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664 Postgrad Med J 2003;79:664–666 Postgrad Med J: first published as 10.1136/pmj.79.937.666 on 3 December 2003. Downloaded from SELF ASSESSMENT ANSWERS

Aborted sudden death in a Q2: What is the pathophysiological basisofthiscondition? What further young male diagnostic tests would you consider doing in this patient? Q1: What is the ECG (fig 1; p 660) Genetic studies have shown that Brugada diagnosis? Why is it important to syndrome and chromosome 3-linked long QT recognise this condition? syndrome (LQT3) are allelic disorders of the The ECG done on his arrival at the emergency cardiac channel (SCN5A, 3p21). The room (see questions) shows (i) sinus tachy- inheritance is autosomal dominant with cardia, (ii) a QRS complex that ends with a variable . The SCN5A gene codes positive deflection (or prominent J wave) for the alpha subunit of the sodium channel. that is, a rsR9 pattern in V1 and V2, and (iii) of this gene results in abnormal- an elevated downsloping ST segment ending ities of the sodium channel, with abnormal in a small negative T-wave deflection. This ion conductance patterns and can be demon- ECG pattern in someone with a history of strated in up to 25% Brugada syndrome syncopy and documented ventricular fibrilla- cases.235 Brugada-type downsloping ST seg- tion/aborted sudden death, is most consistent ment is a normal feature of the ECG in some with the eponymous Brugada syndrome. rodents, whereas in higher mammals, the ST Described first in 1992 by Brugada and segment is usually isoelectric in the normal Brugada, Brugada syndrome is an inherited state. Figure 1 (below) describes the various arrhythmogenic disease, which may presage phases of the cardiac ventricular action ventricular fibrillation and sudden cardiac potential. Failure of the plateau phase or death.1–5 ‘‘dome’’ to develop occurs when the transient The Gussak diagnostic criteria1 for Brugada outward currents, termed I (phases 1 and 3; syndrome are shown in box 1. One must be to fig 1) overwhelms the inward current, mainly Figure 1 Phases of the cardiac ventricular aware that ST elevation in the right praecor- action potential; solid line shows normal dial ECG leads occurs in a variety of clinical the calcium current termed ICa (phase 2; ventricular action potential and dotted line conditions, as shown in box 2, and hence fig 1). This results in a 40%–70% abbreviation shows Brugada-type action potential clinical correlation with diligent characterisa- of the action potential in some, but not all (schematic). tion of the ECG is mandatory before a epicardial sites (schematically represented by diagnosis of Brugada syndrome is made. the dotted line in fig 1), resulting in a marked Brugada syndrome is a recognised cause of dispersion of repolarisation within the ven- re-entry) can result in local re-excitation, sudden cardiac death, and hence the need for tricular muscle. This is manifest on the ECG producing closely coupled extrasystoles, prompt recognition and treatment. Every as marked QT-dispersion. Propagation of the which in turn may initiate circus movement year, in the United States alone, there are dome from sites where it is maintained to re-entry.2 In those cases where the typical about 300 000 new cases of sudden death due sites where it is abolished (termed phase 2 ECG changes are evanescent, programmed to cardiac arrest. Altogether 3%–9% out-of- electrical stimulation (PES) with or without hospital cases of ventricular fibrillation, chemical challenge with certain drugs may unrelated to myocardial infarction, occur in Box 1: Gussak’s criteria unmask the ST segment elevation in V1–V3 those with minimal or no structural and right bundle branch block-like pattern in disease.2 Such cases may include those with many patients.1 Sodium channel blockers Brugada syndrome, congenital and acquired N Major criteria*: long QT syndromes, pre-excitation states http://pmj.bmj.com/ such as Wolff-Parkinson-White syndrome, 1. Presence of the ECG marker of and cases where no ready cause is apparent Brugada syndrome in patients with (so called ‘‘idiopathic’’ ventricular fibrilla- structurally normal heart. Box 2: Causes of ST segment tion). Though seen worldwide, Brugada 2. Appearance of the ECG marker of elevation in right praecordial ECG syndrome in endemic in Southeast Asia and Brugada syndrome after administra- leads Japan, where it is known as sudden unex- tion of sodium channel blocker. plained death syndrome and sudden unex- plained nocturnal death syndrome, and the N Minor criteria*: N Anterior myocardial infarction. incidence has been estimated to range N Right or left bundle branch block. on September 23, 2021 by guest. Protected copyright. between five and 66 events per 100 000 1. Family history of sudden cardiac people.3 In some countries, the prevalence of death. N Right ventricular infarction. Brugada-type ECG changes among those who 2. Syncopy of unknown origin. N Left ventricular aneurysm. were diagnosed with ‘‘idiopathic ventricular 3. Documented episodes of ventricular N Exercise test induced. fibrillation’’, has been estimated to be as high as 40%–60%.2 Studies quote an incidence of tachycardia/ventricular fibrillation. N Acute myocarditis. sudden cardiac death varying between 44%– 4. Positive programmed electrocardios- N Dissecting aortic aneurysm. 62% in those with Brugada-type ECG and timulation test on ventricular tachy- 3 N Acute pulmonary thromboembolism. history of aborted sudden death/syncopy. cardia/ventricular fibrillation. Considerable variation exists in the clinical N Right ventricular outflow tract obstruction 5. Genetic mutations of ion channels presentation, and several ‘‘forms’’ of Brugada (tumour, etc). syndrome have been described: manifest, (yet to be fully defined). N Various central and autonomic nervous concealed, asymptomatic, suspected, and simulated.4 Brugada syndrome affects males system disorders. preferentially, and the mean age of those N Duchenne’s muscular dystrophy...... affected tends to be in the mid to late thirties. N Friedrich’s ataxia. Clinical manifestation of Brugada syndrome *One major and one minor criterion together are attributed exclusively to the malignant are needed for a diagnosis of Brugada N Hypercalcaemia and hyperkalaemia. ventricular that occur in this syndrome. N Heterocyclic antidepressant overdose. condition. Tragically, sudden death may be Typically consists of rsR9 pattern with an N Cocaine intoxication. the first and only clinical event. These elevated terminal portion of the QRS complex arrhythmias often occur at rest, and in some (prominent J-wave ) in V1–V3, non-injury N Thiamine deficiency (beriberi). at night-time. High sympathetic tone, anxi- related elevated descending ST segment and ety, and alcohol consumption have all been negative T-wave in the same leads. proposed as possible provocative factors.2 Adapted from Gussak et al.1 Adapted from Gussak et al.2

www.postgradmedj.com Self assessment answers 665 Postgrad Med J: first published as 10.1136/pmj.79.937.666 on 3 December 2003. Downloaded from (SCB) such as procainamide, ajmaline and References resolving haematoma within a large section flecainide, b-blockers such as propranalol, a- 1 Gussak I, Bjerregaard P, Hammill SC. Clinical of . adrenergic and muscarinic stimulation—all diagnosis and risk stratification in patients with The diagnosis is spontaneous haemorrhage may bring out the typical ECG features, and Brugada syndrome. J Am Coll Cardiol into a renal angiomyolipoma in a patient indeed induce ventricular tachyarrhythmia 2001;37:1635–8. with tuberous sclerosis. Intrarenal, perirenal, and/or ventricular fibrillation in those with 2 Gussak I, Antzelevitch C, Bjerregaard P, et al. The retroperitoneal, and intraperitoneal haemor- Brugada syndrome. While PES and SCB Brugada syndrome: clinical, electrophysiologic rhage are well recognised complications of and genetic aspects. J Am Coll Cardiol 1 challenge may be useful in risk stratifying 1999;33:5–15. angiomyolipomata. Bleeding risk increases patients with Brugada syndrome, their ability 3 Nademanee K. Prognostic value of when they exceed 4 cm in size, and if to identify the symptomatic (cardiac arrest, electrophysiologic studies in Brugada syndrome. symptomatic may require intervention with syncopy) cases is at best modest (for PES, J Am Coll Cardiol 2002;39:1806–7. embolisation or nephric sparing surgery.12 positive and negative predictive values and 4 Surawicz B. Brugada syndrome: manifest, overall accuracy 50%, 46% and 49% respec- concealed, asymptomatic, suspected and Q4: What is the cause of the clotting tively; for SCB challenge, positive predictive simulated. J Am Coll Cardiol 2001;38:775–7. abnormality? value 35%).1 A complete workup of a sympto- 5 Naccarelli GV, Antzelevitch C. The Brugada syndrome: clinical, genetic, cellular, and A normal prothrombin time and prolonged matic patient with Brugada syndrome may molecular abnormalities. Am J Med activated partial thromboplastin time which also include , coronary 2001;110:573–81. is not reversed when the patients plasma is angiography, stress testing, magnetic reso- diluted 1:1 with normal platelet free plasma nance imaging, and rarely, myocardial 4 An unusual cause of suggests anticoagulant activity. biopsy. This patient underwent PES with Anticardiolipin antibodies were subsequently procainamide challenge, which resulted in abdominal pain negative in this case, and clotting studies inducing the ventricular tachyarrhythmia. He require follow up. underwent cardiac catheterisation, which Q1: What is the diagnosis and what are revealed normal coronary artery anatomy the clinical features of this condition? Final diagnosis and left ventricular function. The underlying diagnosis is tuberous sclero- Spontaneous haemorrhage into a renal sis. Tuberous sclerosis complex (TSC), angiomyolipoma in a patient with tuberous Q3: How is this condition treated? 1 described by Bourneville in 1880, is one of sclerosis. What is the prognosis? the neurocutanous syndromes. Inheritance is For the symptomatic Brugada patients (syn- autosomal dominant with spontaneous References copy, aborted sudden death) the treatment of in 60%.12Two loci on chromosomes 1 Franz DN. Diagnosis and management of choice is placement of an implantable cardi- 9 and 16 produce the phenotype, both tuberous sclerosis complex. Seminars in Pediatric overter-defibrillator (ICD) device. The inci- encoding with tumour suppresser 1998;5:253–68. dence of arrhythmic events is similar in function.3 Incidence is estimated as one per 2 Kwiatkowski DJ, Short MP. Tuberous sclerosis. Arch Dermatol 1994;130:348–54. patients receiving either an ICD device, b- 6000 live births and a prevalence of one in 1 3 Smith M. Mapping of the tuberous sclerosis blocker or amiodarone, but only the ICD 10 000. Diagnostic criteria were reviewed in . Int J Neurol 1992;25–26:81–8. 4 device protects patients with Brugada syn- 1998. Clinical features result from hamarto- 4 Roach ES, Gomez MR, Northrup H. Tuberous drome from sudden death. To this date, there mas affecting various organ systems. Cerebral sclerosis complex consensus conference: revised is no pharmacological agent that has been manifestations occur in up to 95% of clinical diagnostic criteria. J Child Neurol shown to confer a survival benefit to patients patients,1 which include cortical tubers, sub- 1998;13:624–8. with Brugada syndrome.12 ependymal nodules, giant cell , 5 Webb DW, Fryer AE, Osborne JP. On the In some countries such as Japan, the (60%), learning difficulties (40%),5 incidence of fits and mental retardation in tuberous sclerosis. J Med Genet 1991;28:395–7. incidence of asymptomatic Brugada syn- and autism (40%–45%).6 Skin involvement 1 6 Smalley SL. Autism and tuberous sclerosis. drome cases is very high and far exceeds (90%–95%) includes facial , J Autism Dev Disord 1998;28:407–14. those with symptoms. In as much as the ICD hypomelanotic macules, forehead fibrous 7 Eble JN. Angiomyolipoma of . Semin device prevents death in symptomatic cases, plaques, Shagreen’s patches, ash leaf spots, Diagn Pathol 1998;15:21–40. many lives could be potentially saved if we and periungual (fig 1; p 661).2 Renal 8 Steiner MS, Goldman SM, Fishman EK. The could successfully identify the high risk, involvement includes and angiomyoli- natural history of renal angiomyolipoma. J Urol http://pmj.bmj.com/ asymptomatic patients as well.3 There is some pomata (45%–66%),12 composed of blood 1993;150:1782. evidence that asymptomatic patients with vessels, , adipose and connec- 9 Washecka R, Hanna M. Malignant renal tumours in tuberous sclerosis. Urology 1991;37:340–3. Brugada syndrome who have a positive tive tissue. Typically they are benign and may 7 10 Neumann HPH, Schwarzkopf G, Henske EP. provocative test may benefit by placement be symptomless, though may differentiate to Renal , cysts and cancer in 8 of an ICD device. When followed up for over in well under 5% and tuberous sclerosis complex. Seminars in Pediatric 33 months, 17% of inducible Brugada syn- may occur bilaterally.9 Renal disease is a Neurology 1998;5:269–75. drome patients had an compared leading cause of death in patients with TSC.10 11 Stovin P, Lum C, Flower D. The in with a mere 2% among those who were not Pulmonary cysts and lymphangioleiomyoma- lymphangiomyomatosis and in tuberous sclerosis. inducible.3 As to what constitutes optimal tosis occur exclusively in women.11 Retinal Thorax 1975;30:497. on September 23, 2021 by guest. Protected copyright. therapy for non-inducible cases of Brugada phakomas, dental pitting, cardiac rhabdo- 12 Van Baal JG, Smits NJ, Keeman JN, et al. The syndrome, is still unclear and more studies evolution of renal angiomyolipomas in patients myomas, gingival fibromas, and rectal polyps with tuberous sclerosis. J Urol 1994;152:35–8. are required to address this question.5 are recognised features.1 Regardless of the presence or absence of symptoms, the prognosis of Brugada syn- Q2: What does the computed A case of severe, unexplained drome is poor, with a 10% per year mortality.5 tomogram of the abdomen (fig 2; breathlessness While no correlation between right bundle p 661) show? branch block and SCD has yet been estab- The non-contrast computed tomogram shows Q1: What is the mechanism of this lished in a population other than those with grossly abnormal kidneys with enlarged focal patient’s breathlessness and how Brugada syndrome, the magnitude of ST areas of fatty change surrounded by streaky segment elevation has been linked to the would you confirm this? material largely replacing the renal tissue. A This man is breathless due to bilateral incidence of life threatening arrhythmias, large uniform soft tissue mass is seen to arise especially in Brugada syndrome.2 Careful diaphragmatic paralysis, which causes pro- from the anteromedial aspect of the right found orthopnoea and paradoxical abdom- to the ECG is mandated in every kidney. case of aborted sudden cardiac death in order inal motion, unlike other common causes of breathlessness. The clinical picture differs to recognise and treat the patient with the Q3: What do the renal scans Brugada syndrome. from orthopnoea of cardiorespiratory origin (figs 3, 4, 5; p 661) show and what is in its strikingly rapid onset on lying flat, with the likely diagnosis? Final diagnosis rapid and complete recovery on sitting up. The initial ultrasound (fig 3; p 661) shows a Paradoxical abdominal motion (that is, Brugada syndrome. homogenous 10 cm mass in the mid-lower movement of the abdominal contents inward abdomen. Subsequent scans (fig 4 and 5; during inspiration) is an important physical Acknowledgements p 661) over a six week period show the mass sign of diaphragmatic weakness. Therefore, We thank our librarian Ms Mary Saramak for to be reduced in size, with a more loculated in the absence of other signs indicating a her help with the literature search. irregular echo pattern consistent with respiratory or cardiovascular cause for the

www.postgradmedj.com 666 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.79.937.666 on 3 December 2003. Downloaded from orthopnoea, a careful search for paradoxical hazardous investigations and treatment. radiation, diabetic ketoacidosis, toxaemia of abdominal motion is important. Treatment is mainly supportive, including pregnancy, and parturition. Diagnosis is Fluoroscopic screening of the diaphragms analgesics, physiotherapy, and reassurance. entirely based on typical clinical features in can be used to confirm bilateral paresis and Corticosteroids (for example, prednisolone, an appropriate setting. Important clinical paradoxical movement. 60 mg daily tapering over two weeks) may be manifestations include vomiting, diarrhoea, given to accelerate recovery and reduce pain, pyrexia, tachycardia, atrial fibrillation, car- Q2: What is the likely clinical but they have not been shown to clearly diac failure, and neurological manifestations diagnosis. How would you try to influence the course of the illness. The including agitation, delirium, and establish this? clinical outcome with diaphragm involve- coma, although not all classical features are Bilateral diaphragmatic weakness is most ment is variable. Some degree of recovery is essential for the diagnosis.2 Suppressed thyr- often observed in the context of generalised usual but may be slow or incomplete.5 The oid stimulating hormone and raised thyroid neurological illnesses affecting muscle (for patient described was treated conservatively hormone levels support the diagnosis but the example, polymyositis or muscular dystro- with analgesics and physical therapy, and degree of elevation of the latter is not always phies), neuromuscular transmission (for advised regarding sleeping posture. Ten exceptional. example, myasthenia gravis), inflammatory months after discharge, he remained well polyneuropathies (for example, Guillain- with only mild orthopnoea. Q3: How is this condition managed and Barre´ syndrome), or anterior horn cell dis- how can one prevent it? ease.1 However, involvement of the dia- Final diagnosis Management of thyroid storm precipitated by phragm in association with the rapid onset Brachial neuritis (neuralgic amyotrophy). RAI therapy is along similar lines as that of of orthopnoea, asymmetric or unilateral thyroid storm caused by any other precipi- shoulder pain, and patchy weakness of arm References 1 Gibson GJ. Diaphragmatic paresis: tant. Thyroid storm should preferably be and shoulder girdle muscles should alert the pathophysiology, clinical features, and managed in conjunction with an endocrinol- clinician to the correct diagnosis of brachial investigations. Thorax 1989;44:960–70. ogist and management includes the admin- neuritis (neuralgic amyotrophy). Accurate, 2 Parsonage MJ, Turner JW. Neuralgic prompt diagnosis requires a high index of istration of Lugol’s iodine, high dose amyotrophy, the shoulder girdle syndrome. Lancet propylthiouracil, corticosteroids, and suppor- suspicion and awareness of the clinical 1948;i:973–8. features, and is important for starting appro- 3 Beghi E, Kurland LT, Mulder DW, et al. Brachial tive measures. There are no specific recom- priate management and avoiding unneces- plexus neuropathy in the population of Rochester, mendations for prevention of thyroid storm Minnesota, 1970–1981. Ann Neurol after RAI, although, in high risk patients, sary investigations or treatment. 45 Brachial neuritis is characterised clinically 1985;18:320–3. prior hospitalisation, rendering patients 4 Tsairis P, Dyck PJ, Mulder DW. Natural history of 6 by pain, atrophy, weakness, and variable euthyroid, and use of antithyroid drugs after brachial plexus neuropathy. Arch Neurol 7 sensory loss around the shoulder girdle.2 RAI therapy have been recommended. Our 1972;27:109–17. patient developed thyroid storm even though Typically, sudden deep pain around the 5 Hughes PD, Polkey MI, Moxham J, et al. Long shoulder girdle—described as sharp, aching, term recovery of diaphragm strength in she had been rendered euthyroid before RAI boring, or throbbing—is associated with neuralgic amyotrophy. Eur Respir J therapy and did not have any associated muscle weakness either simultaneously or 1999;13:379–84. comorbidity. After recovery from thyroid after a variable period of several days to storm, carbimazole was continued till May weeks. Commonly affected muscles include An unusual case of relapsing 1994 for persistent hyperthyroidism when the deltoid, serratus anterior, spinati, biceps, RAI was readministered at a very high dose of triceps, and wrist and finger extensors; Graves’ disease 1110 MBq in view of an isotope uptake study showing an extremely high radioiodine turn- sensory deficit is usually less conspicuous. Q1: What is the diagnosis and how The annual incidence is approximately 1.64 over. On this occasion she was hospitalised per 100 000.3 Men are more commonly frequently is this condition before the administration of RAI therapy and affected, with the highest prevalence in the encountered? carbimazole was recommenced five days after 20–50 year age group.2 Unilateral or bilateral The patient had developed thyroid storm RAI. There was no recurrence of thyroid diaphragmatic weakness is found in about secondary to radioiodine therapy. Thyroid storm and three months later the patient

7% of patients, and may dominate the clinical storm is a rare, life threatening complication became hypothyroid, requiring thyroxine http://pmj.bmj.com/ presentation.4 The precise location of the of hyperthyroidism with an incidence of 1%– replacement. It is likely that thyroid storm lesion, and its pathogenesis remain puzzling; 2% in hospitalised patients with hyperthyr- was successfully prevented by early reintro- viral and autoimmune processes have been oidism, although it has a high mortality of duction of carbimazole after the RAI treat- suggested but not confirmed. around 15%.1 The incidence of the thyroid ment. Nerve conduction studies (NCS) and elec- storm after RAI is variable because of varia- tromyography (EMG) are the most helpful tions in the regimens of RAI, in patient Final diagnosis diagnostic tests; extensive needle electrode selection, and in the use of thyrostatic Thyroid storm secondary to radioiodine examination may be required. In this patient medications before and after RAI. The overall therapy. NCS/EMG revealed normal sensory and incidence is low and in one series only one on September 23, 2021 by guest. Protected copyright. motor conduction velocities, but no evidence patient out of 525 patients treated with References 23 of a neuromuscular junction transmission 550 MBq RAI developed thyroid storm. 1 Mazzaferri EL, Skillman TG. Thyroid storm: a disorder. There was complete denervation of The risk of thyroid storm after RAI treatment review of 22 episodes with special emphasis on the right deltoid muscle, and milder neuro- is difficult to predict in an individual patient the use of guanethedine. Arch Intern Med genic changes in the right supraspinatus, but appears to be higher in patients with 1969;124:684–90. biceps, and brachioradialis. The EMG find- severe hyperthyroidism, in older patients, 2 Mcdermott MT, Kidd GS, Dodson LE, et al. Thyroid storm after RAI therapy. Am J Med ings of active, patchy denervation strongly and in the presence of cardiovascular and cerebrovascular disease.2 1983;75:353. favoured the diagnosis of brachial neuritis, 3 Kumar H, Dayus LJ, Hayton RM, et al. Standard and helped to exclude peripheral nerve or Q2: What is the mechanism and what dose RAI therapy for hyperthyroidism. root involvement. J Endocrinol 1998;156:304 (abstract). Routine laboratory studies on blood, and are the criteria for diagnosis of this 4 Nadler SB, Block T, Hidalgo J, et al. An examination of the are condition? evaluation of radioactive iodine therapy in unremarkable in brachial neuritis. Magnetic The mechanism of thyroid storm is either a thyrotoxicosis. J State Med Soc resonance imaging may be helpful in exclud- reduction in levels of binding proteins or the 1954;106:365–75. ing local neoplastic, infiltrative, traumatic, release of preformed thyroid hormones. 5 Eriksson M, Rubenfeld S, Garber AJ, et al. and musculoskeletal conditions. Examples of the former include postoperative Propranolol does not prevent thyroid storm. N Engl J Med 1977;296:263–4. state or a major systemic illness; the latter is 6 Shafer RB, Nuttal Fq. Thyroid crisis induced by Q3: What is the treatment and encountered as a result of injury to the ? radioiodine. J Nucl Med 1971;12:262–4. prognosis for this patient follicular cells after RAI treatment or even 7 Beierwaltes WH. the treatment of hyperthyroidism Accurate and prompt diagnosis of bra- after vigorous manipulation of the thyroid with radioiodine-131. Semin Nucl Med chial neuritis can help to avoid potentially gland. Other precipitating factors include 1978;8:95–103.

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