GRANULOMATOUS HEPATITIS ASSOCIATED WITH CAT SCRATCH DISEASE

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GRANULOMATOUS HEPATITIS ASSOCIATED WITH CAT SCRATCH DISEASE ALLEN A. LENOIR1,4 GREGORY A. STORCH1,4 KATHERINE DESCHRYVER-KECSKEMETI2 GARY D. SHACKELFORD3 ROBERT J. ROTHBAUM1,5 DOUGLAS J. WEAR6 JERRY L. ROSENBLUM1

intra-abdominal lesions on computed tomography or ultrasonography. At laparotomy, each of them had multiple hepatic granulomata, and microorganisms looking like the cat scratch disease bacillus were identified in the liver of two of the patients. METHODS

Edward Mallinckrodt Department of Pediatrics,1 Department of Pathology,2 and Department of Radiology,3 Washington University School of Medicine; the Division of Infectious Diseases4 and the Division of Gastroenterology,5 Children’s Hospital St Louis, Missouri; and the Department of Infectious and Parasitic Disease Pathology,6 Armed Forces Institute of Pathology, Washington DC, USA

In three patients with cat scratch disease the liver was affected. All three had high fever (39°C) for more than 3 weeks. Two of them had no peripheral adenopathy. Computed tomography of the abdomen revealed focal hepatic defects in two patients and periportal and periaortic adenopathy in the third. At laparotomy, there were nodules on the liver surfaces of all patients and histological examination revealed necrotising granulomata. The Warthin-Starry silver stain showed organisms consistent in appearance with the cat scratch bacillus in the liver and a periaortic lymph node of one patient, in the liver of the second patient, and in the axillary lymph node of the third. In all three patients the clinical findings and radiological abnormalities improved without specific therapy. A review of the surgical pathology files of

Summary

Washington University revealed only two other cases of granulomatous hepatitis in children over a 6-year period. These findings indicate that cat scratch disease should now be included in the differential diagnosis of granulomatous hepatitis, at least in children. The absence of peripheral adenopathy in two of the three patients with granulomatous hepatitis suggests that the clinical spectrum of cat scratch disease may be broader than previously appreciated.

CAT-SCRATCH disease is generally a self-limiting illness characterised by regional lymphadenopathy following an inoculation injury, usually inflicted by a cat. A pleomorphic bacillus identified in affected tissue with the Warthin-Starry silver stain has been implicated as the aetiological agent. This type of organism was first observed in lymph nodes of patients with cat scratch disease,1 and later seen in primary inoculation sites, including the skinand conjunctiva,3but dissemination beyond regional lymph nodes has not been reported. Here we describe three children with a clinical syndrome consistent with cat scratch disease who also had

9

10. 11.

12

13

Two patients were tested for skin reactivity to the cat scratch antigenwith parental consent. (Material for the test was kindly provided by Dr A. M. Margileth, Department of Pediatrics, Uniformed Services University of the Health Sciences; F. Edward Hebert, School of Medicine, Bethesda, Maryland). 01 ml of the antigen was injected into the volar surface of the forearm. Induration greater than 4 mm in diameter at 72 h, as read by the ballpoint pen method,s was considered positive.

Pathology Liver biopsy specimens were available from all three patients, as lymph nodes from the porta hepatis of patient 1 and from the axilla of patient 3. All tissues were routinely processed and stained with haematoxylin and eosin (HE). Additional sections were also stained with a modified Warthin-Starry (WS) silver impregnation stain,6both at Washington University and at the Armed Forces Institute of Pathology. Some HE stained sections were also destained and restained with the WS method. Adjacent sections were also stained with the Ziehl-Neelson method for acid-fast organisms and the modified Brown-Hopps tissue stain." To evaluate the specificity of the findings with the modified WS stain, sections (from the files of the Armed Forces Institute of Pathology) of hepatic granulomata from five patients with sarcoidosis and seven patients with primary biliary cirrhosis were stained and examined, as were sections of hepatic granulomata from two patients seen at Washington University for granulomatous hepatitis of unknown aetiology in whom there was no clinical suspicion of cat scratch disease.

were

CASE-REPORTS

Patient 1

INTRODUCTION

8. Takada Y, Huang C, Hemler ME. Fibronectin receptor structures in the VLA

Skin Tests

family

of heterodimers Nature 1987, 326: 607-09. Dimitriu-Bona A, Burmester GR, Waters SJ, Winchester RJ. Human mononuclear phagocyte differentiation antigens I. Patterns of antigenic expression on the surface of human monocytes and macrophages defined by monoclonal antibodies. J Immunol 1983; 130: 145-52. Robb RJ, Greene WC. Direct demonstration of the identity of T-cell growth factor binding protein and the Tac antigen. J Exp Med 1983; 158: 1332-37 Ledbetter JA, Evans RL, Lipinski M, et al. Evolutionary conservation of surface molecules that distinguish T-lymphocyte helper/inducer and T-cytotoxic/ suppressor subpopulauons in mouse and man J Exp Med 1981; 153: 310-23. Coles MI, Rose ML, Yacoub MH Appearance of cells bearing the interleukin-2 receptor in peripheral blood of cardiac transplant patients and their correlation with rejection episodes. Transpl Proc 1987, XIX: 2546-48. Horst HJ, Flad HD Corticosteroid/interleukin-2 interactions. inhibition of binding of interleukin-2 to interleukin-2 receptors Clin Exp Immunol 1987; 68: 156-62

A 10-year-old white girl was admitted to Children’s Hospital in September, 1984, for evaluation of a month’s fever of 38-40°C of unknown origin. Amoxycillin and erythromycin given in the first week of illness had had no effect. Other complaints were weakness and mild right upper quadrant pain and intermittent left shoulder ache. 4 months earlier the child had received a 6-week-old kitten,

which had scratched her several times and which she often kissed on the mouth. The patient was well grown and well nourished and had no cutaneous lesions, lymph-node enlargement, or organ enlargement. Her haemoglobin (Hb) concentration was 12 4 g/dl. The peripheral white cell count was 7300/µl (66% segmented neutrophils, 1 % band forms, 30% lymphocytes, and 38% monocytes), the platelet count was 641 000/µl, and the erythrocyte sedimentation rate (ESR) was 82 mm/h. Urinalysis gave unremarkable findings. Blood chemistry, including serum aspartate aminotransferase (AST), alkaline phosphatase, total protein, albumin, calcium, and blood urea nitrogen were all normal. Serological studies for salmonellosis, toxoplasmosis, tularaemia, brucellosis, histoplasmosis, and Q fever were negative. Antibody titres to Epstein-Barr virus and cytomegalovirus were consistent with past infection. A bone-marrow aspirate was normal. Bacterial cultures of blood and urine were negative. A tuberculin test was negative, with a positive tetanus antigen control.

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Real-time abdominal ultrasonography showed a normal appearing liver and multiple round 2-3 cm hypoechoic in the periportal and upper abdominal masses retroperitoneal areas, consistent with enlarged lymph nodes. Computed tomography, with and without intravenous contrast agent, also showed a normal liver and the periportal and retroperitoneal masses, as well as splenomegaly. Chest radiography, upper gastrointestinal series, barium enema, and intravenous urography were negative. Laparotomy revealed yellow nodules 0-2-1 cm in diameter on the surface of the liver, a mass of enlarged (1-3 cm) lymph nodes near the portal vein and coeliac axis, and 1 nodule on the surface of the spleen. Cultures of the liver and periaortic nodes were negative for bacteria, fungi, and mycobacteria. Therapy consisted of antipyretics only. The patient became afebrile a week after surgical exploration and has remained well during the 24 months of follow-up. 20 months after the illness abdominal ultrasonography showed a normal-appearing liver and resolution of the periportal and retroperitoneal lymph node enlargement, and a cat scratch skin test produced 12 x 12 mm of induration.

Patient 2 A

3-year-old white girl was admitted to another hospital in December,1981, for 3 weeks of fever of 38-39°C. She had been scratched by a kitten on the right ear lobe and the right cheek in the preceding month. The only significant physical findings were the healing scratches. She was discharged without a diagnosis. No antibiotics were given. Abdominal computed tomography done because of persistent fever, revealed multiple low-density nodular lesions in the liver. These

nodules

became

isodense

with

normal

liver

parenchyma after intravenous contrast administration. When referred to Children’s Hospital for further evaluation 5 weeks after the onset of fever she had been afebrile for 4 days. Physical examination was remarkable only for the healing scratches and palmar telangiectasiae. Her Hb was 10-8 g/dl and there was no evidence of haemolysis on the peripheral blood smear. The peripheral white cell count was 9000/µl (38% segmented neutrophils, 8% band forms, 48% lymphocytes, 4% monocytes, and 2% eosinophils). The platelet count was 684 000/µl. The urinalysis was unremarkable. Biochemical tests for liver function and blood urea nitrogen were normal. Serological studies for antibodies to Chlamydia trachomatis, EpsteinBarr virus, and cytomegalovirus, and for histoplasmosis,

months after laparotomy showed that the hepatic lesions were much smaller and only faintly visible. The patient remains symptomless 5 years later. Patient 3 An 8-year-old white boy with left axillary adenopathy and fever of up to 40 9 °C 4 weeks after a cat scratch on the left wrist was diagnosed as having cat scratch disease. No defervescence occurred with penicillin for approximately 2 weeks. 6 weeks after the onset of illness, during an afebrile period, he had a brief syncopal episode. Neurological evaluation, including a radionuclide brain scan,

electroencephalography, cranial computed tomography, and examination of cerebrospinal fluid, was unrevealing. Fever above 40°C recurred and persisted. Computed tomography of the upper abdomen revealed multiple low-density lesions in the liver, leading to referral to Children’s Hospital. He was well grown and was not in apparent distress with a temperature of 38’7°C and 0-5 cm cervical nodes, 0-5 cm inguinal nodes, and a 2-3 cm left axillary node. There was a 3-4 mm non-tender erythematous papule at the site of the scratch. There was no hepatosplenomegaly. The nervous system was normal except for five beats of ankle clonus bilaterally. The Hb was 10-8 g/dl without evidence of haemolysis on the peripheral blood smear. The peripheral white cell count was 16 200/µl(54% segmented neutrophils, 12% band forms, and 34% lymphocytes). The urinalysis was unremarkable. Biochemical tests for liver and renal function were normal. Serological evaluation for antibodies to Epstein-Barr virus, cytomegalovirus, hepatitis B virus, Chlamydia trachonzatis, and Mycoplasma pneumoniae, and for tularaemia, brucellosis, histoplasmosis, salmonellosis, Q fever, Rocky Mountain spotted fever, leptospirosis, syphilis, and toxoplasmosis were negative. Tests for rheumatoid factor and antinuclear antibody were negative. Bacterial cultures of blood, cerebrospinal fluid, urine, throat, and stool were all negative. A tuberculin test was negative with

toxoplasmosis, toxocariasis, tularaemia, brucellosis, fever, blastomycosis, Q leptospirosis, syphills, coccidioidomycosis, and amoebiasis were all negative. Antinuclear antibody was not detected and angiotensinconverting-enzyme activity was normal. A nitroblue tetrazolium stimulation test was normal. A bone-marrow aspirate was remarkable only for hypercellularity. Cultures of the marrow for mycobacteria, fungi, and anaerobic and aerobic bacteria were negative, as were routine cultures of blood, urine, and stool. Tuberculin tests on the patient and her parents were non-reactive. Her chest radiograph was normal. Laparotomy revealed multiple 0-1-3 cm firm yellow nodules close to the surface of the liver. Cultures of these nodules for mycobacteria, fungi, and anaerobic and aerobic

bacteria were negative. After surgery the child remained afebrile without antibiotic therapy. Abdominal computed tomography 4

Fig 1-Sagittal ultrasound scan through the right lobe of the liver of patient 3 showing poorly defined hypoechoic lesions(arrows). Distance between major divisions on horizontal and vertical axes is 10 mm.

1134

discharge abdominal computed

months. 5 months after

tomography positive (11 x

normal, and

was

10

mm

a cat

scratch skin test

was

induration). RESULTS

Fig 2-Non-contrast enhanced computed tomography scan patient 3 shows multiple nodular lesions throughout the liver.

positive tetanus radiograph and

of

and candida an

upper

antigen controls. A chest gastrointestinal series were

normal. Abdominal ultrasonography demonstrated multiple hypoechoic defects in the liver parenchyma (fig 1), seen only with a 5 MHz linear array transducer. Repeat computed tomography to evaluate the entire abdomen, including retroperitoneum, revealed multiple low-density liver lesions up to 1 cm in diameter (fig 2) that were isodense with adjacent normal liver after intravenous contrast injection. Approximately 100 nodules 2 x 2 mm in diameter were visible at laparotomy. Cultures of liver nodules and the axillary node for bacteria, mycobacteria, and fungi were

negative. The fever remitted postoperatively without antibiotic and the patient has remained symptomless for 9

treatment

Hepatic Granulomata Hepatic nodules from all 3 patients contained large areas where hepatocytes had been replaced by a dense fibrous reaction entrapping bile ducts and containing multiple discrete granulomata (fig 3A). Multiple sections through the granulomata revealed 1 small focus of necrosis in patient 2 and neutrophils and macrophages in the centres of many granulomata in patients 1 and 3 (fig 3B). Vessels near the granulomata were proliferating and sometimes large and plexiform and their lumens were almost occluded by swollen endothelial cells. The lumens of more distant vessels were thrombosed. In some sections the centres of the granulomata in patients 1 and 2 contained gram-negative bacilli with the characteristic appearance of the cat scratch disease bacillus. The bacilli were clumped around blood vessels or formed long filaments along collagen fibers (fig 3C 4). The modified Brown-Hopps stain revealed small gram-negative bacilli in similar locations in patient 1. Sections at multiple levels through the granulomata revealed foci of bacilli in one level but not in adjacent levels. The bacilli were unevenly distributed in the granulomata, and did not appear in all sections. No other bacteria or acid-fast organisms were observed.

Lymph-node Granulomata Both the periaortic lymph node (patient 1) and the axillary lymph node (patient 3) had hyperplastic and hypertrophic

Fig 3-Liver biopsy and lymph node specimens from patient 1. (A) Liver showing surviving hepatocytes (top), fibrosis entrapping bile ducts (centre), and a discrete granuloma (bottom), HE x 25. (B) Wall of a second hepatic granuloma (top) and neutrophils and macrophages in centres of granuloma, HE

x

160.

(C) Long chains of silver-stained cat scratch bacilli in collagen fibres in centre of hepatic granuloma shown in (B), WS

x

1000.

(D) Lymph necrosis in

node showing Y-shaped bacilli in of a granuloma (WS).

centre

an area

of

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follicles. The periaortic lymph nodes had suppurative while those of the axillary lymph node were caseating. Some sections showed a few characteristic "Y"-shaped branched bacilli in the suppurative centres (fig 3D) or in chains along collagen fibers in the caseating centres

centres.

Warthin-Starry stains of sections of hepatic granulomata patients with sarcoidosis, primary biliary cirrhosis, or granulomatous hepatitis of unknown aetiology did not reveal any structures suggestive of the cat scratch disease from

bacillus.

DISCUSSION

reported here illustrate a newly of recognised syndrome granulomatous hepatitis associated with cat scratch disease. It occurred in otherwise healthy children and was characterised by high fever (39°C) that persisted for more than 3 weeks, macroscopic hepatic granulomata, and a self-limiting course. Two patients did not have the classical peripheral lymphadenopathy and inoculation site papule of cat scratch disease. In the third patient hepatic involvement was associated with severe but otherwise typical cat scratch disease. The clinical diagnosis of cat scratch disease requires three of the following criteria: (1) a history of contact with an animal, usually a cat, and a scratch or primary dermal or eye lesion; (2) a positive cat scratch disease skin test; (3) negative laboratory findings for other causes of lymphadenopathy; and (4) characteristic histological findings in lymph node biopsy specimens. Patients 1 and 3 satisfied all four criteria. In patient 2 the history of cat contact, the presence of otherwise unexplained granulomatous inflammation, and the self-limiting course led to the diagnosis of cat scratch disease even before the organism was found in her liver. Her parents refused to have her skin tested. An unusual finding in two of the three patients reported is the demonstration of organisms looking like the cat scratch disease bacillus at sites distant from the primary inoculation complex. Organisms were seen in the liver in two patients and also in the periaortic nodes from one of them. Although the Warthin-Starry stain is not specific for the cat scratch disease bacillus, the organisms seen had the distinctive morphological and staining characteristics observed in stains of peripheral lymph nodes, skin, and conjunctiva from patients with typical cat scratch disease.1-3 These characteristics include a tendency for the organisms to branch, to grow between collagen fibers, and to clump around blood vessels. Moreover, no such bacilli were found in Warthin-Starry stains of sections of hepatic granulomata from 14 patients with granulomatous hepatitis associated with diseases other than cat scratch disease. Another cause of intra-abdominal possible lymphadenopathy is yersinia infection. Although we have not excluded this diagnosis serologically, it is less likely than cat scratch disease because of the strong clinical evidence for the latter (see above), because none of the patients had mesenteric enteritis (either clinically or at laparotomy), and because in all these patients the cultures done were adequate to detect Yersinia pseudotuberculosis or Y enterocolitica. There have been reports of hepatic involvement in cat scratch disease. Two recent reviews,8which together include over two thousand cases, do not mention liver involvement, although there have been isolated case-reports of anicteric hepatitis or hepatomegaly.1’ 14 One patient, The three

cases

described by Rocco et al had clinical findings similar to those noted in our patients.15 Computed tomography in this 16-year-old black boy showed focal defects in the liver, which were confirmed as hepatic granulomata. This patient also had hepatosplenomegaly, mildly abnormal serum aminotransferase levels, and positive cat scratch skin test, but there was no history of contact with cats and special stains of the liver were negative for cat scratch bacillus. Despite the paucity of previous reports, the cases reported here raise the question of whether hepatic involvement in cat scratch disease might be more common than appreciated. Our patients had neither hepatomegaly nor abnormal liver function tests, and their hepatic involvement would have if ultrasonography or computed gone unnoticed tomography had not been done in an attempt to diagnose treatable causes of protracted fever. Such investigations are not routinely done in patients with cat scratch disease. Sonography is attractive for seeking liver involvement because it does not involve radiation exposure, but we found that high-resolution ultrasonography was required to better demonstrate the subtle lesions in patient 3, and that only adenopathy and not hepatic lesions were detected by non-invasive studies in patient 1. The presence of cat scratch bacillus in the livers of patients 1 and 2 demonstrates that in at least some patients liver involvement is associated with invasion of the liver by the causative organism. The focal distribution of organisms, particularly in older lesions, may explain our inability to demonstrate the organism in the liver of patient 3, who had been ill for approximately 7 weeks at the time of the biopsy. 1,16 An alternative explanation is that in some patients the granulomatous reaction in the liver may represent a response to the presence of organisms elsewhere in the body. How bacilli reach the liver is unknown. Patient 1’s habit of kissing her kitten raises the possibility of an enteral route. Alternatively, the organism may have entered the liver and periportal lymph nodes haematogenously from a cutaneous inoculation site. Patient 1 also had evidence of splenic involvement. If spread is haematogenous, further studies

might identify

other

previously unappreciated

organ

involvement.

Recognition of the association between granulomatous disease of the liver and cat scratch disease has important clinical implications. We suggest that cat scratch disease should now be included in the differential diagnosis of granulomatous hepatitis, even when peripheral adenopathy and an inoculation papule are absent, as in patients 1 and 2. The aetiology has been undetermined in as many as one-third of patients with granulomatous hepatitis;17 it is possible that some of these were unrecognised cases of cat scratch disease. Cat scratch disease may be a particularly important cause of granulomatous hepatitis in children. A review of the surgical pathology files at Washington University revealed that apart from the three cases reported here, there were only two other cases of granulomatous hepatitis in children during a 6-year period, which suggests that cat scratch disease mav account for a substantial proportion of cases of granulomatous hepatitis in childhood. Clearly, further studies using appropriate staining techniques are needed to determine the frequency of cat scratch disease as a cause of granulomatous hepatitis in both adults and children. Reliable methods of culturing the organism, once developed, should provide a more defmitive means for corroborating the presence of the cat scratch bacillus in liver and other organs.

1136

Granulomatous hepatitis in cat scratch disease seems to be self-limiting, so in patients with fever and otherwise unexplained hepatic defects or periaortic lymphadenopathy detected by computed tomography or ultrasonography, invasive procedures may be deferred given a strong history of cat contact. However, treatable conditions such as tuberculosis, fungal infection, and lymphoma must also be carefully considered. Studies of more patients with granulomatous hepatitis due to cat scratch disease should help determine the most appropriate course of management for individual patients. We thank Dr Robert Harris, Dr Onkar Shanna, and Dr Gregory Brotzman for referring the patients; the housestaff of Children’s Hospital at Washington University for help in the care of these patients; and Ms Jane Heaney for helping to prepare this manuscript.

Correspondence should be addressed to G. A. S., Children’s Hospital at Washington University Medical Center, 400 South Kingshighway, St Louis, Missouri 63110, USA.

REFERENCES 1 Wear 2.

DJ, Margileth AM, Hadfield TL, Fischer GW, Schlagel CJ, King FM Cat scratch disease a bacterial infection. Science 1983; 221: 1403-05. Margileth AM, Wear DJ, Hadfield TL, Schlagel CJ, Spigel GT, Mulbauer JE Cat scratch disease bacteria in the primary inoculation site. JAMA 1984; 252: 928-31.

Hypothesis

3 Wear DJ, Malaty RH, Zimmerman LE, Hadfield TL, Margileth AM. Cat scratch disease bacilli in the conjunctiva of patients with Parinaud’s oculoglandular syndrome. Ophthalmology 1985; 92: 1282-87. 4 McGovern JJ, Kunz LJ, Blodgett FM Nonbacterial regional lymphadenitis ("cat scratch fever") An evaluation of the diagnostic intradermal test. N EnglJ Med 1955; 252: 166-71. 5 Sokal JE Measurement of delayed skin-test responses. N Engl J Med 1975; 293: 501-02. 6. Allen RC, Luna LG, Wear DJ. Modified Warthin-Starry technique for bacilli of cat scratch disease and spirochetes of syphilis. AFIP Letter 1986; 144: 13. 7. Luna LG. Manual of histologic staining methods of the Armed Forces Institute of Pathology. New York McGraw-Hill, 1968. 8. Carithers HA. Cat scratch disease: an overview based on a study of 1,200 patients Am J Dis Child 1985, 139: 1124-33. 9. Margileth AM, Wear DJ, English C Cat scratch disease: a systemic bacterial infection Report of 23 patients with severe, systemic, prolonged, or recurrent disease. J Infect Dis 1987; 155: 390 10 Lambert H, Hausser E Anicteric hepatitis; a new possible complication of cat scratch disease. Rev Med Suisse Romande 1965; 85: 689-93. 1 1. Katner HP, Treen B, Panky GA, Glasgow G, Cortez LH, Dalovisio J. Pleural effusion and anicteric hepatitis associated with cat scratch disease. Chest 1986; 89: 302-03. 12 Korbitz BL. Systemic cat scratch disease with hepatosplenomegaly, multiple lymphadenopathy, and hepatic dysfunction. Rocky Mt Med J 1973; 70: 23-27. 13. Greenbaum B, Nelson P, Marchildon M, Donaldson M. Hemolytic anemia and hepatosplenomegaly associated with cat scratch fever. J Pediatr 1986; 108: 428-30. 14 Kmlow WB. Cat scratch disease Report of case presenting with hepatosplenomegaly. Connect State Med J 1954, 18: 960-62. 15. Rocco VK, Roman RJ, Eigenbrodt EH. Cat scratch disease report of a case with hepatic lesions and a brief review of the literature Gastroenterology 1985, 89: 1400-06. 16 Hamoudi AC, Katmeh G, Hamoudi AB. Looking for cat scratch disease bacillus Lancet 1985; ii. 208 17. Harrington PT, Gutierrez JJ, Ramirez-Ronda CH, Quinones-Soto R, Bermudez RH, Chaffey J Granulomatous hepatitis Rev Infect Dis 1982; 4: 638-55.

between systoles. Because the Q-T interval varies with heart rate, it must be corrected to the value it would have at a standard heart rate when comparisons are to be made. The most frequently used correction is that of Bazett,2 and states that the corrected Q-T interval is

myocardium

A CELLULAR BASIS FOR THE PRIMARY LONG Q-T SYNDROMES

Q_Tc- Q-T; v%, R_R DAVID ATTWELL

JOHN

A. LEE

Department of Physiology, University College London, Gower St, London WC1E 6BT

In several syndromes sudden death is Summary associated with a long Q-T interval on the electrocardiogram. Current treatment is aimed at correcting a notional imbalance of cardiac sympathetic drive. Although this approach can be effective, the primary disorder may be a defect in the cellular mechanism that alters the length of the ventricular action potential, and hence the Q-T interval, in response to a change of heart rate. Such defects may be underdiagnosed because the long Q-T syndromes are defined simply in terms of a prolonged Q-T interval, without consideration of the fact that susceptibility to arrhythmias is likely to be due, not to a lengthened Q-T per se, but to an absence or alteration of the normal Q-T shortening in response to an increase of heart rate. People susceptible to R-on-T related arrhythmias could be identified by measurement of the dependence of the Q-T interval on heart rate and how quickly the Q-T interval adapts to a change in rate. INTRODUCTION

The Q-T interval of the electrocardiogram represents the duration of the electrical activity of the ventricles-ie, the time between ventricular depolarisation and repolarisation.1 In normal subjects, the Q-T interval shortens with tachycardia. A shortening of ventricular systole at high heart rates is functionally advantageous because it allows more time for ventricular filling and blood supply to the

where the R-R interval is measured in seconds. Many factors can shorten or lengthen the corrected Q-T interval. Shortening of the Q- Tc is associated with digitalis, hyperthermia, and hypercalcaemia. Lengthening may be

produced by amiodarone,3quinidine, procainamide, acute myocardial infarction.4 A long Q- T may also observed as a primary defect, as described below.

or

be

While a shortened Q- T is without serious consequences, is associated with ventricular fibrillation and sudden death. The electrocardiographic manifestation of this hazard is the so-called R-on-T phenomenon: when the Q or R wave of one cardiac cycle falls on the T wave of the preceding cycle, the low conduction speed of the resulting ventricular action potential makes circus movements and ventricular fibrillation likely. 5,6 Although a lengthened Q- Tc may pass without symptoms at normal heart rates, a lengthened Q- Tc at high heart rates favours myocardial disaster, because the R-on-T phenomenon is then more

a

long Q- T

likely to occur. PRIMARY LONG

Q-T SYNDROMES

Two syndromes have been associated with a primary hereditary prolongation of the corrected Q-T interval.’ In both there is a family history of syncopal episodes and sudden death due to paroxysmal ventricular arrhythmias. The Jervell and Lange-Nielsen syndrome8 has an autosomal

recessive mode of inheritance and is associated with bilateral, severe, congenital perceptive deafness. In the Romano-Ward syndrome9,10 the inheritance is autosomal dominant and there is no association with deafness. Typically, both disorders present in childhood, although in the Romano-Ward syndrome subjects may present in their