J Clin Pathol 1992;45:361-363

Malignant hyperpyrexia: a rare cause ofpostoperative death

R J Prescott, S P Roberts, G Williams

AbstractA middle aged man developed very highfever, status epilepticus, and terminalacute renal failure with myoglobinuriaafter surgery. A post mortem examina-tion showed widespread muscle necrosiswith hypercontraction bands. Muscleenzyme studies and electron microscopicexamination disclosed central core dis-ease, a condition closely related tomalignant hyperpyrexia. This conditionis a genetically inherited disorder whichcan be triggered by certain volatileanaesthetic agents or Suxamethonium.In this patient the condition may havebeen triggered by either the Isofluraneor the postoperative status epilepticus.

Department ofHistopathology,Christie Hospital andHolt Radium Institute,Withington,Manchester M20 9EXR J PrescottDepartment ofAnaesthesia, SteppingHill Hospital,StockportS P RobertsDepartment ofPathology, Universityof ManchesterG WilliamsCorrespondence to:Dr R J PrescottAccepted for publication5 September 1991

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Case reportA 50 year old British man underwentcraniotomy for excision of a tuberculum sellameningioma. He had no past or family historyof anaesthetic problems. The anaesthesia usedwas Thiopentone, Atracurium, Fentanyl,nitrous oxide and Isoflurane, rather thanHalothane. Suxamethonium was not given.His vital signs were normal, and he had no

fever on return to the ward.Two hours after recovery, he had a single

generalised seizure which settled withPhenytoin. Two hours later he went intostatus epilepticus which lasted for one hour.He had a persistent tachycardia of 107 beats a

minute, a temperature of 42°C, and a

metabolic acidosis (arterial blood pH of 7-1).

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Figure I Renal tubular casts showing strong positive staining with antisera againstmyoglobin protein (immunoperoxidase).

A computed tomography scan showed rightfrontal lobe contusion and haemorrhage withbrain shift; this was considered to besecondary to the surgical procedure. A bloodclot was removed during which he was givenSuxamethonium. He remained feverish,acidotic, and hypokalaemic (serum K+ =2-32 mmol/l).The following day he developed acute renal

failure associated with myoglobinuria. Hisneurological signs warranted limited frontallobectomy, he became hypotensive, and died.

PathologyThe meningioma measured 1 cm in diameterand had a typical meningotheliomatouspattern without malignant features. Postmortem examination of the brain showedhaemorrhage and contusions in the residualright fronto-parietal lobe. There was noevidence of brain shift or coning-relatedphenomena. Histological examination dis-closed no pathological abnormalities in thenon-traumatised areas, in particular thehypothalamus which contains the temperatureregulating centres.The kidneys were swollen and pale, each

weighing in excess of 200 g. The cortico-medullary interface was indistinct and therewas bleeding in the pelvicalyceal system.Histological examination showed acutetubular necrosis of both proximal and distaltubules associated with numerous, deeplyeosinophilic casts. The latter stained stronglywith antisera to myoglobin, using a standardimmunoperoxidase technique (fig 1). The vasarecta contained nucleated red blood cells,related to the terminal hypotension.

Sections of striated muscle from severalanatomical sites showed extensive segmentalnecrosis and hypercontraction bands, asso-ciated with very little, if any, inflammatoryresponse. No regenerative features werepresent, indicating rapid, acute rhabdomyo-lysis. The viable areas showed variation inmyofibre diameter, sarcoplasmic vacuolationand internalisation of nuclei (fig 2).These appearances were identical with

those of an antemortem quadriceps musclebiopsy which also disclosed central coredisease, selectively affecting 64% of type Ifibres. This was shown by standard histo-chemical techniques using nicotinamideadenosine diaphorase-tetrazolium reductase(NADH-TR) and adenosine triphosphataseenzymes at various pH of 94,4,6, and 4-2(fig 3). Electron microscopic examination

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Prescott, Roberts, Williams

Figure 2 Striated muscle showing necrosis and internalisation of nuclei (haematoxylinand eosin).

confirmed the presence of cores devoid ofmitochondria and myofilaments.Given these findings, combined with the

clinicobiochemical derangements, malignanthyperpyrexia was diagnosed. The mechanismof death was considered to be prolongedrhabdomyolysis resulting in myoglobinuriaand acute tubular necrosis. The myoglobin-uria might have been related to the hyper-pyrexia, status epilepticus, or the operation.An intracranial cause for the observed hyper-pyrexia cannot totally be excluded even in theabsence of any histological abnormality in thebrain, particularly the hypothalamus. Giventhe muscle central core disease and thepresence of two possible triggering events(the administration of Isoflurane and statusepilepticus), it is more likely that the under-lying mode of death was related to the malig-nant hyperpyrexia.

Figure 3 Histochemical appearance of quadriceps muscle, showing central core defectsin the darker stained type Ifibres (NADH-TR).

DiscussionMalignant hyperpyrexia is an autosomaldominant inherited condition usually present-ing postoperatively with a progressive rise inbody temperature at a rate of 2-60C per hour.'It was first described in 1960.2 The incidence inthe United Kingdom has been quoted as 1 in200 000 and the male:female ratio as 2:1.1Malignant hyperpyrexia is triggered by the

neuromuscular junction blocking agentSuxamethonium and by volatile anaestheticagents; Halothane is the commonest agentdescribed but Isoflurane has also beenimplicated.34 Ingestion of large amounts ofethanol and conditions of physical stressincluding trauma and status epilepticus are alsotriggering stimuli.'The underlying abnormality has been

attributed to a genetically determined, latent,molecular defect residing in the sarcoplasmicreticulum. There is either decreased sequestra-tion ofcalcium in the sarcoplasmic reticulum orincreased release, or both. This defect isaggravated by the aforementioned exogenousagents. The sustained release of calcium ionsproduces hypercontraction of muscle fibres,necrosis, and liberation of myoglobin,potassium ions, lactic acid and enzymesincluding creatine phosphokinase (CPK). Themechanism of the temperature rise is not wellunderstood but it seems that the hyper-metabolic state acts as a positive feedback loopcausing the temperature and metabolism toincrease further. Late recognition and severityof disease account for a mortality around 50%for all cases.'

Screening of relatives is an important aspectofmalignant hyperpyrexia and includes musclebiopsy. The demonstration of increased con-tracture response to caffeine or a caffeine/Halothane mixture of in vitro fresh muscle isdiagnostic.

Histological examination of antemortemmuscle may show no abnormality, or a widerange of non-specific changes, including varia-tion in fibre diameter, fibre splitting, atrophicfibres, central nuclei, nuclear chains, tubularaggregates and sarcoplasmic vacuolation.5Despite this spectrum of reported changes, arecent study has described the constellation ofdiffusely distributed nuclei, moth-eaten fibres,and central cores as diagnostic of malignanthyperpyrexia myopathy.6 Internal nuclei in atleast 3% of fibres were considered abnormal.Moth-eaten fibres and central cores bothrepresent mitochondrial loss and are best seenin NADH-TR histochemical preparations fortype I fibres. Moth-eaten fibres have one ormore pale areas with irregular outlines and softedges; cores are central, round, sharply definedareas of pallor.

Electron microscopic examination is alsonon-specific, ranging from normality to dilatedlateral cisternae in the sarcoplasmic reticulum,breaches in the plasma membranes in hyper-contracted fibres, focal aggregation ofglycogengranules and increased numbers of enlargedmitochondria. The ultrastructure of moth-eaten fibres and central cores shows loss ofmitochondria and occasional fibrils displaying

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Malignant hyperpyrexia: a rare cause ofpostoperative death

limited Z-band streaming, a feature related tosevere contraction of individual myofibrils.The association of malignant hyperpyrexia

with central core disease is well established,7 somuch so, that all patients with this condition,including the relatives, should be considered tobe at risk from malignant hyperpyrexia unlessin vitro contracture tests indicate otherwise.The association with Duchenne's muscular

dystrophy and other myopathies is less definitebut it does lend support to the concept that the,as yet unidentified, malignant hyperpyrexiagene is probably located near to the othermyopathy related genes.

We thank Mr A Strang, consultant neurosurgeon, for allowingthis case to be reported, and the Medical Illustration Depart-ment, Manchester Medical School, for the histologicalphotography.

1 Ellis FR, Halsall PJ. Malignant hyperpyrexia. Br J HospMed 1980;24:318-27.

2 Denborough MA, Lovell RRH. Anaesthetic deaths in afamily. Lancet 1960;ii:45.

3 Joseph MM, Shah K, Viljoen JF. Malignant hyperthermiaassociated with Isoflurane anesthesia. Anesth Analges1982;61:71 1-12.

4 Boheler J, Eger EI. Isoflurane and malignant hyperthermia.Anesth Analges 1982;61:712-13.

5 Harriman DGF. Malignant hyperthermia myopathy-acritical review. Br J Anaesth 1988;60:309-16.

6 Harriman DGF, Sumner DW, Ellis FR. Malignant hyper-pyrexia myopathy. Q J Med 1973;42:639-64.

7 Brownell AKW. Malignant hyperthermia: relationship toother diseases. Br J Anaesth 1988;60:303-8.

J Clin Pathol 1992;45:363-366

Dieulafoy's vascular malformation as a cause oflarge intestinal bleeding

D J Farrell, M K Bennett

AbstractFour cases of Dieulafoy's vascularmalformation of the caecum are

reported. Three were associated withmassive large bowel haemorrhage, one

of which was fatal. The remaining casehad a calibre persistent submucosalartery within the caecum that was foundincidentally in a resection specimen.This vascular malformation should be

considered when dealing with specimensresected for massive lower gastrointes-tinal bleeding.

Dieulafoy's vascular malformation, alsoknown as calibre persistent submucosalartery, is a rare but well known cause of uppergastrointestinal bleeding.' It has been foundalmost exclusively in the stomach, althoughcases in the duodenum2 and jejunum3 havealso been reported. Recently it has beenrecognised that it may occur in the colon andcan cause massive bleeding.4 To date therehave been six cases of large bowel haemor-rhage from a Dieulafoy type ulcer.Y7 Wereport four more cases.

Department ofHistopathology,Freeman Hospital,High Heaton,Newcastle upon TyneNE7 7DND J FarrellMK BennettCorrespondence to:Dr D J Farrell

Accepted for publication5 September 1991

Case reportsCASE 1

A 77 year old man was admitted with severe

continuous bleeding from the rectum andlower abdominal pain which he had had for sixhours. He had previously undergone repair of aperforated gastric ulcer and was known to havepolycythemia rubra vera. He was in circulatoryshock and required transfusion of 8 unitsof blood over the following 10 hours. Anemergency oesophago-gastro-duodenoscopic

examination was normal. Because of continuedbleeding, emergency superior mesentericangiography was performed which showedarterial bleeding in the caecal tip. Anemergency right hemicolectomy was thereforecarried out. At surgery blood had filled thewhole of the large bowel but there seemed to benone in the small bowel.

After inflation ofthe specimen with barium toshow the vessels, macroscopic examinationshowed a small ulcer 0-2 cm in diameter insidethe tip ofthe caecum. Microscopic examinationof the caecal ulcer showed a thrombus coveringa muscular artery of large diameter within thesubmucosa and extending into the mucosawhich had ruptured into the lumen (fig 1).There was no evidence of arteritis. There wasa localised inflammatory response in theimmediately adjacent mucosa but the bowelwas otherwise unremarkable. The appearanceswere identical with those of a Dieulafoy ulcer asdescribed in the stomach.'

CASE 2A 64 year old man with known alcoholic liverdisease was admitted with anorexia, weightloss, increasing dyspnoea and melaena. Onexamination he had the stigmata of chronicliver disease. Because of repeated nose bleedshe required multiple transfusions but con-tinued to be anaemic. He was also known tohave oesophageal varices. He continued to passlarge volumes of melaena with blood clots dailyand had evidence of a chest infection. Despitesupportive measures he died eight days afteradmission.

Post mortem examination showed a wide-spread, diffuse non-Hodgkin's lymphoma.Altered blood was present in the stomach and

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