Epilepsy-associated death in the Southwestern Ontario: A clinicopathological correlation study

Patients with epilepsy are at elevated risk for premature mortality, of which sudden unexpected death in epilepsy (SUDEP) is one of the leading causes. SUDEP incidence varies significantly depending on the population and the methods used to document the cause of death. We performed retrospective case review at the London Health Sciences Centre for the period of 2000 to 2018. Clinical information, scene investigations, general pathology findings, toxicology, and neuropathology findings were obtained, examined, and confirmed by two neuropathologists and one epileptologist. The characteristics were compared and summarized. We also evaluated the impact of 2010 revision of Ontario Coroner Act Regulation, which significantly limited whole brain examination. Among the 12,206 cases reviewed, we identified 152 cases with a known history of epilepsy. Ninety-seven cases (64%) were classified as SUDEP. There were significantly more SUDEP decedents found dead unwitnessed at night in prone position, than non-SUDEP. Generalized seizures were strongly associated with SUDEP. A male predominance was observed in SUDEP group between 15 and 35 years old. Near half of the brains examined were “unremarkable.” There was no difference in neuropathology findings between SUDEP and non-SUDEP groups. After implementation of the 2010 revision of Ontario Coroner Act Regulation, fixed whole brain examination was reduced from 88% to 7% of the epilepsy-related death investigation. Except a lower diagnosis rate of “inflammatory/infectious changes,” there were no significant differences in neuropathology findings. This is the first detailed clinical-pathological study on epilepsy-related death based on a Canadian cohort. This study reinforces the previously reported findings in SUDEP and highlights the importance of clinicopathological correlation for accurate classification of epilepsy-related death.     

Sudden death in childhood and adolescence

Sudden natural deaths of individuals between the ages of 2 and 20 years which occurred during a 20-year period were identified from mortuary records. Necropsy reports and histological sections were reviewed; 169 sudden natural deaths were identified amongst 1012 deaths in that age group. Ninety-two sudden deaths occurred to children with recognized disorders; congenital heart disease, asthma, and epilepsy were the commonest problems identified. Amongst the 77 deaths of apparently healthy children, infection was the most frequently recognized disease. Only 11 deaths were unexplained, comprising 1 per cent of the necropsy population or 6.5 per cent of sudden natural deaths, a much smaller proportion than pertains in infancy. Necropsy examination of children dying suddenly yields useful information.     

Intracranial causes of death and their mechanisms

Intracranial causes of death trail in incidence behind cardiovascular and respiratory system pathologies in most deaths occurring in hospitals. When intracranial pathology becomes more important is in the forensic arena, where it is often supposed that in troublesome cases such as sudden and unexpected deaths or where there appears to be no anatomic cause of death revealed in the general autopsy, the cause must be in the brain. This hope is often dashed after a careful neuropathological examination. Intracranial causes of death are discussed here mostly within the context of the forensic exercise where complex processes may be involved such as: electrophysiological dysfunctions; disorders of respiratory control; dysfunction of the intracranial pressure/volume equilibrium.     

Cardiovascular protective effect of melatonin in sudden unexpected death in epilepsy: a hypothesis

Epilepsy is the most common neurological disorder, approximately 1% of the population worldwide have epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, AED number and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. Furthermore, the evidence from the last 10 years suggests that melatonin has an important role in the epileptogenesis process and influences the cardiovascular system as well. The positive effect of melatonin has been demonstrated against different convulsive stimuli in several rodents, including seizures induced by pentylenetetrazole kainate, glutamate, maximal electrical shock and electrically kindled stimulation of amygdala. Clinical studies have also demonstrated a positive role of melatonin on the seizure frequency in children and reduced spiking activity and seizure frequency in patients with intractable epilepsy. In the rat hearts, studies in vivo and in vitro using pharmacological concentrations of melatonin confirmed an anti-arrhythmic effect of this hormone and studies in humans have been shown that chronic heart disease patients have significantly lower melatonin levels in their blood stream than do normal individuals. Thus, caution should be taken in generalization of these findings to epileptic population. Moreover, it is important to note that when dealing with intractable epilepsy that do not respond to any conventional treatment, the additional of melatonin may be evaluated. Taken together, in this paper we suggested a possible relationship between cardiac abnormalities, melatonin and SUDEP.     

Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases

Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy‐related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia‐related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization‐activated cyclic nucleotide‐gated cation (HCN1–4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1–4 genes in a large SUDEP cohort collected from 1993 to 2009. Post‐mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12–82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl‐cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro‐cardiac ion channel genes.     

An image of sudden death: utility of routine post-mortem computed tomography scanning in medico-legal autopsy practice

Post-mortem computed tomography (CT) is an established technique at Victorian Institute of Forensic Medicine (VIFM) used to assist pathologists in determining cause and manner of death. It also plays an important role in identification of deceased individuals as exemplified by the 2009 “Black Saturday” Victorian bushfires in which the remains of 164 individuals were subjected to disaster victim identification procedures. CT scanning is now explicitly incorporated into the Victorian Coronial legislation (Coroners Act 2008), and is an important component of the preliminary examination process whereby a pathologist reviews the circumstances of a death, any pre-existing medical history, whole body CT images, the external appearances of the body and expedited (overnight) toxicological screen results, so that a recommendation to the Coroner may be formulated regarding the likely cause of death and necessity for autopsy. This process has seen a reduction in autopsies from a mean of 62% over the last 5 years to 47% of admissions in less than 12 months. VIFM pathologists perform the primary interpretation of CT images in consultation with a radiologist. A process of quality audit has been instituted in order to detect systematic errors in this interpretation, in addition to a structured education programme directed to correct those errors. New imaging techniques, notably whole body CT angiography and dual energy CT have the prospect of even more substantial forensic application.     

Medullary tyrosine hydroxylase catecholaminergic neuronal populations in sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure‐related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre‐Bötzinger complex (pre‐BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre‐BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post‐mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non‐epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH‐immunoreactive (TH‐IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C‐fos immunoreactivity was also semi‐quantitatively evaluated in these regions. We found no significant difference in the density of TH‐IR neurones or labeling index between the groups in all regions. Significantly more TH‐IR neurones were present in the DMM region than VLM in non‐epilepsy cases only (P < 0.01). Regional variations in TH‐IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c‐fos labeling in the VLM and MR in SUDEP than non‐epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH‐IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c‐fos neurones compared to control groups which may be relevant to the mechanism of death.     

Sudden death in childhood and adolescence

Sudden death in childhood and adolescence is fortunately rare. However, when it occurs, it can have a devastating effect on the family. Therefore, these cases should be thoroughly investigated, including a complete post mortem examination by a specialist in paediatric pathology. The aim is to identify the cause of death, and potentially prevent future deaths. This review will provide an overview of the epidemiology of sudden death in childhood and adolescence and will outline the wide range of causes of death identified. Certain aspects of the paediatric post mortem examination will be discussed, and will finish with a section on deaths in children with chronic medical conditions.     

Sudden unexpected death in epilepsy: an important concern

Epilepsy is one of the most common neurologic problems worldwide. Unfortunately, individuals with epilepsy are at higher risk of death than the general population, and sudden unexpected death in epilepsy is the most important direct epilepsy-related cause of death. In this review article, our research group focused on the risk factors, mechanisms and preventative measures obtained from clinical and experimental studies on sudden unexpected death in epilepsy.     

Sudden infant death syndrome associated with rotavirus infection

Rotavirus was detected in the stools of five children stricken with sudden infant death syndrome (SIDS) over a three-week period. While none of the children had acute gastroenteritis, four of the five had acute upper respiratory infections. Rotavirus was also identified in tracheal aspirates from two of the infants. Extensive investigations failed to reveal the presence of any other viruses or toxins in specimens obtained from the five children with SIDS. Rotavirus was not found in the stool specimens obtained from a control group of 36 infants including six who died of causes other than SIDS. Future attempts at the prevention of rotavirus infections should be directed at populations susceptible to sudden infant death syndrome.     

Neuropathology of epilepsy: epilepsy-related deaths and SUDEP

Most pathologists will encounter deaths in patients with epilepsy in their practice, including sudden deaths. A systematic approach to these post-mortem examinations is required, including gathering relevant clinical details and around the circumstances of death, in order to correctly categorise these cases. Macroscopic and histological examination of the brain can reveal (i) the underlying cause of the epilepsy, as cortical dysplasia or tumours, (ii) sequel of previous seizures, including hippocampal sclerosis and contusions and (iii) potentially the cause of death. Sudden and unexpected death in epilepsy (SUDEP) is still under-reported as a cause of death. Although by definition there is no structural or toxicological cause of death at post-mortem, clinical and experimental studies together with neuropathological findings are beginning to identify alterations in central autonomic regions, including the brainstem, critical for cardio-respiratory regulation. Neuropathology investigations following post-mortem examinations form an essential component in the identification of disease mechanisms in epilepsy-related deaths and their future prevention.     

Neuropathology of epilepsy: epilepsy-related deaths and SUDEP

Most pathologists will encounter deaths in patients with epilepsy in their practice, including sudden deaths. A systematic approach to these post-mortem examinations is required, including gathering relevant clinical details and around the circumstances of death, in order to correctly categorise these cases. Macroscopic and histological examination of the brain can reveal (i) the underlying cause of the epilepsy, as cortical dysplasia or tumours, (ii) sequel of previous seizures, including hippocampal sclerosis and contusions and (iii) potentially the cause of death. Sudden and unexpected death in epilepsy (SUDEP) is still under-reported as a cause of death. Although by definition there is no structural or toxicological cause of death at post-mortem, clinical and experimental studies together with neuropathological findings are beginning to identify alterations in central autonomic regions, including the brainstem, critical for cardio-respiratory regulation. Neuropathology investigations following post-mortem examinations form an essential component in the identification of disease mechanisms in epilepsy-related deaths and their future prevention.     

心源性猝死33例尸检临床病理分析

目的 分析心源性猝死的临床特点以及尸检病理学特征.方法 收集与医疗纠纷有关的不明原因死亡的87例尸体解剖资料进行病理组织学检查.结果 心源性猝死33例,其中,冠心病20例(占64%),主动脉夹层动脉瘤破裂4例,心肌炎5例,肥厚性心肌病2例,冠状动脉炎和肺动脉脂肪栓塞各1例.结论 正确、系统地进行尸体解剖,可以明确猝死原因,提高医疗质量,并为医疗纠纷鉴定提供可靠的鉴定依据.     

Sudden arrhythmic death and cardiomyopathies in the young: a molecular and pathology overview

Cardiovascular disease is a significant cause of sudden death (SD) requiring autopsy investigation. Non-ischaemic causes of SD are more prevalent in young people (<35 years of age) and conditions such as cardiomyopathies and channelopathies account for about one half of cases.The pathologist's task is to provide the correct diagnosis and, when dealing with a genetic disease, to initiate pre-symptomatic cardiologic and genetic cascade screening of first-degree family members. Early identification is important because SD can be the first and last clinical presentation of the underlying disease and the only medical examination undertaken is the autopsy. A standardized and detailed post-mortem procedure on the SD victims, in combination with molecular testing (“molecular autopsy”), will provide vital information for the family in preventing a further tragedy. Therefore proper sampling to allow post-mortem DNA analysis as well as accurate morphological evaluation, are mandatory, as recommended in the guidelines for autopsy investigation of SD from the Association for European Cardiovascular Pathology.     

Sudden unexpected death in patients with malignancy: a clinicopathologic study of 28 autopsy cases

Sudden unexpected death (SUD) in patients with malignancy has not been comprehensively studied. We defined SUD as intrinsic natural death within 24h after initial clinical presentation of the disease responsible for the death. Intra- and postoperative death and cases associated with a myelosuppressive state were excluded. Of 2,216 autopsy cases with malignancy registered at Saitama Cancer Center, Japan, 28 SUD cases (1.3%) were studied clinicopathologically. Fifteen cases (53.6%) died of non-neoplastic cardiovascular events (CVEs), with acute myocardial infarction (AMI) being the most common death (n=13). Ten cases (35.7%) died of neoplasm-related complications (NRCs), and a miscellaneous pathophysiology was apparent, including cardiac involvement by tumor cells (n=3), fistula formation between great vessels and the alimentary canal (n=3), hepatic rupture (n=2), cardiac tamponade (n=1), and neoplastic pulmonary emboli (n=1). An anaphylaxis reaction (AR) was the cause of SUD in three cases (10.7%). Our results imply that the main route for prevention of SUD in patients with malignancy is incorporation of measure against ischemic heart disease. In addition, a variety of mechanisms causing SUD as a complication of malignant neoplasms should be recognized, including AR. Accumulation of SUD cases is necessary to better understand the causes of SUD in patients with malignancy.     

The autopsy in sudden unexpected adult death: Epilepsy

There are up to 500 epilepsy-related deaths annually in the UK, many of which are unwitnessed. Likely mechanisms for sudden and unexpected death in epilepsy (SUDEP) are cerebrogenic cardiac arrhythmias, or central respiratory depression occurring during the peri-ictal period. Pathologists should be informed of the circumstances of the death, severity of seizures, seizure control and the certainty of the clinical diagnosis of epilepsy; this allows accurate clinicopathological correlation. SUDEP autopsies include neuropathological assessment, histological examination of other organs and toxicology, and require the elimination of other causes of sudden death. Macroscopic (non-fatal) abnormalities described in SUDEP include evidence of previous cerebral injury, hippocampal sclerosis and cerebellar atrophy. Histological examination may reveal neuronal loss and gliosis consistent with seizure-related brain injury. Hippocampal sclerosis shows subfield-specific patterns of neuronal loss, granule cell dispersion and mossy fibre sprouting. Rarely, acute neuronal injury is seen as evidence of a more recent cerebral event. This article discusses the pathological findings and possible mechanisms in SUDEP, and future directions for pathology-based research.     

Sudden unexpected death as a consequence of indinavir-induced nephropathy. A case report

A 60-year-old male had tested in 1986, at age 46, positive for human immunodeficiency virus (HIV). In mid-1996 he was started on a protease inhibitor regimen, which included indinavir, lamivudine and stavudine, and remained on this therapy until his death. In April 1999 he was hospitalized after a fainting episode. Although examination focusing on cardiac disease did not disclose any remarkable findings, he died suddenly one week after being discharged from hospital. At autopsy the kidneys were enlarged, with a total weight of 500 g, patchy pale gray and pinkish. Microscopy showed leukocytic cell casts in many of the tubules and collecting ducts. In many of these casts there were clefts left by crystals. In the interstitium, both in the cortex and the medulla, there was focal inflammation and fibrosis. Death was attributed to sudden cardiac dysfunction, probably ventricular fibrillation as a consequence of severe nephropathy with electrolyte disturbances. It is likely that kidney damage developed secondary to the indinavir treatment as indinavir can cause not only nephrolithiasis but also crystal-induced acute renal failure.