Sudden Unexpected Death in Epilepsy: A PersonaliZed Prediction Tool

OBJECTIVE: To develop and validate a tool for individualised prediction of Sudden Unexpected Death in Epilepsy (SUDEP) risk, we re-analysed data from one cohort and three case-control studies undertaken 1980-2005. METHODS: We entered 1273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model. RESULTS: Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalised tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM +/-12.5, and 22.9, SEM +/-11.0 respectively). The mean cross-validated (95% Credibility Interval) Area Under the Receiver Operating Curve was 0.71 (0.68 to 0.74) for our model versus 0.38 (0.33 to 0.42) and 0.63 (0.59 to 0.67) for the baseline average and generalised tonic-clonic seizure frequency models respectively. Model performance was weaker when applied to non-represented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age of epilepsy onset and family history of epilepsy. Anti-seizure medication adherence was associated with lower risk. CONCLUSIONS: Even when generalised to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not only focus on the frequency of convulsions

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

The long-term course of temporal lobe epilepsy: From unilateral to bilateral interictal epileptiform discharges in repeated video-EEG monitorings

INTRODUCTION: Bilateral interictal epileptiform discharges (IED) and ictal patterns are common in temporal lobe epilepsy (TLE) and have been associated with decreased chances of seizure freedom after epilepsy surgery. It is unclear whether secondary epileptogenesis, although demonstrated in experimental models, exists in humans and may account for progression of epilepsy. MATERIAL AND METHODS: We reviewed consecutive video-EEG recordings from 1992 to 2014 repeated at least two years apart (mean interval 6.14 years) in 100 people diagnosed with TLE. RESULTS: Ictal EEG patterns and IED remained restricted to one hemisphere in 36 people (group 1), 46 exhibited bilateral abnormalities from the first recording (group 2), 18 progressed from unilateral to bilateral EEG pathology over time (group 3). No significant differences between the three groups were seen with respect to age at epilepsy onset, duration, or underlying pathology. Extra-temporal IED during the first EEG recording were associated with an increased risk of developing bilateral epileptiform changes over time (hazard ratio 3.67; 95% CI 1.4, 9.4). CONCLUSION: Our findings provide some support of progression in TLE and raise the possibility of secondary epileptogenesis in humans. The development of an independent contra-lateral epileptogenic focus is known to be associated with a less favorable surgical outcome. We defined reliable EEG markers for an increased risk of progression to more widespread or independent bitemporal epileptogenicity at an early stage, thus allowing for individualized pre-surgical counselling

Apoptotic cell clearance in chronic inflammation of lateral neck cysts

The mechanism driving accumulation of large numbers of apoptotic and necrotic neutrophils in inflamed lateral neck cysts (LNC), in the absence of infection, remains obscure. The cellular content of cysts obtained from 17 patients was co-cultured with human macrophages. Phagocytosis levels of cyst-derived neutrophils were determined and compared to the uptake of spontaneously apoptotic neutrophils. Simultaneously, the expression of cytokines in macrophages exposed to cyst contents was measured. In comparison to spontaneously apoptotic neutrophils, the phagocytosis of LNC-derived neutrophils by macrophages was inefficient. An inverse correlation between neutrophil content in LNC and their uptake was observed. Macrophages co-cultured with cyst contents responded with variable expression of IL-6, TNF-α and IL-10. The hindered clearance of apoptotic neutrophils in LNC may lead to secondary necrosis of these cells and stimulation of the inflammatory reaction. Together with local production of anti-inflammatory cytokines, this may fuel chronic inflammation in the cysts

Audit of practice in SUDEP post mortems and neuropathological findings.

Sudden Unexpected Death in Epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP

Somatic complications of epilepsy surgery over 25 years at a single center

INTRODUCTION: Epilepsy surgery is an effective treatment for refractory focal epilepsy. Risks of surgery need to be considered when advising individuals of treatment options. We describe the frequency and nature of physical adverse events associated with epilepsy surgery in a single center. MATERIAL AND METHODS: We reviewed the prospectively maintained records of adults who underwent epilepsy surgery at our center between 1990 and 2014 to identify peri/postsurgical adverse events. These were categorized into neurological deficits and those related to surgery (e.g. wound infections). Neurological deficits were categorized as expected or unexpected and into transient (≤3 months) or persistent (>3 months), RESULTS: There were 911 procedures with no peri-operative deaths. Persistent neurological adverse events were seen following 157 (17.2%) procedures. The most common persistent expected complication was quadrantanopia after temporal lobe resections (72/764, 9.4%). Unexpected persistent neurological complications occurred in 20 procedures (2.2%) and included: quadrantanopia (6, 0.7%); hemianopia (2, 0.2%); hemi/mono-paresis/sensory loss (9, 1%); dysphasia (10, 1%); frontalis muscle weakness (2, 0.2%); and oculomotor weakness (1, 0.1%). 106 surgery related adverse events occurred in 83 procedures, with severe infections requiring bone-flap removal in 24 (2.6%) procedures and intracranial infections in 8 (0.9%). The risk of post-resective severe infection increased by 4 fold (OR 4.32, 95% CI 2.1 to 8.9, p < 0.001) with use of subdural EEG monitoring prior to resection. In consequence, in August 2011 we introduced antibiotic coverage in all individuals undergoing intracranial monitoring. Also, after August 2011 there was greater use of Stereo-EEG (SEEG) than subdural (OR 9.0 CI 0.36 to 224.2, p = 0.18 ns). One complicated by severe infection. Other surgical complications included haematoma (0.3%), hydrocephalus (0.3%) and CSF leak (1.2%). None had permanent complications. CONCLUSIONS: Adverse event rates are similar to other series. Epilepsy surgery carries well defined surgical and neurological risks. The risks of somatic adverse events, in addition to neuropsychiatric and neuropsychological complications need to be made clear to individuals considering this treatment option

Factors affecting seizure outcome after epilepsy surgery: an observational series

IMPORTANCE: Surgical treatment can bring seizure remission in people with focal epilepsy, but requires careful selection of candidates. OBJECTIVES: To determine which preoperative factors are associated with post-operative seizure outcome. DESIGN: We audited seizure outcome of 693 adults who had resective epilepsy surgery between 1990 and 2010 and used survival analysis to detect preoperatively identifiable risk factors of poor seizure outcome. RESULTS: Seven factors were significantly associated with increased probability of recurrence of seizures with impaired awareness post-surgery: MRI findings (eg hazard ratio adjusted for other variables in the model 2.5; 95% CI 1.6 to 3.8 for normal MRI compared with hippocampal sclerosis (HS)), a history of secondarily generalised convulsive seizures (2.3; 95% CI 1.7 to 3.0 for these seizures in the previous year vs never), psychiatric history (1.3; 95% CI 1.1 to 1.7), learning disability (1.8; 95% CI 1.2 to 2.6), and extratemporal (vs temporal) surgery (1.4; 95% CI 1.02, 2.04). People with an older onset of epilepsy had a higher probability of seizure recurrence (1.01; 95% CI 1.00, 1.02) as did those who had used more anti-epileptic drugs (1.05; 95% CI 1.01, 1.09). Combinations of variables associated with seizure recurrence gave overall low probabilities of 5-year seizure freedom (eg a normal MRI and convulsive seizures in the previous year has a probability of seizure freedom at five years of approximately 0.19). CONCLUSIONS AND RELEVANCE: Readily identified clinical features and investigations are associated with reduced probability of good outcome and need consideration when planning presurgical evaluation

AP-1 Is a Component of the Transcriptional Network Regulated by GSK-3 in Quiescent Cells

The protein kinase GSK-3 is constitutively active in quiescent cells in the absence of growth factor signaling. Previously, we identified a set of genes that required GSK-3 to maintain their repression during quiescence. Computational analysis of the upstream sequences of these genes predicted transcription factor binding sites for CREB, NFκB and AP-1. In our previous work, contributions of CREB and NFκB were examined. In the current study, the AP-1 component of the signaling network in quiescent cells was explored.Using chromatin immunoprecipitation analysis, two AP-1 family members, c-Jun and JunD, bound to predicted upstream regulatory sequences in 8 of the 12 GSK-3-regulated genes. c-Jun was phosphorylated on threonine 239 by GSK-3 in quiescent cells, consistent with previous studies demonstrating inhibition of c-Jun by GSK-3. Inhibition of GSK-3 attenuated this phosphorylation, resulting in the stabilization of c-Jun. The association of c-Jun with its target sequences was increased by growth factor stimulation as well as by direct GSK-3 inhibition. The physiological role for c-Jun was also confirmed by siRNA inhibition of gene induction.These results indicate that inhibition of c-Jun by GSK-3 contributes to the repression of growth factor-inducible genes in quiescent cells. Together, AP-1, CREB and NFκB form an integrated transcriptional network that is largely responsible for maintaining repression of target genes downstream of GSK-3 signaling

Efficacy of acupuncture for chronic low back pain: protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Chronic back pain is a major public health problem and the primary reason patients seek acupuncture treatment. Therefore, an objective assessment of acupuncture efficacy is critical for making informed decisions about its appropriate role for patients with this common condition. This study addresses methodological shortcomings that have plagued previous studies evaluating acupuncture for chronic low back pain.</p> <p>Methods and Design</p> <p>A total of 640 participants (160 in each of four arms) between the ages of 18 and 70 years of age who have low back pain lasting at least 3 months will be recruited from integrated health care delivery systems in Seattle and Oakland. They will be randomized to one of two forms of Traditional Chinese Medical (TCM) acupuncture needling (individualized or standardized), a "control" group (simulated acupuncture), or to continued usual medical care. Ten treatments will be provided over 7 weeks. Study participants and the "Diagnostician" acupuncturists who evaluate participants and propose individualized treatments will be masked to the acupuncture treatment actually assigned each participant. The "Therapist" acupuncturists providing the treatments will not be masked but will have limited verbal interaction with participants. The primary outcomes, standard measures of dysfunction and bothersomeness of low back pain, will be assessed at baseline, and after 8, 26, and 52 weeks by telephone interviewers masked to treatment assignment. General health status, satisfaction with back care, days of back-related disability, and use and costs of healthcare services for back pain will also be measured. The primary analysis comparing outcomes by randomized treatment assignment will be analysis of covariance adjusted for baseline value. For both primary outcome measures, this trial will have 99% power to detect the presence of a minimal clinically significant difference among all four treatment groups and over 80% power for most pairwise comparisons. Secondary analyses will compare the proportions of participants in each group that improve by a clinically meaningful amount.</p> <p>Conclusion</p> <p>Results of this trial will help clarify the value of acupuncture needling as a treatment for chronic low back pain.</p> <p>Trial registration</p> <p>Clinical Trials.gov NCT00065585.</p

The Spin Structure of the Nucleon

We present an overview of recent experimental and theoretical advances in our understanding of the spin structure of protons and neutrons.Comment: 84 pages, 29 figure