[An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation challenging]. / Följsamhet till ordination en av utmaningarna i epilepsivården.

The Swedish national guidelines for epilepsy stipulate regular health care contacts in the years following diagnosis, referral for epilepsy surgery in cases of pharmacoresistant epilepsy, multidisciplinary teams, and adequate patient information particularly for women of childbearing age. The last years have seen advances in many research areas of relevance for the basic epilepsy care, and Sweden has contributed regarding pharmacotherapy, seizure-related risks, sudden unexpected death in epilepsy (SUDEP), and digital tools. An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation of this knowledge challenging and increases the risk of unequal access to care. Innovation and focus on prioritized groups, such as newly diagnosed and persons with pharmacoresistant epilepsy or comorbidities, will be needed.

An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

Pathological causes of sudden death in autopsied children with reference to peculiar findings: An Egyptian perspective.

Childhood is a long period extending up to the age of 18 years. Childhood encompasses different developmental stages; each stage has specific characteristics. This 5-year study included 244 autopsied children who died unexpectedly due to natural causes. This study was conducted in the forensic pathology unit of the Egyptian Forensic Medicine Authority (EFMA). Pathological causes of death were diagnosed in 181 cases, representing nearly three-quarters (74.2 %) of cases. Males represented 60.8 % of these cases. More than half (51.4 %) of deaths due to natural disease occurred within the first month of life. The diagnosis was established for the first-time during autopsy in 58 % of cases. Prematurity complications and infections were the cause of death in 35.9 % and 30.4 % of deaths attributed to natural pathologies, respectively. Prematurity complications are the most common cause of death in perinatal (63.6) and neonatal (71.4 %) periods. Whereas infection is the most common cause of death during infancy (55 %), childhood (52.8 %), and adolescence (43.8 %). Pneumonia was the most common infection (61.8 %). This study highlighted cases with peculiar pathologies that include cardiomyopathies (idiopathic dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and Arrhythmogenic right ventricular cardiomyopathy (ARVD)), Waterhouse-Friderichsen syndrome (WFS), ruptured cerebral cavernous hemangioma, and cerebellar medulloblastoma.

Variations in subtle cystic tumors of the atrioventricular node: Five autopsy cases.

Cystic tumor of the atrioventricular node (CTAVN) is the most common primary cardiac tumor cause of sudden death but is rarely found during forensic autopsy. We present five autopsy cases of sudden death from undiagnosed CTAVN. The tumors varied in their histological appearance, which may be related to their variation in clinical presentation. Some of the cases had been diagnosed with epilepsy before death; it seems that syncopal attacks caused by CTAVN may be misdiagnosed as epilepsy. When performing forensic autopsy, CTAVN should be considered in the differential diagnosis of sudden death. Careful examination of the cardiac conduction system is important in every sudden death case regardless of age.

A sudden death, an aortic rupture, and an unexpected cause: a report about suspected child abuse.

All unexpected deaths of children require an autopsy to determine the cause of death. In cases of aortic rupture, the immediate cause of death is easily identified at autopsy. Although the majority of aortic ruptures are caused by high-energy trauma, other causes should not be missed.We present and discuss the case of a 29-month-old child who died suddenly at home. Her recent medical history and the ecchymotic lesions observed on external examination of the body appeared potentially suspicious of physical abuse. The autopsy concluded that death was due to complete rupture of the abdominal aorta with associated vertebral disjunction. At first glance, the overall forensic picture could suggest a traumatic death. However, careful inspection of the retroperitoneum revealed a discrete atypical mass of infiltrative tissue within the hematoma. Histopathological examinations confirmed tumor proliferation of the soft tissues, triggering vascular and spinal injuries. Other paraneoplastic elements or metastases were ultimately revealed (orbital and subcutaneous). Overall, this was a rare and fatal case of abdominal aortic rupture induced by tumors. Due to the mechanisms and the forces needed to cause vertebral dislocations and aortic rupture, the combination of the two is highly suggestive of child abuse when an accidental traumatic history is absent or inconsistent with the injuries. Nevertheless, this case illustrates the importance of a systematic and rigorous forensic examination, rather than ignoring other possible diagnoses.

Sudden unexpected death of a young adult due to subarachnoid hemorrhage associated with polyarteritis nodosa: Clinicopathological appearance and literature review.

A 28-year-old male was found dead in his bedroom. There were no anomalies in his birth and medical history, and there was no family history of sudden unexpected death (SUD). Autopsy showed subarachnoid hemorrhage (SAH) with basilar top inflammatory pseudoaneurysm rupture accompanied by fibrinoid necrosis in the aneurysm wall. Active and healed arteritides in small- to medium-sized arteries were identified in the brain, heart, and systemic connective tissue, which was consistent with polyarteritis nodosa (PAN). Furthermore, pneumatosis cystoides intestinalis was observed in the ascending colon. Hepatitis B virus infection and antineutrophil nuclear antibodies were negative. Genetic investigation using whole-exome sequencing showed no mutations among autoinflammatory-related genes, including UBA1, MEFV, and ADA2. SAH due to rupture of a pseudoaneurysm formed by PAN was considered as the cause of death in the present case. Although myocardial ischemia linked to coronary arteritis is a recognized trigger for SUD in PAN, our study showed that rupture of inflammatory pseudoaneurysm in the cerebral artery can also cause SUD in younger subjects with PAN, even if prodromal symptoms are not evident before death.

Sudden unexpected death from subvalvular hemorrhagic cyst complicated with coronary heart disease in an adult.

Cardiac blood cysts are rare benign tumors. It is commonly found in the heart valve and left ventricle of newborns by autopsy and is rarely seen in adults [1, 2]. The typical histopathology of cardiac blood cysts is a closed, round, blood-containing cystic mass attached to the heart valve or endocardium. This article reports a rare case of sudden death due to a giant subaortic cardiac blood cyst with coronary heart disease in an adult patient and summarizes the pathological features, aiming to provide a reference for the forensic pathological identification of cardiac blood cysts.

Reduced long-term mortality after successful resective epilepsy surgery: a population-based study.

BACKGROUND: We investigated all-cause and epilepsy-related mortality in patients operated with resective epilepsy surgery and in non-operated patients with drug-resistant epilepsy. Our hypothesis was that patients who proceed to surgery have lower mortality over time compared with non-operated patients. METHOD: Data from 1329 adults and children from the Swedish National Epilepsy Surgery Register and 666 patients with drug-resistant epilepsy who had undergone presurgical work-up but not been operated were analysed. The operated patients had follow-ups between 2 and 20 years. We used the Swedish Cause of Death Register to identify deaths. Autopsy reports were collected for patients with suspected sudden unexpected death in epilepsy (SUDEP). Kaplan-Meier and Cox regression analyses were performed to identify predictors for mortality and SUDEP. RESULTS: SUDEP accounted for 30% of all deaths. Surgery was associated with lower all-cause mortality (HR 0.7, 95% CI 0.5 to 0.9), also when adjusted for age, sex and tonic-clonic seizures at inclusion. The benefit of surgery seemed to persist and possibly even increase after 15 years of follow-up. Risk factors of mortality for operated patients were persisting seizures and living alone. Of the operated patients, 37% had seizures, and these had a higher risk of mortality (HR 2.1, 95% CI 1.4 to 3.0) and SUDEP (HR 3.5, 95% CI 1.7 to 7.3) compared with patients with seizure freedom at last follow-up. CONCLUSIONS: In this large population-based epilepsy surgery cohort, operated patients had a lower all-cause mortality compared with non-operated patients with drug-resistant epilepsy. Seizure freedom was the most important beneficial factor for both all-cause mortality and SUDEP among operated patients.

Non-colloid-cyst primary brain tumors: A systematic review of unexpected fatality.

OBJECTIVE: Primary brain tumors have the potential to present a substantial health hazard, ultimately resulting in unforeseen fatalities. Despite the enhanced comprehension of many diseases, the precise prediction of disease progression continues to pose a significant challenge. The objective of this study is to investigate cases of unexpected mortality resulting from primary brain tumors and analyze the variables that contribute to such occurrences. METHODS: This systematic review explores research on individuals diagnosed with primary brain tumors who experienced unexpected deaths. It uses PRISMA standards and searches PubMed, Google Scholar, and Scopus. Variables considered include age, gender, symptoms, tumor type, WHO grade, postmortem findings, time of death - time taken from first medical presentation or hospital admission to death, comorbidity, and risk factors. RESULTS: This study examined 46 studies to analyze patient-level data from 76 individuals with unexpected deaths attributed to intracranial lesions, deliberately excluding colloid cysts. The cohort's age distribution showed an average age of 37 years, with no significant gender preference. Headache was the most common initial symptom. Astrocytomas, meningiomas, and glioblastoma were the most common lesions, while the frontal lobe, temporal lobe, and cerebellum were common locations. Meningiomas and astrocytomas showed faster deaths within the first hour of hospital admission. CONCLUSION: The etiology of unforeseen fatalities resulting from cerebral tumors elucidates an intricate and varied phenomenon. Although unexpected deaths account for a very tiny proportion of total fatalities, it is probable that their actual occurrence is underestimated as a result of underreporting and misdiagnosis.

Lesions of the Cardiac Conduction System and Sudden Death.

ABSTRACT: When a young previously healthy person dies suddenly, occasionally, the scene is noncontributory and the autopsy and drug screen are negative. In such cases, additional studies, including genetic assessment and cardiac conduction system examination, should be performed. We performed a literature search and reviewed our own material to identify possible or definite conduction system anomalies that may cause death. We identified intrinsic conduction system disease including cystic tumor of the atrioventricular node, atrioventricular node (cystic tumor of the AV node), and fibromuscular dysplasia of the atrioventricular node artery to be likely causes of death. Extrinsic causes, in which a generalized disease affects the conduction system, include tumors, autoimmune disease, infiltrative disorders, and others, are a second category of diseases that can affect the conduction system and cause atrioventricular block and sudden death.

Hemorragia Intracerebral Imprevisible en un Hombre Joven: La Importancia de la Tomografía computarizada craneal post-mortem / Unpredictable Intracerebral Hemorrhage in a Young Male: The Importance of Post-Mortem Cranial Computed Tomography

La muerte súbita es aquella que ocurre dentro de las 24 horas posteriores al inicio de los síntomas y se caracteriza por ser clínicamente inexplicable, inesperada y repentina. Debido a la naturaleza de la muerte súbita, no es posible llegar a un diagnóstico preciso sin una autopsia. En esta comunicación breve, evaluaremos el caso de un empleado de crucero de 33 años, sin historial médico/farmacológico previo, el cual falleció súbitamente mientras reposaba en su camarote. Debido a las sospechas iniciales de una posible muerte causada por una sobredosis de cocaína, se le realizó un panel toxicológico abarcador el cual resultó negativo. Empero, una tomografía computarizada (TC) craneal sin contraste revirtió la hipótesis inicial y la autopsia neuropatológica -sorpresivamente- confirmó que la verdadera causa de muerte fue la ruptura de un aneurisma sacular desconocido en el polígono de Willis.

Sudden death occurs within 24 hours after the onset of symptoms and is characterized by being clinically inexplicable, sudden, and unexpected. Due to the nature of sudden death, it is not possible an accurate diagnosis without performing an autopsy. In this brief communication, we will evaluate the case of a 33-year-old cruise employee, with no prior medical/pharmacological history, who suddenly died while resting in his cabin. Due to initial suspicions of a possible cocaine overdose death, a comprehensive toxicology panel was performed, although yielding a negative result. A cranial computed tomography without contrast reversed the initial hypothesis and the neuropathological autopsy -surprisingly- confirmed that the true cause of death was the rupture of an unknown saccular aneurysm in the Circle of Willis.

Factors associated with unexplained sudden deaths among adults aged 18-45 years in India - A multicentric matched case-control study.

BACKGROUND OBJECTIVES: In view of anecdotal reports of sudden unexplained deaths in India's apparently healthy young adults, linking to coronavirus disease 2019 (COVID-19) infection or vaccination, we determined the factors associated with such deaths in individuals aged 18-45 years through a multicentric matched case-control study. METHODS: This study was conducted through participation of 47 tertiary care hospitals across India. Cases were apparently healthy individuals aged 18-45 years without any known co-morbidity, who suddenly (<24 h of hospitalization or seen apparently healthy 24 h before death) died of unexplained causes during 1 st October 2021-31 st March 2023. Four controls were included per case matched for age, gender and neighborhood. We interviewed/perused records to collect data on COVID-19 vaccination/infection and post-COVID-19 conditions, family history of sudden death, smoking, recreational drug use, alcohol frequency and binge drinking and vigorous-intensity physical activity two days before death/interviews. We developed regression models considering COVID-19 vaccination ≤42 days before outcome, any vaccine received anytime and vaccine doses to compute an adjusted matched odds ratio (aOR) with 95 per cent confidence interval (CI). RESULTS: Seven hundred twenty nine cases and 2916 controls were included in the analysis. Receipt of at least one dose of COVID-19 vaccine lowered the odds [aOR (95% CI)] for unexplained sudden death [0.58 (0.37, 0.92)], whereas past COVID-19 hospitalization [3.8 (1.36, 10.61)], family history of sudden death [2.53 (1.52, 4.21)], binge drinking 48 h before death/interview [5.29 (2.57, 10.89)], use of recreational drug/substance [2.92 (1.1, 7.71)] and performing vigorous-intensity physical activity 48 h before death/interview [3.7 (1.36, 10.05)] were positively associated. Two doses lowered the odds of unexplained sudden death [0.51 (0.28, 0.91)], whereas single dose did not. INTERPRETATION CONCLUSIONS: COVID-19 vaccination did not increase the risk of unexplained sudden death among young adults in India. Past COVID-19 hospitalization, family history of sudden death and certain lifestyle behaviors increased the likelihood of unexplained sudden death.

Technology of genomic balancing of chromatin of autologous hematopoietic stem cells for gene therapy of fatal immune-mediated diseases of civilization, extended life expectancy and sudden human death prevention.

A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNAnmr) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNAnmr. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis. AIMS: The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients. METHODS: The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death. RESULTS: Thirty-four patients from 15 families were included, and five identified variants were novel. Probands' mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06). CONCLUSIONS: LDS is associated with high burden of cardiovascular complications at a young age.

Childhood contact with social services and risk of suicide or sudden death in young adulthood: identifying hidden risk in a population-wide cohort study.

BACKGROUND: Childhood out-of-home care is associated with premature death in adulthood, in particular death by suicide, accidents and violence. However, little is known about the mortality risk in the much larger population of adults that had contact with social services in childhood but never entered out-of-home care. We determine the association between all tiers of contact with children's social services and risk of suicide and other sudden deaths in young adulthood. METHODS: This population-wide, longitudinal, record-linkage study of adults in Northern Ireland born between 1985 and 1997 (n=437 008) followed each individual from age 18 years to July 2021 (maximum age 36 years). Cox regression models estimated the association between level of contact with social services in childhood (no contact; referred but assessed as not in need (NIN); child in need (CIN) and child in care (CIC)) and risk of death by suicide and sudden death in young adulthood. RESULTS: Individuals with childhood social care contact (n=51 097) comprised 11.7% of the cohort yet accounted for 35.3% of sudden deaths and 39.7% of suicide deaths. Risk of suicide or sudden death increased stepwise with level of childhood contact and was highest in adults with a history of out-of-home care (suicide HR 8.85 (95% CI 6.83 to 11.4)). Individuals assessed as NIN, and those deemed a CIN, had four times the risk of death by suicide in young adulthood compared with unexposed peers (HR 4.25 (95% CI 3.26 to 5.53) and HR 4.49 (95% CI 3.75 to 5.39), respectively). CONCLUSION: Childhood contact with social services is a risk marker for death by suicide and sudden death in young adulthood. Risk is not confined to adults with a history of out-of-home care but extends to the much larger population that had contact with social services but never entered care.

Unexpected death involving the spleen - an overview.

The spleen is located in the left upper quadrant of the abdominal cavity and has both immunological and haematological functions. A variety of quite different entities may be associated with sudden death due to splenic involvement. These range from simple traumatic disruption of the parenchyma of a normal spleen with marked intra-abdominal haemorrhage, to conditions such as malaria and infectious mononucleosis where splenomegaly predisposes to rupture. Haematological diseases such as malignancies and haemoglobinopathies may causes sudden death due to haemorrhage or red cell sequestration. Asplenia or polysplenia may be associated with significant congenital heart disease. Hyposplenia, both structural and functional, may also result in rapid demise from sometimes unusual bacterial infections. Vascular abnormalities causing death include entities such as splenic artery aneurysms. Thus, deaths from splenic pathology may be due to localised issues or may be part of more generalised disease. For this reason the autopsy in cases of splenic-associated deaths must be comprehensive and include special testing such as microbiological screening and/or haematologic/genetic evaluation.

A case of suspected primary mediastinal large B-cell lymphoma: An uncommon cause of sudden death.

Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive tumor originating from thymic B-cells. Clinically, it presents with general signs such as cough, chest pain and dyspnea. Although these symptoms are not specific, they are severe enough to reveal the disease. We report an autopsy case of a 25-year-old man, with a recent past history of cough and dyspnea, for which he consulted twice the emergency department and no diagnosis was made. He presented to the Emergency Unit, with a sudden onset of a dyspnea followed by a loss of consciousness. He was shortly declared dead after, a medico-legal autopsy was requested. On external examination, no traumatic lesions on the body were found, an important cyanosis of the face and ears, was, however, found. On autopsy, a mediastinal mass was found, measuring 19 cm × 25 cm and weighing 600 g, extending to the infra-hyoid region and to the thoracic cage and infiltrating the pericardium. Trachea had a necrotic mucosa with a partially obstructive lymph node mass. The diagnosis of a primary mediastinal large B-cell lymphoma was suspected based on pathological and immunohistochemical findings. The cause of death was finally attributed to respiratory failure due to this tumor.