Sudden unexpected death in an adolescent with epilepsy: All roads lead to the heart?

The incidence of sudden unexpected death in epilepsy (SUDEP) has been estimated from 0.5-1.4/1,000 person-years in people with treated epilepsy, and 9/1,000 person-years in candidates for epilepsy surgery. Potential risk factors for SUDEP include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure type and winter temperatures. The arrythmogenic side-effect of antiepileptic drugs and seizures may increase the risk of SUDEP. In this report, we describe a patient with prolonged post-ictal tachycardia in EEG video recordings with a typical case of SUDEP: a 16-year-old boy with medically intractable complex partial seizures. Magnetic resonance imaging revealed left mesial temporal sclerosis. During non-invasive video-EEG monitoring, the patient presented a post-ictal heart rate increased for five hours. Two months after video-EEG, he died from SUDEP during a tonic-clonic secondary generalized seizure. The possibility of cardiac involvement in the pathogenesis of SUDEP has been suggested by many studies. Evaluation of this patient with EEG-video monitoring, including measurement of heart rate, contributed to an identification of ictal tachycardia that may have played a role in the SUDEP. Premature mortality seems to be increased in patients with epilepsy, and cardiac abnormalities may be a possible cause of SUDEP. (Cardiol J 2011; 18, 2: 194-196)

Pediatric epilepsy surgery and sudden unexpected death epilepsy: the contribution of a Brazilian epilepsy surgery program

Individuals with epilepsy are at higher risk of death than those from the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Epilepsies in the pediatric group are more frequently associated with known potentially risk factors for SUDEP, and a treatment resulting in an improved seizure control may also decrease mortality. The aim of this study is to identify the incidence of SUDEP in a group of operated-on children and adolescents. We analyzed 267 patients up to 18 years old, with medically intractable epilepsy submitted to surgery. We considered the age at surgery, the seizure type, the pathological findings, and the seizure outcome. Data were prospectively collected, according to the protocols of our institution`s ethics committee. The percentage of boys was 58.05. A good outcome was achieved in 72.6% of the cases and a bad outcome in 27.4%. Nine patients died during follow-up, six from clinical complications, and one from SUDEP. All patients who died during the long-term follow-up had persisted with refractory postoperative seizures. The patient who died from SUDEP died during a generalized tonic-clonic seizure. Of the patients, 72.6% had excellent postoperative outcome, and one patient died of SUDEP. All patients who died had had disabling seizures` persistence. The surgical treatment of epilepsy in children and adolescents is an efficient therapy for the medically intractable symptomatic epilepsies and also for the reduction of mortality and SUDEP risks.

Subclinical hyperthyroidism and sudden unexpected death in epilepsy

Epilepsy is the most common serious neurological condition and 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 high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. In parallel, several studies have shown a link between hormones and epilepsy. However, exact knowledge regarding the association of thyroid hormones and epilepsy is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease, we propose in this paper that SUDEP, at least in some cases, could be related with subclinical thyroid dysfunction. (C) 2009 Elsevier Ltd. All rights reserved.

Benefits of sunlight: Vitamin D deficiency might increase the risk of sudden unexpected death in epilepsy

Epilepsy is the most common serious neurological condition and 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 high seizure frequency is a potential risk factor. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role. In parallel, studies have shown a link between vitamin D dysfunction and epilepsy. Moreover, several evidences in the literature suggest an association between low vitamin D and seizures, indicating the possibility of anticonvulsant properties of this hormone. Quite interesting, a growing body of data suggests that low vitamin D levels may adversely affect cardiovascular health, directly associated with death from heart failure and sudden cardiac death. In view of the above findings, our research group focused in this review article that SUDEP, at least in some cases, could be related with low vitamin D levels. (C) 2009 Elsevier Ltd. All rights reserved.

Does the lunar phase have an effect on sudden unexpected death in epilepsy?

The incidence of sudden unexpected death in epilepsy (SUDEP) in Our epilepsy unit over an 8-year period was analyzed to determine a possible association between phase of the moon and SUDEP. Analysis revealed that the number of SUDEPs was highest in full moon (70%), followed by waxing moon (20%) and new moon (10%). No SUDEPs Occurred during the waning cycle. These preliminary findings suggest that the full moon appears to correlate with SUDEP. (C) 2008 Elsevier Inc. All rights reserved.

Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers

Objective This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers. Methods Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS. Results The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n=8), or CYP2C19*17*2 (n=1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n=9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity. Conclusions Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R=-0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.

Investigation of IGF2/ApaI and H19/RsaI polymorphisms in patients with cutaneous melanoma

Objective: The etiology of cutaneous melanoma is complex, involving both heterogeneous genetic and environmental components. The aim of our study was to verify if single polymorphic sites within IGF2 and H19 genes and their consequent haplotypes influence risk and/or prognosis of familial melanoma. Design: Twenty one patients with clinical criteria of hereditary melanoma (early onset, presence of multiple primary melanoma, and/or one or more affected first- or second-degree relatives) and previously screened for CDKN2A mutations were genotyped by IGF2/ApaI and H19/RsaI PCR-RFLPs. Data were compared between patients and a control group (100 healthy young individuals) using Chi-square and Fisher`s exact tests. We also investigated if these polymorphic sites could be microRNAs potential targets, using RegRNA software. Results: Although the IGF2 and HI9 genotypes/haplotypes were not significantly associated with melanoma, two of the most severe cases (very early onset or multiple melanomas) showed to be heterozygous for both genes. We found an overlap between IGF2/ApaI and miR-615-5p, and between H19/RsaI and miR-574-3p. Conclusions: Some studies have shown H19, and IGF2 genes (or related genes or protein, for example, IGF2R and IMP-3) differential expression in melanoma. However, no study has attempted to examine markers across this cluster in relation to melanoma until now. Since the base change may impair the pairing of microRNA and its binding site, our results suggest a new window for future studies of IGF2 and H19 genetic variability and posttranscriptional regulation. Due to the importance and based on the present results, we suggest that the genotype/haplotype analysis of IGF2 and H19 polymorphisms should be better investigated in large populations with cutaneous melanoma, attempting to tie the association with progression of the disease. (C) 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.

Giant right coronary artery aneurysm presenting as a paracardiac mass

Coronary artery aneurysms, commonly atherosclerotic, are usually asymptomatic and can be diagnosed incidentally during investigation for ischemic heart disease or on autopsy. An asymptomatic giant right coronary artery aneurysm presenting as a paracardiac mass discovered on autopsy is reported here. Even though there was great concern due to its large size, complex atherosclerotic lesions, and potential obstruction of blood flow, it had no direct link to the cause of death. We also review the literature on giant right coronary artery aneurysms exceeding 5 cm in the last 10 years. (C) 2008 Elsevier Inc. All rights reserved.

mRNA Expression Profile of Multidrug Resistance Genes in Childhood Acute Lymphoblastic Leukemia. Low Expression Levels Associated With a Higher Risk of Toxic Death

Background. Increased activity of multidrug resistance (MDR) genes has been associated with treatment failure in acute leukemias, although with controversial reports. The objective of the present study was to assess the expression profile of the genes related to MDR: ABCB1, ABCC1, ABCC3, ABCC2, and LRP/MVP in terms of the clinical and biological variable and the survival of children with acute lymphoblastic leukemia (ALL). Procedure. The levels of mRNA expression of the drug resistance genes ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP were analyzed by quantitative real-time PCR using the median Values as cut-off points, in consecutive samples from 140 children with ALL at diagnosis. Results. Expression levels of the ABCG2 gene in the patient group as a whole (P=0.05) and of the ABCG2 and ABCC1 genes in patients classified as being at high risk were associated with higher rates of 5-year event-free survival (EFS) (P=0.04 and P=0.01). Expression levels of the ABCG2 gene below the median were associated with a greater chance of death related to treatment toxicity for the patient group as a whole (P=0.009) and expression levels below the median of the ABCG2 and ABCC1 genes were associated with a greater chance of death due to treatment toxicity for the high-risk group (P=0.02 and P=0.03, respectively). Conclusion. The present data suggest a low participation of the drug efflux genes in treatment failure in patients with childhood ALL. However, the low expression of some of these genes may be associated with a higher death risk related to treatment toxicity. Pediatr Blood Cancer 2009;53:996-1004. (C) 2009 Wiley-Liss, Inc.

Precise Temporal Regulation of roughest is Required for Correct Salivary Gland Autophagic Cell Death in Drosophila

The Drosophila roughest (rst) locus encodes an immunoglobulin superfamily transmembrane glycoprotein implicated in a variety of embryonic and postembryonic developmental processes. Here we demonstrate a previously unnoticed role for this gene in the autophagic elimination of larval salivary glands during early pupal stages by showing that overexpression of the Rst protein ectodomain in early pupa leads to persistence of salivary glands up to at least 12 hours after head eversion, although with variable penetrance. The same phenotype is observed in individuals carrying the dominant regulatory allele rst(D), but not in loss of function alleles. Analysis of persistent glands at the ultrastructural level showed that programmed cell death starts at the right time but is arrested at an early stage of the process. Finally we describe the expression pattern and intracellular distribution of Rst in wild type and rstD mutants, showing that its downregulation in salivary glands at the beginning of pupal stage is an important factor in the correct implementation of the autophagic program of this tissue in space and time. genesis 47:492-504, 2009. (C) 2009 Wiley-Liss, Inc.

Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

Polyunsaturated fatty acids (PUFAs) are known to inhibit cell proliferation of many tumour types both in vitro and in vivo. Their capacity to interfere with cell proliferation has been linked to their induction of reactive oxygen species (ROS) production in tumour tissues leading to cell death through apoptosis. However, the exact mechanisms of action of PUFAs are far from clear, particularly in brain tumours. The loss of bound hexokinase from the mitochondrial voltage-dependent anion channel has been directly related to loss of protection from apoptosis, and PUFAs can induce this loss of bound hexokinase in tumour cells. Tumour cells overexpressing Akt activity, including gliomas, are sensitised to ROS damage by the Akt protein and may be good targets for chemotherapeutic agents, which produce ROS, such as PUFAs. Cardiolipin peroxidation may be an initial event in the release of cytochrome c from the mitochondria, and enriching cardiolipin with PUFA acyl chains may lead to increased peroxidation and therefore an increase in apoptosis. A better understanding of the metabolism of fatty acids and eicosanoids in primary brain tumours such as gliomas and their influence on energy balance will be fundamental to the possible targeting of mitochondria in tumour treatment.

Thyroid gland and cerebella lesions: New risk factors for sudden cardiac death in schizophrenia?

People with schizophrenia show a two to threefold increased risk to die prematurely than those without schizophrenia. Patients` life style, suicide, premature development of cardiovascular disease, high prevalence of metabolic syndrome and sudden cardiac death are well-known causes of the excess mortality. The exact pathophysiological cause of sudden death in schizophrenia is unknown, but it is likely that cardiac arrhythmia and respiratory abnormalities play potential role. Some antipsychotics may be associated with cardiovascular adverse events (e.g., QT interval prolongation) and lesions in specific brain regions, such as cerebella may be associated with respiratory abnormalities, suggesting that metabolic and brain dysfunction could lead to sudden cardiac death in patients with schizophrenia. However, exact knowledge regarding the association of these findings and schizophrenia is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease and cerebella progressive atrophy has been observed in patients with schizophrenia, we propose in this paper that subclinical thyroid dysfunction and cerebella volume loss could be considered as new risk factor for sudden cardiac death in schizophrenia. (C) 2010 Elsevier Ltd. All rights reserved.

Could sudden death syndrome (SDS) in chickens (Gallus gallus) be a valid animal model for sudden unexpected death in epilepsy (SUDEP)?

Epilepsy is the most common serious neurological disorder and approximately 1% of the population worldwide has epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning fisk factors for SUDEP is conflicting, but potential risk factors include: young 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. Similarly, sudden death syndrome (SDS) is a disease characterized by an acute death of well-nourished and seeming healthy Gallus gallus after abrupt and brief flapping of their wings and incidence of SDS these animals has recently increased worldwide. Moreover, the exactly cause of SDS in Gallus gallus is unknown, but is very probable that cardiac abnormalities play a potential role. Due the similarities between SUDEP and SDS and as Gallus gallus behavioral manifestation during SDS phenomenon is close of a tonic-clonic seizure, in this paper we suggest that epilepsy could be a new possible causal factor for SDS. (C) 2009 Elsevier Ltd. All rights reserved.

Insulin Affects Tissue Organization and the Kinetics of Epithelial Cell Death in the Rat Ventral Prostate After Castration

Prostate growth and physiology are regulated by steroid hormones and modulated by multiple endocrine factors We investigated the action of insulin on the tissue organization and kinetics of epithelial cells in the rat ventral prostate (VP) in response to castration up to 120 hours after surgery by using an acute protocol of alloxan induced diabetes Diabetes caused a reduction in volume density (Vv(o)/) and volume of the epithelium The effects of castration on the epithelium were accelerated in the diabetic animals as determined by changes in V(o)/, and volume The smooth muscle cells became atrophic and apparently relaxed in response to castration in contrast to the spinous aspect observed in nondiabetic castrated rats Counting of apoptotic nuclei in the epithelium showed the classical apoptosis peak at 72 hours in nondiabetic rats and an advance of the apoptosis peak to 48 hours after castration in diabetic rats Insulin restored the time of the peak to 72 hours These results were confirmed after immunostaining for cleaved caspase 3 and suggest a survival and antiapoptotic effect on VP epithelial cells in both the presence and absence of androgen stimulation This idea is supported by the observation that insulin also reduced the overall rate of apoptosis at all experimental points analyzed before and after castration

PRECLINICAL INVESTIGATION OF THE RETINAL BIOCOMPATIBILITY OF SIX NOVEL VITAL DYES FOR CHROMOVITRECTOMY

Purpose: To investigate the retinal biocompatibility of six novel vital dyes for chromovitrectomy. Methods: An amount of 0.05 mL of 0.5% and 0.05% light green (LG), fast green (FG), Evans blue (EB), brilliant blue (BriB), bromophenol blue (BroB), or indigo carmine (IC) was injected intravitreally in the right eye, whereas in the left eye balanced salt solution was applied for control in rabbits` eyes. Clinical examination, fluorescein angiography, histology with light microscopy, and transmission electron microscopy were performed after 1 and 7 days. Retinal cell layers were evaluated for morphologic alterations and number of cells. The electroretinographic changes were assessed at baseline, 24 hours and 7 days. Results: Fluorescein angiography disclosed hypofluorescent spots only in the 0.5% EB group. Light microscopy and transmission electron microscopy disclosed slight focal morphologic changes in eyes exposed to 0.05% IC, FG, BriB, similar to the control at 1 and 7 days. In the lower dose groups, EB, LG, and BroB caused substantial retinal alterations by light microscopy. At the higher dose, BroB and EB produced diffuse cellular edema and vacuolization within the ganglion cells, bipolar cells, and photoreceptors. FG and IC at 0.5% caused slight retinal alterations similar to balanced salt solution injection. LG at 0.5% caused diffuse vacuolization of bipolar cells after 1 and 7 days. Injection of 0.5% EB caused a significant decrease in neuroretinal cell counts in comparison to control eyes in the 7-day examination (P < 0.05). Electroretinography revealed intermittent prolonged latency and decreased amplitude in eyes injected with 0.5% EB, LG, BriB, and BroB, while at the lower dose, only LG and EB induced few functional changes. Conclusion: The progressive order of retinal biocompatibility, from safest to most toxic, was IC, FG, BriB, BroB, LG, EB.