive external ophthalmoplegia, abnormal retinal pigmentation, and cardiac

conduction defects. A unique case is reported in which there was rapid development ofprogressivecongestive cardiac failure that required cardiac transplantation.A review of published reports of mitochondrial myopathy shows that a minority of cases (<

20%) have cardiac involvement. This had previously been limited to abnormalities of cardiacconduction with progressive heart block. Myocardial biopsy has, however, shown ultrastructuralevidence of a generalised mitochondrial disorder which hitherto has not been associated with a

functional deficit.

The association of external ophthalmoplegia, abnor-mal retinal pigmentation, and complete heart blockwas first reported by Kearns and Sayre in 1958,'although Sandifer had already described a case ofbundle branch block in association with externalophthalmoplegia.2 The high risk of sudden deathfrom the cardiac conduction defect in this syndromehas become less important with the development ofimplantable pacemakers, and prolonged survival hasbeen reported.' The aetiology of the condition isunknown but the pathology has only recently beenelucidated.

Several early necropsy studies did not showany specific abnormality of the myocardium.'4Endomyocardial biopsy also showed non-specificchanges-for example, interstitial fibrosis and hyper-trophy5 on light microscopy. Only on electronmicroscopy has any specific abnormality beendetected, namely glycogen accumulation andproliferation of abnormal mitochondria.3 5It is nowrecognised that the Keams-Sayre syndrome formspart of a heterogeneous group of mitochondrialcytopathies.67Although abnormalities of myocardial ultrastruc-

ture have been found in the Kearns-Sayre syndromethese have not been associated with myocardialdysfunction. We report a patient with Kearns-Sayresyndrome who presented with congestive cardiacfailure caused by dilated cardiomyopathy which wasso severe that heart transplantation was required.

Requests for reprints to Dr K S Channer, Cardiology Department,Bristol Royal Infirmary, Bristol BS2 8HW.

Accepted for publication 22 October 1987

Case report

INITIAL PRESENTATIONA 21 year old man presented with a two monthhistory of dry cough and progressive dyspnoea. Atthe time of admission he became breathless when heclimbed a single flight of stairs and he was orthop-noeic. He did not have chest pain. There was nohistory of a preceding influenza-like illness. In thepast he had had bilateral ptosis surgically correctedwhen he was 16 years old and had been investigatedfor abnormal retinal pigmentation (visual evokedresponses and electroretinograms were normal).He smoked 20 cigarettes a day and drank about 20

pints of beer a week. He had two siblings who werewell and there was no family history of note.He was plump and normally developed. The pulse

rate was 100 beats/minute with frequent extrasys-toles, and the blood pressure was 110/80 mm Hg.The jugular venous pressure was grossly elevated tothe level of his pinna and did not fall on inspiration.The apex was readily palpable in the 6th intercostalspace in the anterior axillary line, and auscultationshowed normal heart sounds. There was palpablehepatomegaly. Chest and neurological examinationappeared normal. Fundal examination showedabnormal pigmentation around the macula (fig 1).

INVESTIGATIONSFull blood count, blood sugar, thyroid function tests,and concentrations of fasting lipids, serum urea, andelectrolytes were all normal. Antinuclear factor andrheumatoid factor were negative. The concentrationof serum bilirubin was increased at 27 mmol/l(normal < 17 mmol/l), as was aspartate aminotrans-

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Cardiomyopathy in the Kearns-Sayre syndrome

Fig 1 Retinal photograph showing the typical "salt andpepper" retinal pigmentation of mitochondrial myopathy.

ferase activity at 41 units/l (normal 6-35 units/l).Alkaline phosphatase activity was normal. Chest xray showed pulmonary oedema with cardiomegaly(cardiothoracic ratio 17-8/30-6). The electrocar-diogram showed sinus tachycardia with ventricularextrasystoles and left axis deviation. Echocardiogra-

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phy showed biventricular dilatation and generalisedpoor function, but all the valves appeared to benormal. The isotope ventriculogram gave a cal-culated ejection fraction for the right ventricle of15% and 17% for the left ventricle. Twenty fourhour ambulatory electrocardiography showedfrequent ventricular extrasystoles and technical ven-tricular tachycardia (runs of three consecutiveextrasystoles).

COURSEA diagnosis of dilated cardiomyopathy was made andhe was treated with diuretics, enalapril, warfarin, andamiodarone. On this regimen the pulmonary oedemacleared and he became less breathless. Two monthslater, however, he deteriorated and was readmittedwith increasing dyspnoea, cough productive of pinkfrothy sputum, and lethargy. He had four pilloworthopnoea. On examination he was in severe con-gestive cardiac failure with bilateral pitting ankleoedema, high venous pressure, sinus tachycardia,and gallop rhythm.

Cardiac catheterisation at this time showed raisedright heart pressures with mean right atrial pressureof 24 mm Hg. Right ventricular pressure was 60/30and pulmonary artery pressure was 60/40 (mean of45mm Hg). Pulmonary wedge pressure was 38 mm Hgand left ventricular pressure was 78/30. Cardiacoutput was 2-9 I/min. During the catheterisation a 2:1

1,.1|

I' Leftward..e

w i d,, 1....g.or ......e

DwnwcLrd gaze'Fig 2 Limitation in the extent of eye movements by external ophthalmoplegia.

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atrioventricular block developed. During this secondadmission his voice weakened and a bovine coughdeveloped. Indirect laryngoscopy showed aparalysed left vocal cord which raised the possibilityof Ortner's syndrome.He was transferred to Harefield Hospital where an

urgent heart transplantation was performed. He hada postoperative course complicated by a cardiacarrest, status epilepticus, and he required artificialventilation for about 10 days. He gradually recoveredand ten weeks after the transplantation he wastransferred back to Bristol for rehabilitation.On readmission there was considerable distal wast-

ing ofthe hands, forearms, and legs with contracturesof both achilles tendons. He had ophthalmoplegiaand weak sternomastoids. His cardiovascular statewas satisfactory with no signs of heart failure.The history of corrected ptosis and finding of

abnormal retinal pigmentation with the developmentof ophthalmoplegia and skeletal myopathy led to thediagnosis of the Kearns-Sayre syndrome.

Channer, Channer, Campbell, Rees

NEUROLOGICAL INVESTIGATIONSElectroencephalography was abnormal with a gen-eralised excess ofvery slow wave activity particularlyover the left hemisphere. There were occasionalsharp wave discharges suggestive of a liability toseizures. Computed axial tomography of the brainshowed no midline shift and no focal changes. Theventricular system showed mild dilatation. Nerveconduction studies showed normal motor and sen-sory velocities and normal amplitudes of evokedmotor potentials apart from those muscles which hadatrophied completely. Electromyographic samplingshowed generalised and diffuse non-specific abnor-malities with loss of interference patterns related tothe number of units that had atrophied within themuscles.On review 12 months after cardiac transplantation

he was fully independent without dyspnoea onexertion. He had a persistent right foot drop andweakness of dorsiflexion of the left foot. There waspersistent wasting of calf muscles bilaterally. There

Fig 3 Electron photomicrograph of myocardial biopsy specimen showing large numbers of abnormal mitochondria. Themitochondria are large, vacuolated, and contain electron densities.

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Cardiomyopathy in the Kearns-Sayre syndromewas weakness and wasting of the intrinsic handmuscles and wasting of the forearm muscles but noclinical weakness. Eye movements were markedlyimpaired (fig 2). All the reflexes were present.

HISTOPATHOLOGYThe excised heart weighed 500 g without the upperatria. The ventricular cavities were dilated and therewas adherent thrombus at the apices. The specimenwas fixed routinely in formol saline and processed forboth histological and ultrastructural examination.Light microscopy ofthe myocardium showed degen-eration of myocardial fibres with perinuclearvacuolation and nuclear pleomorphism andenlargement. There was diffuse and focal interstitialfibrosis that was particularly noticeable in the sub-endocardial region. Although these features werepresent in both ventricles the left ventricle showedthe most severe changes. Foci of myofibrillar degen-eration were also noted as demonstrated by trichromestaining. There were no features ofan active myocar-ditis. Electron microscopy showed no significantabnormality of the myofibrils but showed variousmitochondrial abnormalities. Mitochondria wereincreased in number but in addition were of varyingsize and shape, with giant mitochondria measuringup to 1 8 jgm in diameter. Within the mitochondriathere were electron dense areas and vacuoles (fig 3).In many the cristae were disrupted.

Discussion

The Kearns-Sayre syndrome is characterised by thetriad of chronic progressive external ophthalmo-plegia, abnormal retinal pigmentation, and cardiacconduction defects and is part of a heterogenousgroup of mitochondrial myopathies. The first ofthese myopathies was described by Luft et al in 19628and they are all characterised by abnormal musclemitochondrial morphology on electron microscopy.Recently attempts have been made to separatedifferent clinical syndromes, for example myoclonusepilepsy with ragged red fibres (MERRF) and mito-chondrial myopathy/encephalopathy, lactic acidosis,and stroke-like episodes (MELAS),69 but there is noassociation with either specific morphologicalchanges or mitochondrial enzyme abnormalities.7

In the biggest published series of patients, fromone centre, with mitochondrial myopathy defined bymuscle biopsy, 40 (61 %) of66 cases presented beforeage 20 years and the commonest presentation wasptosis in 37 (56%) often with chronic progressiveexternal ophthalmoplegia, which ultimately affected48 (73%) of cases.' Many cases (47 (71%)) also hadproximal limb weakness or easy fatigue, often withabsent reflexes but occasionally with extensor plantar

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responses. Abnormal retinal pigmentation occurredin 24 (36%) and was usually of a "salt and pepper"appearance and without associated visual defect.Sensorineural deafness occurred in 17 (26%) andimportant central nervous system disease withcerebellar ataxia or dementia in 18 (27%). Similarfrequencies of abnormalities have been reported incumulative series culled from published reports.'0 "

Our case is typical in that onset was before the age of20 years with ptosis and "salt and pepper" retinalpigmentation. Neither external ophthalmoplegia norskeletal muscle weakness was noticeable before car-diac surgery but these are often mild and ignored bythe patient.7 After his complicated postoperativecourse the skeletal abnormalities and ophthalmo-plegia became obvious.

Cardiac function in the Kearns-Sayre syndrome asassessed clinically7 and by haemodynamic' andimaging techniques has always previously beenshown to be normal. Indeed, cardiac involvement inmitochondrial myopathies has hitherto been limitedalmost exclusively to the conducting tissue (thoughthe development of cardiomyopathy has beenforecast as a consequence of prolonged longevityresulting from pacing).3 Of the 66 cases from theNational Hospital of Nervous Diseases, 11 (17%)had electrocardiographic abnormalities withoutovert myocardial dysfunction.7 These included in 11cases, non-specific ST segment or T wave abnor-malites (often T wave flattening),9 and in nine casesconduction defects ranging from pre-excitation syn-drome in one, first degree heart block (two cases),non-specific intraventricular conduction defects(two cases), right bundle branch block (three cases),and complete heart block (one case). Two patientshad permanent pacemakers. In our case, the elec-trocardiogram was abnormal before transplantationwith left axis deviation indicative of left anteriorhemiblock and transient second degree atrioven-tricular block. Progressive heart block from leftanterior hemiblock to symptomatic complete heartblock over a seven year period has been documented'and prophylactic pacing has been advocated forpatients with the syndrome and evidence of conduc-tion disturbance short of complete heart block.5Previous cardiac biopsy specimens have showncharacteristic mitochondrial abnormalities'5 similarto those seen in skeletal muscle. The morphologicalhallmark first reported by Luft et al is the ragged redfibre, seen with the modified Gomori trichrome stain,which contains peripheral and intermyofibrillaryaccumulations of abnormal mitochondria.8 Thesemitochondrial abnormalities are seen on electronmicroscopy. The mitochondria are increased in num-ber and may form large aggregates. They may appearmorphologically normal but are often abnormally

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490 Channer, Channer, Campbell, Reeslarge with vacuoles or dense inclusions (made uplargely of lipid). The cristae are disrupted and mayform concentric whorls or honeycomb patterns.6Excessive accumulation of glycogen particles is alsoseen. Many of the morphological abnormalities ofmitochondria are, however, non-specific and may beseen in other muscle diseases; they probablyrepresent non-specific responses to noxious stimuli.'2One other case of cardiac failure in this syndrome

has been described.'3 In this case, a 23 year old man,first presented at the age of 12 with high outputcardiac failure and again at the age of 16. At the timeof his second presentation a profound lactic acidosisand considerable deterioration in the myopathydeveloped. He responded to treatment with pred-nisone and thiamine. Endomyocardial biopsy wasnot performed, and it was suggested that his cardiacfailure resulted from a chronic high output statecaused by the disturbances in muscle glycolyticmetabolism producing excess lactate and pyruvate(akin to beriberi). Our case presented with severerapidly progressive congestive cardiac failure and it ispossible that this was precipitated by other factors.Abnormal cardiac muscle may be more susceptible tothe toxic effects of alcohol, and although the drinkinghistory of our patient would not be expected toproduce cardiomyopathy in an otherwise normalheart it may have contributed to the speed andseverity of his deterioration. In alcoholic car-diomyopathy'4 '5 and other cardiomyopathies cardiacmuscle may show mitochondrial abnormalities,'6 butthe clinical features make our case otherwise typicalof mitochondrial myopathy.7

We thank Dr Ariela Pomerance for the description ofthe excised heart and for providing tissue for ultra-structural examination, Mr Rodney Grey for thephotograph of the retina, and Dr Hilary Morgan forthe neurophysiological studies.

References

1 Kearns TP, Sayre GP. Retinitis pigmentosa, externalophthalmoplegia, and complete heart block. ArchOphthalmol 1958;60:280-9.

2 Sandifer PH. Chronic progressive ophthalnoplegia ofmyopathic origin. J Neurol Neurosurg Psychiatry1946;9:81-3.

3 Charles R, Holt S, Kay JM, Epstein EJ, Russell Rees J.Myocardial ultrastructure and the development ofatrioventricular block in Kearns-Sayre syndrome.Circulation 1981;63:214-9.

4 Jager BV, Fred HL, Butler RB, Carnes WH.Occurrence of retinal pigmentation, ophthalmo-plegia, ataxia, deafness and heart block. Am J Med1960;29:888-93.

5 McComish M, Compston A, Jewitt D. Cardiac abnor-malities in chronic progressive external ophthalmo-plegia. Br Heart J 1976;38:526-9.

6 Di Mauro S, Bonilla E, Zeviani M, Nakagawa M,DeVivo DC. Mitochondrial myopathies. Ann Neurol1985;17:521-37.

7 Petty RKH, Harding AE, Morgan-Hughes JA. Theclinical features of mitochondrial myopathy. Brain1986;109:915-38.

8 Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. Acase of severe hypermetabolism of nonthyroid originwith a defect in the maintenance of mitochondrialrespiratory control: a correlated clinical, biochemicaland morphological study. J Clin Invest 1962;41:1776-804.

9 Pavlakis SG, Phillips PC, DiMauro S, DeVivo DC,Rowland LP. Mitochondrial myopathy, ence-phalopathy, lactic acidosis and stroke like episodes: adistinct clinical syndrome. Ann Neurol 1984;16:481-8.

10 Fukuhara N. Myoclonus epilepsy and mitochondrialmyopathy. In: Scarlato G, Cerri C, eds. Mitochond-rial pathology in muscle diseases. Padua: PiccinMedical Publishers, 1983:89-110.

11 Rowland LP, Hays AP, DiMauro S, DeVivo DC,Behrens M. Diverse clinical disorders associated withmorphological abnormalities of mitochondria. In:Scarlato G, Cerri C, eds. Mitochondrial pathology inmuscle diseases. Padua: Piccin Medical Publishers,1983:142-58.

12 Morgan-Hughes JA, Landon DN. Mitochondrial res-piratory chain deficiencies in man. Some histo-chemical and fine structural observations. In: ScarlatoG, Cerri C, eds. Mitochondrial pathology in musclediseases. Padua: Piccin Medical Publishers, 1983:20-37.

13 Mastalgia FL, Thompson PL, Papadimitriou JM.Mitochondrial myopathy with cardiomyopathy, lacticacidosis and response to prednisone and thiamine.Aust NZ J Med 1980;10:660-4.

14 Hibbs RG, Ferrans VJ, Black WC, Weilbaecher DG,Walsh JJ, Burch GE. Alcoholic cardiomyopathy: anelectron microscopic study. Am Heart J 1965;69:766-79.

15 Alexander GS. Electron microscopic observations inalcoholic heart disease. Br Heart J 1967;29:200-6.

16 Van Noorden S, Olsen EGJ, Pearse AGE. Hypertro-phic obstructive cardiomyopathy, a histological, his-tochemical, and ultrastructural study of biopsymaterial. Cardiovasc Res 1971;5:118-31.

Addendum

Since this report was prepared, two other cases ofKearns-Sayre syndrome presenting with heart blockand heart failure have been reported.'

Reference

1 Gallastegui J, Hariman RJ, Handler B, Lev M, BharatiS. Cardiac involvement in the Kearns-Sayre syn-drome. Am J Cardiol 1987;60:385-8.

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