Sudden death and Takayasu’s arteritis: The role of histopathological investigation

Introduction

Autopsy is the gold standard for determining the cause and mode of death. However, in some cases, autopsy does not provide enough information to define the cause of death with certainty. This occurs relatively frequently in cases of sudden death, in particular in young people who were apparently in good health with no relevant comorbidities. The absence of macroscopically evident data is common when death is caused by mechanisms or alterations that can only be assessed by microscopic examination and histopathological analysis. For this reason, a forensic pathologist routinely collects samples of tissues for histopathological examination during the autopsy. Vasculitis is the inflammation of blood vessel walls but is rarely evident at autopsy, and differential diagnosis is only possible through microscopic and immunohistochemical analysis. Takayasu’s arteritis (TA) is a granulomatous vasculitis of large blood vessels. ¹ It is a chronic inflammatory vasculitis that affects the aorta and its major branches, the pulmonary artery and less frequently the coronary arteries. TA is also known as “wristless disease” because the radial pulse can be absent bilaterally in affected patients.

The vessels affected are prone to arterial stenosis, thrombosis and the formation of aneurysms. To date, there is little published epidemiological data on TA, probably due to its rarity in Western populations. TA is most prevalent in Asia; however, recent epidemiological studies suggest that TA is becoming increasingly diagnosed in Europe with a prevalence of 0.4 to 1.5 cases/million. The highest prevalence in the world is estimated to be in Japan (40 cases per million inhabitants) and lowest in North America (0.9 cases per million). ² The most frequently affected age groups are adolescents and young adults aged 10 to 30 years, with a female to male ratio of about 4:1. The aetiology remains unclear. In most cases, the prognosis of patients with TA is favourable, as it generally responds well to oral steroids such as prednisolone. The clinical presentation can vary and depends on the affected arteries, and sometimes it is not detected until complications occur. ³ The asymptomatic, or silent, phase of this vasculitis may be long and then followed by a systemic or early phase, characterised by non-specific symptoms including fever, night sweats, general malaise, asthenia, weight loss, arthromyalgia, moderate anaemia, nausea, vomiting and erythema nodosum. If untreated, this leads to an inflammatory vascular phase which eventually results in a stenotic or late phase characterised by abnormalities of the vasculature.

Other clinical manifestations include: the attenuation or absence of peripheral arterial pulses, vascular murmurs or bruits, arterial hypertension due to renal artery stenosis, retinopathy, aortic regurgitation, congestive heart failure, dilated cardiomyopathy, neurological manifestations (including dizziness, convulsions and amaurosis) and pulmonary hypertension. Diagnostic criteria (the Ishikawa criteria) have been formulated which include the more frequent manifestations of the disease, and these offer high levels of sensitivity and specificity. ⁴ In 1990, Ishikawa’s criteria were replaced by the American College of Rheumatology criteria, followed in 1995 by a modification of the Ishikawa criteria proposed by Sharma et al. ¹ The diagnosis of TA, like any other disease, is the “synthesis” of clinical, bio-temporal and instrumental findings and cannot be limited by classification criteria which, while representing the most sensitive and specific manifestations of disease, do not include other relevant elements. ⁶ Corticosteroids are the first choice of treatment for TA, with other steroid sparing immunosuppressive drugs used in some cases. Surgical therapy, when necessary, must be carried out early and consists of revascularisation with bypass of the ischemic areas. However, this pathology can sometimes be fatal due to complications such as ruptured aneurysm, pulmonary artery dissection, ⁷ hypertensive heart failure, granulomatous myocarditis, ⁸ pulmonary hypertension, coronary artery disease ⁹ and aortic regurgitation. ¹⁰

Here, we report a case of sudden death in a 50-year-old woman who only complained of vertigo and did not suffer from any known cardiovascular diseases except for arterial hypertension. We aim to evaluate a possible association between TA and sudden death by emphasising the role of histopathological investigation in post-mortem diagnosis and the prevention of complications in this rare disease.

Case report

A 50-year-old woman died suddenly after going to the emergency room because of dizziness and nausea. The woman’s medical history was collected through an interview with the primary care physician and her family. A careful analysis of the data revealed that the woman was in good health and was a sportswoman, and there was no history of comorbidities or cardiovascular risk factors. There was only arterial hypertension controlled with antihypertensive medication and a previous history of vertigo in the absence of other signs or symptoms, for which the woman took medication. An autopsy was ordered by the judicial authorities in order to determine the cause and manner of death and to investigate for any malpractice or signs of incorrect medical treatment. The autopsy showed the presence of thoracic and abdominal aortic sclerosis (Figure 1) with diffuse coronary sclerosis. The lungs (Figure 2) and brain (Figure 3) appeared oedematous and congested, but with no other pathological findings. The toxicological analysis did not detect alcohol, drugs or psychotropic drugs in any biological liquids. A histopathological examination was then performed, which showed the presence of an embolus in the left anterior descending coronary artery (Figure 4) and a thrombosis of the aortic wall (Figure 5). The emboli and aortic atheroma were analysed microscopically, which demonstrated the presence of an eosinophilia (Figure 6) compatible with various forms of vasculitis. The histopathological examination also showed the presence of a non-infectious vasculitis associated with ANCA-mediated autoimmune mechanisms. The vessels from all other organs examined in the autopsy were analysed, and no eosinophilic inflammation was found. Therefore, the limitation of vasculitis to the aorta allowed for a confident diagnosis of TA and excluded other possible vasculitis. Microscopic analysis of the heart sections also showed areas of disrupted disks (Figure 7), consistent with ventricular fibrillation, associated with small areas of necrosis (Figure 8), homogenisation of widespread eosinophilic sarcoplasms and the presence of wavy fibres (Figure 9). These aspects were more frequently found at the cardiac apex. These findings demonstrated that the cause of death was myocardial ischaemia leading to left ventricular fibrillation and sudden death. OPEN IN VIEWER

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Figure 2.

Oedematous and congested lungs.

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Figure 3.

Analysis of the brain.

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Figure 4.

Embolus in the left anterior descending coronary artery.

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Figure 5.

Thrombosis of the aortic wall.

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Figure 6.

Evidence of eosinophilia.

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Figure 7.

Microscopic analysis of the heart.

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Figure 8.

Small areas of necrosis.

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Figure 9.

Presence of wavy fibres.

Discussion

An unexpected non-traumatic fatal event occurring within 1 h of the onset of symptoms in an apparently healthy person is defined as sudden death. Sudden death, without an apparent cause and without an autopsy, is defined in adults as Sudden Unexplained Death Syndrome (SUDS) or in infants aged <1 year as Sudden Unexplained Death in Infancy (SUDI). When the results of the autopsy and toxicological examination are not clear and the heart appears structurally normal at macroscopic and histological examination, sudden death is defined as Sudden Arrhythmia Death Syndromes (SADS) (in the adult) or Sudden Infant Death Syndrome (SIDS) (in the infant). Approximately 17 million deaths worldwide are attributable to cardiovascular disease, 25% of which are sudden cardiac deaths. The risk is higher in men than in women and increases with age due to the increasing prevalence of coronary heart disease in old age. ¹¹ Coronary artery disease, decompensation or valvulopathies are more common in the elderly. Different heart diseases are associated with sudden cardiac death (SCD) in young subjects. In young people, there are 1.3 to 8.5 cases of SCD per 100,000 subjects and autopsy is often inconclusive. Many causes of SCD are inherited in an autosomal dominant pattern, so an early diagnosis of the primary cause of death in cases of SCD is crucial for the prevention of fatal events in the victim’s family. The causes of SCD in young patients that are visible on autopsy include hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. Autopsy-negative SCD is linked to inherited arrhythmias such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, Wolff-Parkinson-White syndrome and idiopathic ventricular fibrillation, ¹² as well as other canalopathies, cardiomyopathies, myocarditis and drug abuse. Even after autopsy, between 2% and 54% of sudden deaths remain unexplained. ¹¹ Recent studies report that about 5% of SCD occur during sports activity and there are around 15,000 cases per year of SCD during sports in North America and Europe. ¹³ An autopsy may not provide enough data to detect the cause of death when it occurs due to pathologies that can only be detected microscopically, which is common in sudden deaths. Sudden death may also be a rare complication of TA.^14,15 Here, we demonstrated a correlation between TA and sudden death caused by aortic involvement and coronary embolisation. This association is not a common finding; therefore, we emphasise the correlation between systemic vasculitis and sudden death in healthy subjects and this case demonstrates how we may prevent fatal events through cardiological follow-up in patients suffering from unexplained vertigo and hypertension where there are no other specific risk factors. From a forensic point of view, we underline the crucial role of histopathological data, especially when the macroscopic results do not provide a clear cause of death. Histopathology may prove to be essential in cases of sudden death, especially in showing the presence of rare syndromes such as TA. Histopathological investigation has a key role in solving cases of forensic interest, but may also provide microscopic evidence of rare or inherited diseases, thus enabling steps to be taken to prevent fatal events in family members and exclusion of third-party responsibilities in these fatal events. ¹⁶ Genetic testing of blood samples should only be carried out when results of the histopathology investigation are negative; this limits the costs incurred from genetic surveys when signs of the most common gene mutations associated with sudden deaths can be found via histopathological investigation.

Conclusions

Autopsy may not always provide useful results in cases of sudden death, and in such cases, histopathological investigations may play a crucial role in determining the cause of death.

In cases of sudden death, it is therefore necessary to follow a diagnostic protocol: carefully taking a complete medical history; autopsy examination with sampling of the whole heart, supra-aortic vessels and thoracic and abdominal aorta; histopathological and immunohistochemical investigations; and genetic investigation in cases where the histopathological investigation is negative.