Peri-ictal heart rate variability parameters as surrogate markers of seizure severity

This study aims at defining objective parameters reflecting the severity of peri-ictal autonomic changes and their relation to post-ictal generalized electroencephalography (EEG) suppression (PGES), with the view that such changes could be detected by wearable seizure detection systems and prove useful to assess the risk of sudden unexpected death in epilepsy (SUDEP). To this purpose, we assessed peri-ictal changes in heart rate variability (HRV) and correlated them with seizure duration, intensity of electromyography-based ictal muscle activity, and presence and duration of post-ictal generalized EEG suppression (PGES). We evaluated 75 motor seizures from 40 patients, including 61 generalized tonic-clonic seizures (GTCS) and 14 other major motor seizure types. For all major motor seizures, HRV measurements demonstrated a significantly decreased parasympathetic activity and increased sympathetic activity in the post-ictal period. The post-ictal increased sympathetic activity was significantly higher for GTCS as compared with non-GTCS. The degree of peri-ictal decreased parasympathetic activity and increased sympathetic activity was associated with longer PGES (>20 s), longer seizure duration, and greater intensity of ictal muscle activity. Mean post-ictal heart rate (HR) was an independent predictor of PGES duration, seizure duration, and intensity of ictal muscle contraction. Our results indicate that peri-ictal changes in HRV are potential biomarkers of major motor seizure severity.     

TGF-B3 Dependent Modification of Radiosensitivity in Reporter Cells Exposed to Serum From Whole-Body Low Dose-Rate Irradiated Mice

Prior findings in vitro of a TGF-β3 dependent mechanism induced by low dose-rate irradiation and resulting in increased radioresistance and removal of low dose hyper-radiosensitivity (HRS) was tested in an in vivo model. DBA/2 mice were given whole-body irradiation for 1 h at low dose-rates (LDR) of 0.3 or 0.03 Gy/h. Serum was harvested and added to RPMI (4% mouse serum and 6% bovine serum).This medium was transferred to reporter cells (T-47D breast cancer cells or T98G glioblastoma cells). The response to subsequent challenge irradiation of the reporter cells was measured by the colony assay. While serum from unirradiated control mice had no effect on the radiosensitivity in the reporter cells, serum from mice given 0.3 Gy/h or 0.03 Gy/h for 1 h removed HRS and also increased survival in response to doses up to 5 Gy. The effect lasted for at least 15 months after irradiation. TGF-β3 neutralizer added to the medium containing mouse serum inhibited the effect. Serum from mice given irradiation of 0.3 Gy/h for 1 h and subsequently treated with iNOS inhibitor 1400W did not affect radiosensitivity in reporter cells; neither did serum from the unirradiated progeny of mice given 1h LDR whole-body irradiation.     

Heart rate variability analysis indicates preictal parasympathetic overdrive preceding seizure‐induced cardiac dysrhythmias leading to sudden unexpected death in a patient with epilepsy

Evidence for seizure‐induced cardiac dysrhythmia leading to sudden unexpected death in epilepsy (SUDEP) has been elusive. We present a patient with focal cortical dysplasia who has had epilepsy for 19 years and was undergoing presurgical evaluation. The patient did not have any cardiologic antecedents. During long‐term video–electroencephalography (EEG) monitoring, following a cluster of secondarily generalized tonic–clonic seizures (GTCS), the patient had prolonged postictal generalized EEG suppression, asystole, followed by arrhythmia, and the patient died despite cardiopulmonary resuscitation. Analysis of heart rate variability showed a marked increase in the parasympathetic activity during the period preceding the fatal seizures, compared with values measured 1 day and 7 months before, and also higher than the preictal values in a group of 10 patients with GTCS without SUDEP. The duration of the QTc interval was short (335–358 msec). This unfortunate case documented during video‐EEG monitoring indicates that autonomic imbalance and seizure‐induced cardiac dysrhythmias contribute to the pathomechanisms leading to SUDEP in patients at risk (short QT interval). A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.

     

The CCC2000 Birth Cohort Study of Register-Based Family History of Mental Disorders and Psychotic Experiences in Offspring

Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11–12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82–5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64–13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors.Key words: psychosis, schizophrenia, epidemiology, family liability, general population, psychiatric family history     

The role of nitric oxide radicals in removal of hyper-radiosensitivity by priming irradiation

In this study, a mechanism in which low-dose hyper-radiosensitivity (HRS) is permanently removed, induced by low-dose-rate (LDR) (0.2–0.3 Gy/h for 1 h) but not by high-dose-rate priming (0.3 Gy at 40 Gy/h) was investigated. One HRS-negative cell line (NHIK 3025) and two HRS-positive cell lines (T-47D, T98G) were used. The effects of different pretreatments on HRS were investigated using the colony assay. Cell-based ELISA was used to measure nitric oxide synthase (NOS) levels, and microarray analysis to compare gene expression in primed and unprimed cells. The data show how permanent removal of HRS, previously found to be induced by LDR priming irradiation, can also be induced by addition of nitric oxide (NO)-donor DEANO combined with either high-dose-rate priming or exposure to prolonged cycling hypoxia followed by reoxygenation, a treatment not involving radiation. The removal of HRS appears not to involve DNA damage induced during priming irradiation as it was also induced by LDR irradiation of cell-conditioned medium without cells present. The permanent removal of HRS in LDR-primed cells was reversed by treatment with inducible nitric oxide synthase (iNOS) inhibitor 1400W. Furthermore, 1400W could also induce HRS in an HRS-negative cell line. The data suggest that LDR irradiation for 1 h, but not 15 min, activates iNOS, and also that sustained iNOS activation is necessary for the permanent removal of HRS by LDR priming. The data indicate that nitric oxide production is involved in the regulatory processes determining cellular responses to low-dose-rate irradiation.     

Lactate metabolism during exercise in patients with mitochondrial myopathy

Patients with mitochondrial DNA mutations often have elevated plasma lactate at rest and during exercise, but it is unknown whether the high lactate levels are caused by a high production, an impaired oxidation or a combination. We studied lactate kinetics in 10 patients with mtDNA mutations and 10 matched healthy control subjects at rest and during cycle exercise with a combination of femoral arterio-venous differences of lactate, and lactate tracer dilution methodology. During exercise, lactate concentration and production rates were several-fold higher in patients, but despite mitochondrial dysfunction, lactate was oxidized in muscle to the same extent as in healthy control subjects. This surprisingly high ability to burn lactate in working muscle with defective mitochondria, probably relates to the variability of oxidative capacity among muscle fibers. The data suggests that lactate is not solely an indicator of impaired oxidative capacity, but an important fuel for oxidative metabolism, even in muscle with severely impaired mitochondrial function.