Sudden unexpected death in epilepsy, incidence, circumstances and risk factors

Although Sudden Unexpected Death in Epilepsy (SUDEP) has attracted increasing attention from the scientific community during the last 20 years, important gaps in knowledge still exist that hamper the development of methods aiming at prevention of this, the most devastating consequence of epilepsy. We are still missing large population-based studies on the incidence of SUDEP. Our understanding of the circumstances surrounding SUDEP is incomplete which is a major limitation when it comes to development of potential SUDEP-preventing devices. Finally, our understanding of risk factors for SUDEP is limited to a few established risk factors. The purpose of this study was to examine the incidence, circumstances and risk factors for SUDEP in Sweden. The project is based on a study population (n=78 524) which comprises all persons living in Sweden at 1. July 2006, who at some point during 1998-2005 where registered with the diagnosis code for epilepsy (ICD G 40) in the Swedish National Patient Register (SNPR). To identify cases of SUDEP, the study population was linked to the National Cause-of- Death Register. During the follow-up time from July 1, 2006 to December 31, 2011, we identified 9605 deaths. All death certificates in the study population between 1 July 2006 and 31 December 2011 with epilepsy mentioned on death certificate and all deaths during 2008 (n=3166) were reviewed. Based on the information in the death certificates, obvious non-SUDEP deaths were excluded from further analysis. For all others we analyzed patient medical records, autopsy and police reports and information was extracted using a standardized protocol. From the study population, five epilepsy controls per SUDEP case, of the same sex, who were alive at the case´s time of death, were randomly selected by the National Board of Health and Welfare. During 2008, 1890 individuals from the study population died. Of these, 99 met Annegers‘ SUDEP criteria (49 definite, 19 probable, and 31 possible) (paper I). Definite and probable SUDEP accounted for 3.6% of all deaths in the study population during 2008, and 5.2% when possible was included. In the age group 0-15 years, the relative contribution of SUDEP (definite, probable and possible) to overall deaths was 36.0%. SUDEP incidence was 1.20/1000 person-years (definite/ probable) and 1.74/1000 if possible SUDEP was included. Epilepsy was mentioned in any position of the death certificate in 63.6% of the 99 SUDEP cases. Of the 329 SUDEP deaths identified from July 1, 2006 to December 31, 2011 (167 definite, 89 probable, 73 possible), more than half (58%) occurred at night and 91% died at home, whereof 65% were found deceased in bed (paper II). Death was witnessed in 17% of all SUDEP cases and when a seizure was witnessed in conjunction with SUDEP (n=49) all were generalized tonic-clonic seizures (GTCS). Where a body position was documented (43%), more than two thirds (70%) were found prone. Dying at night made it more likely (80%) to be found prone than other times (55%) (p<0.001). Among adult SUDEP cases, 75% were living alone, and only 14% of all SUDEP cases shared a bedroom. In papers III and IV, 255 SUDEP cases (167 definite, 88 probable) were compared to their matched 1148 controls. Those with a history of GTCS had a tenfold increased SUDEP risk and the risk was increased to 32-fold with 4-10 GTCS during the last year of observation. When a history of nocturnal GTCS was present, a nine-fold SUDEP risk was observed and a 15-fold risk was seen if nocturnal GTCS were present during the last year of observation. No increased risk of SUDEP was seen in those experiencing exclusively non-GTCS during the preceding year. There was a fivefold increased risk of SUDEP among those living alone, while the risk was reduced to twofold when sharing household but not bedroom. Individuals experiencing ≥1 GTCS and not sharing a bedroom with someone had 67-fold increased risk of SUDEP compared to individuals not having GTCS, who shared their bedroom with someone, with attributable proportion due to interaction estimated at 0.69 (95% confidence interval, CI 0.53-0.85). Polytherapy, especially taking three or more AEDs was associated with a 69% reduced SUDEP risk after adjusting for GTCS frequency and other covariates. Levetiracetam as monotherapy was associated with a significantly lower SUDEP risk when compared to no AED treatment (odds ratio, OR 0.10, 95% CI 0.03-0.61). Lamotrigine, valproic acid and levetiracetam were associated with a significantly reduced risk when used as part of a polytherapy. Use of statins was associated with a reduced risk of SUDEP (OR 0.34, 95% CI 0.11-0.99). Our results show that SUDEP is an important contributor to mortality in epilepsy patients, and accounts for one third of deaths in children with epilepsy and one fifth of deaths among young adults with epilepsy. Since the majority died at home in bed, at night with indications of a previous GTCS, SUDEP can be considered an event related to night time and unobserved GTCS. We found no excess risk of SUDEP among individuals experiencing non-GTCS only, which has important clinical implications. GTCS and lack of supervision were the main risk factors. Moreover, our results suggest that up to 69% of SUDEP cases could be prevented in individuals with GTCS who live alone, if they were made free from GTCS or did not sleep alone. Polytherapy was associated with a substantially reduced SUDEP risk indicating that physicians should to consider AED polytherapy more pro-actively for patients with poorly controlled GTCS

History-dependent friction and slow slip from time-dependent microscopic junction laws studied in a statistical framework

To study the microscopic origins of friction, we build a framework to describe the collective behaviour of a large number of individual micro-junctions forming a macroscopic frictional interface. Each micro-junction can switch in time between two states: A pinned state characterized by a displacement-dependent force, and a slipping state characterized by a time-dependent force. Instead of tracking each micro-junction individually, the state of the interface is described by two coupled distributions for (i) the stretching of pinned junctions and (ii) the time spent in the slipping state. We show how this framework represents an overarching structure for important models existing in the friction literature. We then use it to study systematically the effect of the time-scale that controls the duration of the slipping state. We first find the steady-state friction force as a function of the sliding velocity. As the framework allows for a whole family of micro-junction behaviour laws, we show how these laws can be chosen to obtain monotonic (strengthening or weakening) or non-monotonic velocity dependence at the macroscale. By then considering transient situations, we predict that the macroscopic static friction coefficient is strongly influenced by the way the interface was prepared, in particular by the slip dynamics of the previous sliding event. We also show that slow slip spontaneously occurs in the framework for a wide range of behaviour laws.Comment: 20 pages, 10 figure

On the speed of fast and slow rupture fronts along frictional interfaces

The transition from stick to slip at a dry frictional interface occurs through the breaking of the junctions between the two contacting surfaces. Typically, interactions between the junctions through the bulk lead to rupture fronts propagating from weak and/or highly stressed regions, whose junctions break first. Experiments find rupture fronts ranging from quasi-static fronts with speeds proportional to external loading rates, via fronts much slower than the Rayleigh wave speed, and fronts that propagate near the Rayleigh wave speed, to fronts that travel faster than the shear wave speed. The mechanisms behind and selection between these fronts are still imperfectly understood. Here we perform simulations in an elastic 2D spring--block model where the frictional interaction between each interfacial block and the substrate arises from a set of junctions modeled explicitly. We find that a proportionality between material slip speed and rupture front speed, previously reported for slow fronts, actually holds across the full range of front speeds we observe. We revisit a mechanism for slow slip in the model and demonstrate that fast slip and fast fronts have a different, inertial origin. We highlight the long transients in front speed even in homogeneous interfaces, and we study how both the local shear to normal stress ratio and the local strength are involved in the selection of front type and front speed. Lastly, we introduce an experimentally accessible integrated measure of block slip history, the Gini coefficient, and demonstrate that in the model it is a good predictor of the history-dependent local static friction coefficient of the interface. These results will contribute both to building a physically-based classification of the various types of fronts and to identifying the important mechanisms involved in the selection of their propagation speed.Comment: 29 pages, 21 figure

Central and extrapontine myelinolysis following correction of extreme hyponatremia. Case report and review of the literature

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenWe report a case of a 43-year-old woman who developed osmotic demyelination syndrome following correction of extreme hyponatremia that was considered to be of chronic nature. The serum sodium level was 91 mmol/L on admission to hospital. It was decided to correct the serum sodium slowly with the goal that the rate of correction would be no more than 12 mmol/l per 24 hours. This was achieved during the first two days of treatment but during the third day the rise in serum sodium was 13 mmol/l. On the 11th day of admission the patient had developed manifestations of pseudobulbar palsy and spastic quadriparesis. Magnetic resonance imaging study confirmed central and extrapontine myelonolysis. The patient received supportive therapy and eventually made full recovery. Current concepts in the pathophysiology of osmotic demyelination syndrome and the treatment of hyponatremia are reviewed. We recommend that the rate of correction of chronic hyponatremia should not exceed 8 mmol/l per 24 hours.Við greinum frá 43 ára gamalli konu sem fékk osmósuafmýlingarheilkenni (osmotic demyelination syndrome) í kjölfar leiðréttingar sérlega svæsinnar blóðnatríumlækkunar sem álitin var af langvinnum toga. Styrkur natríums í sermi var aðeins 91 mmól/l við komu á sjúkrahús. Stefnt var að hægfara leiðréttingu natríumlækkunarinnar og var markmiðið að hraði leiðréttingar yrði ekki meiri en 12 mmól/l á sólarhring. Það tókst fyrstu tvo daga meðferðar en á þriðja degi hækkaði natríumstyrkurinn um 13 mmól/l. Á 11. degi reyndist konan komin með merki um sýndarmænukylfulömun (pseudobulbar palsy) ásamt stjarfaferlömun (spastic quadriparesis) og staðfesti segulómmyndun miðbrúar- og utanbrúarafmýlingarskemmdir. Konan fékk almenna stuðningsmeðferð og náði smám saman fullum bata. Fjallað er um meinalífeðlisfræði osmósuafmýlingarheilkennis og meðferð blóðnatríumlækkunar. Við mælum með að hraði leiðréttingar langvinnrar blóðnatríumlækkunar sé ekki umfram 8 mmól/l á sólarhring

Restless legs syndrome - a review

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open Allur texti - Full textRestless legs syndrome (RLS) is a common disorder with a prevalence between 10-20% in Iceland. There are two forms of RLS, idiopathic and secondary. Symptom onset of RLS before the age of 45 suggests an idiopathic form with no known underlying cause but inheritance. Symptom onset after age of 45 indicates a secondary form with an underlying cause without inheritance. Causes for secondary forms are for example: iron depletion, uraemia and polyneuropathy. Symptoms of RLS are uncomfortable and unpleasant deep sensations in the legs that are felt at rest, accompanied by an urge to move the legs, typically just before sleep. Accompanying RLS is a sleep disturbance that can lead to daytime somnolence, decreased quality of life, poor concentration, memory problems, depression and decreased energy. Dopamine agonists are currently the first line treatment for RLS. Keywords: restless legs, periodic limb movements, sleep disturbance, dopamine agonists.Fótaóeirð er algengur kvilli sem hrjáir um 10-20% þjóðarinnar. Til eru tvennskonar form fótaóeirðar, frumlægt (primary) og afleitt (secondary). Þegar einkenni koma fram fyrir 45 ára aldur er oftast um frumlægt form að ræða án þekktra undirliggjandi orsaka og ættlægni til staðar. Þegar einkenni koma fram eftir 45 ára aldur er það yfirleitt afleitt form fótaóeirðar með undirliggjandi orsökum en ekki ættlægni. Dæmi um orsakir afleiddrar fótaóeirðar eru járnskortur, nýrnabilun og fjöltaugabólga. Einkenni fótaóeirðar lýsa sér sem djúplæg óþægindatilfinning í fótum sem kemur fram við setu eða legu, sérstaklega rétt fyrir svefn. Þessi tilfinning leiðir til óviðráðanlegrar löngunar til að hreyfa fæturna en við það geta einkennin lagast eða horfið tímabundið. Fótaóeirð fylgir oft svefntruflun sem síðan getur leitt til dagsyfju, skertra lífsgæða, einbeitingarörðugleika, minnistruflana, lækkaðs geðslags og þverrandi orku. Fyrsta val í meðferð fótaóeirðar eru dópamínörvarar

Slow slip and the transition from fast to slow fronts in the rupture of frictional interfaces

The failure of the population of micro-junctions forming the frictional interface between two solids is central to fields ranging from biomechanics to seismology. This failure is mediated by the propagation along the interface of various types of rupture fronts, covering a wide range of velocities. Among them are so-called slow fronts, which are recently discovered fronts much slower than the materials' sound speeds. Despite intense modelling activity, the mechanisms underlying slow fronts remain elusive. Here, we introduce a multi-scale model capable of reproducing both the transition from fast to slow fronts in a single rupture event and the short-time slip dynamics observed in recent experiments. We identify slow slip immediately following the arrest of a fast front as a phenomenon sufficient for the front to propagate further at a much slower pace. Whether slow fronts are actually observed is controlled both by the interfacial stresses and by the width of the local distribution of forces among micro-junctions. Our results show that slow fronts are qualitatively different from faster fronts. Since the transition from fast to slow fronts is potentially as generic as slow slip, we anticipate that it might occur in the wide range of systems in which slow slip has been reported, including seismic faults.Comment: 35 pages, 5 primary figures, 6 supporting figures. Post-print version with improvements from review process include