Improving prediction of sudden unexpected death in epilepsy: From SUDEP-7 to SUDEP-3.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in epilepsy. The aim of this study is to evaluate the validity of the SUDEP-7 inventory and its components as tools for predicting SUDEP risk, and to develop and validate an improved inventory. METHODS: The study included 28 patients who underwent video-electroencephalography (EEG) monitoring and later died of SUDEP, and 56 age- and sex-matched control patients with epilepsy. The SUDEP-7 score, its individual components, and an alternative inventory were examined as predictors of SUDEP. RESULTS: SUDEP-7 scores were significantly higher among SUDEP patients compared with controls, both at time of admission (p = 0.024) and most recent follow-up (p = 0.016). SUDEP-7 scores declined only among controls, who demonstrated reduced seizure frequency. Seizure freedom after epilepsy surgery was also associated with survival. Several components of the SUDEP-7 inventory were independently associated with higher risk of SUDEP, including more than three generalized tonic-clonic (GTC) seizures (p = 0.002), one or more GTC seizures (p = 0.001), or one or more seizures of any type within the last year (p = 0.013), and intellectual disability (p = 0.031). In stepwise regression models, SUDEP-7 scores did not enhance the prediction of SUDEP over either GTC seizure frequency or seizure frequency alone. A novel SUDEP-3 inventory comprising GTC seizure frequency, seizure frequency, and intellectual disability (p < 0.001) outperformed the SUDEP-7 inventory (p = 0.010) in predicting SUDEP. SIGNIFICANCE: Our findings demonstrate the limitations of the SUDEP-7 inventory. We propose a new three-item SUDEP-3 inventory, which predicts SUDEP better than the SUDEP-7.

Initiating an epilepsy surgery program with limited resources in Indonesia.

To share the experiences of organizing the epilepsy surgery program in Indonesia. This study was divided into two periods based on the presurgical evaluation method: the first period (1999-2004), when interictal electroencephalogram (EEG) and magnetic resonance imaging (MRI) were used mainly for confirmation, and the second period (2005-2017), when long-term non-invasive and invasive video-EEG was involved in the evaluation. Long-term outcomes were recorded up to December 2019 based on the Engel scale. All 65 surgical recruits in the first period possessed temporal lobe epilepsy (TLE), while 524 patients were treated in the second period. In the first period, 76.8%, 16.1%, and 7.1% of patients with TLE achieved Classes I, II, and III, respectively, and in the second period, 89.4%, 5.5%, and 4.9% achieved Classes I, II, and III, respectively, alongside Class IV, at 0.3%. The overall median survival times for patients with focal impaired awareness seizures (FIAS), focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures were 9, 11 and 11 years (95% CI: 8.170-9.830, 10.170-11.830, and 7.265-14.735), respectively, with p = 0.04. The utilization of stringent and selective criteria to reserve surgeries is important for a successful epilepsy program with limited resources.

Automated detection of sudden unexpected death in epilepsy risk factors in electronic medical records using natural language processing.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. However, there is a gap in how often providers counsel patients about SUDEP. One potential solution is to electronically prompt clinicians to provide counseling via automated detection of risk factors in electronic medical records (EMRs). We evaluated (1) the feasibility and generalizability of using regular expressions to identify risk factors in EMRs and (2) barriers to generalizability. METHODS: Data included physician notes for 3000 patients from one medical center (home) and 1000 from five additional centers (away). Through chart review, we identified three SUDEP risk factors: (1) generalized tonic-clonic seizures, (2) refractory epilepsy, and (3) epilepsy surgery candidacy. Regular expressions of risk factors were manually created with home training data, and performance was evaluated with home test and away test data. Performance was evaluated by sensitivity, positive predictive value, and F-measure. Generalizability was defined as an absolute decrease in performance by <0.10 for away versus home test data. To evaluate underlying barriers to generalizability, we identified causes of errors seen more often in away data than home data. To demonstrate how small revisions can improve generalizability, we removed three "boilerplate" standard text phrases from away notes and repeated performance. RESULTS: We observed high performance in home test data (F-measure range = 0.86-0.90), and low to high performance in away test data (F-measure range = 0.53-0.81). After removing three boilerplate phrases, away performance improved (F-measure range = 0.79-0.89) and generalizability was achieved for nearly all measures. The only significant barrier to generalizability was use of boilerplate phrases, causing 104 of 171 errors (61%) in away data. SIGNIFICANCE: Regular expressions are a feasible and probably a generalizable method to identify variables related to SUDEP risk. Our methods may be implemented to create large patient cohorts for research and to generate electronic prompts for SUDEP counseling.

SUDEP in Spain: An Epilepsy Monitoring Unit based case series.

PURPOSE: SUDEP is the first cause of mortality related to epilepsy. However, in Spain there are no published cases or series from Epilepsy Monitoring Units that could expose the characteristics of SUDEP in our population. METHOD: We reviewed all patients treated at our Spanish Epilepsy Reference Centre who died between 2010-2018. SUDEP cases were classified as definite, probable, possible or near-SUDEP. Epilepsy type, demographics and case detection issues were described. RESULTS: From 1250 evaluated patients, 102 died during the study period. Seven patients were diagnosed with SUDEP or near-SUDEP: two definite SUDEP, one definite SUDEP plus, two probable SUDEP and two near-SUDEP. Specific problems for detection and registration of SUDEP inherent to the Spanish healthcare system and the legal framework were defined. Only 43% of cases were known by the referral neurologist. SUDEP incidence was 1.3 per 1000 patient/year, comprising 0.56% of all deaths in our cohort. Two cases were female, the average age was 36 years (18-61). All patients had focal epilepsy and suffered from generalized tonic-clonic seizures. All witnessed cases occurred after a focal to bilateral tonic-clonic seizure. Four cases occurred during sleep and all non-witnessed cases were found in prone position. One case occurred during video-EEG monitoring. CONCLUSIONS: Our casuistic represents the first Epilepsy Monitoring Unit based case series of SUDEP conducted in Spain. The incidence in our population agrees with the reported in other countries. However, in our population, SUDEP is probably underdiagnosed due to administrative and legal issues.

Cost-effectiveness of perampanel for the treatment of primary generalized tonic-clonic seizures (PGTCS) in epilepsy: A Spanish perspective.

BACKGROUND: Persistent seizures are associated with physical injury, reduced quality of life, and psychosocial impairment. Perampanel is approved for the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS). OBJECTIVE: This study aimed to determine the cost-effectiveness of perampanel as adjunctive therapy to other antiepileptic drugs (AED) compared with AED maintenance therapy alone for the treatment of PGTCS. METHODS: We developed a Markov model for PGTCS where transitions were based on treatment response rates. The analysis was conducted over a 33-year time horizon from the Spanish National Health Service (NHS) and societal perspectives. Efficacy data were derived from clinical studies. Resource use, market shares, costs, and utilities were obtained from Kantar Health's National Health and Wellness Survey. Drug costs were obtained from the Consejo General de Colegios Oficiales de Farmacéuticos. One-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case analysis from the NHS perspective, perampanel was associated with an incremental cost-effectiveness ratio (ICER) of €16,557/quality-adjusted life year (QALY) relative to AED maintenance therapy for the treatment of PGTCS. Incremental costs were €5475 and incremental QALYs were 0.33. In one-way sensitivity analyses, the ICERs were strongly influenced by discounting rate for costs and health effects, with little influence of other parameters, including perampanel cost and utilities. In probabilistic sensitivity analyses, the probability of perampanel being cost-effective at a willingness-to-pay threshold of €30,000/QALY was 89.3%. From the societal perspective, perampanel provided a cost-savings of €5288 per patient compared with AED maintenance therapy alone. CONCLUSION: Our study demonstrates that perampanel is likely to be a cost-effective option.

Clinical Features of Patients with Diffuse Alveolar Hemorrhage due to Negative-Pressure Pulmonary Edema.

PURPOSE: Diffuse alveolar hemorrhage (DAH) with negative-pressure pulmonary edema (NPPE) is an uncommon yet life-threatening condition. We aimed at describing the circumstances, clinical, radiological, and bronchoscopic features, as well as the outcome of patients with NPPE-related DAH. METHODS: We performed a retrospective, observational cohort study, using data prospectively collected over 35 years in an intensive care unit (ICU). RESULTS: Of the 149 patients admitted for DAH, we identified 18 NPPE episodes in 15 patients, one admitted four times for recurrent NPPE-related DAH. The patients were primarily young, male, and athletic. The NPPE setting was postoperative (n = 12/18, 67%) or following generalized tonic-clonic seizures (n = 6/18, 33%). Hemoptysis was almost constant (n = 17/18, 94%), yet rarely massive (>200 cc, n = 1/18, 6%), with anemia observed in 10 (56%) episodes. The DAH triad (hemoptysis, anemia, and pulmonary infiltrates) was observed in 50% of episodes (n = 9/18), and acute respiratory failure in 94% (n = 17/18). Chest computed tomography revealed diffuse bilateral ground glass opacities (n = 10/10, 100%), while bronchoscopy detected bilateral hemorrhage (n = 12/12, 100%) and macroscopically bloody bronchoalveolar lavage, with siderophage absence in most (n = 7/8, 88%), indicating acute DAH. While one episode proved fatal, the other 17 recovered rapidly, with a mean ICU stay lasting 4.6 (2-15) days. Typically, the evolution was rapidly favorable under supportive care. CONCLUSION: NPPE-related DAH is a rare life-threatening condition occurring primarily after tonic-clonic generalized seizure or generalized anesthesia. Clinical circumstances are a key to its diagnosis. Early diagnosis and recognition likely allow for successful management of this potentially serious complication, whereas ictal-DAH appears ominous in epileptic patients.

Sudden unexpected death in a mouse model of Dravet syndrome.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

SUDEP, suspected positional airway obstruction, and hypoventilation in postictal coma.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with chronic uncontrolled epilepsy. Despite intense interest in SUDEP from the medical and scientific communities in recent years, its etiologies are still largely unresolved. A 35-year-old woman had SUDEP after having a generalized seizure in the prone position. The cause of her death was likely asphyxia from the convergence of postictal coma and suspected positional airway obstruction and hypoventilation, rather than the commonly suspected periictal cardiac arrhythmia or central apnea. SUDEP may share a similar etiology with sudden infant death syndrome (SIDS) and is likely preventable, at least in a proportion of cases.

[Contemporary opinions on classification, pathogenesis and treatment of drug-resistant epilepsy]. / Wspólczesne poglady na klasyfikacje, patogeneze i postepowanie w padaczce lekoopornej.

Epilepsy is one of the most frequent neurological disorders, both in children and adult persons. About 0.5-1% of general population suffer from epilepsy, which means that about 50 million people in the world are affected. First years of life and very late adulthood are periods in human's life particularly predisposing to epilepsy. Repetitive epileptic seizures may cause many life-threatening situations and significantly lower patient's quality of life. To the most serious complications belong status epilepticus and sudden unexpected deaths due to epilepsy (SUDEP). Absences from work or school caused by seizures, difficulties in social life, frequent injuries and necessity of polytherapy are also important for patients. All these factors result in low self-esteem and poor quality of life. The main aim of the treatment was control of epileptic seizures. However, despite of new antiepileptic drugs developed almost every year, in one third of all patients with epilepsy seizures remain out of control. Those patients are regarded to have "drug-resistant epilepsy". Despite of significant scale of the problem, there is no one definition of the phenomenon. In the presented review the authors outline current definitions, recent opinions on pathogenesis and risk factors, and provide practical rules of pharmacotherapy of epilepsy, which should help to restrict drug-resistancy.

[Sudden death and mortality in epilepsy]. / Hirtelen halál es mortalitás epilepsziában.

Mortality in epilepsy is 2-3 times higher than in the age- and sex-matched general population. It is the highest in young male epilepsy patients with generalised tonic-clonic seizures living in low socio-economical situation. The main factors of early mortality unrelated to seizures are the neurological conditions underlying epilepsy. Suicide is an important factor first of all in temporal lobe epilepsy. The group of mortality directly related to epilepsy is made up of the high-mortality grand mal status epilepticus rarely seen in treated epilepsy; the accidents related to seizures and sudden unexpected death (SUDEP). The reasons directly related to epilepsy make up about 40 per cent of epilepsy mortality. There is a 20-24-fold increase of the risk of sudden death in epilepsy compared to sudden death in the general population. The main risk of SUDEP is the "severity" of epilepsy signaled by generalized tonic-clonic seizures, resistance to antiepileptic drugs, polytherapy and frequent drug-modifications in adulthood epilepsy. Seizure-dependent autonomic changes as cardiac rhythm and breathing disturbances as well as some antiepileptic drugs and treatment modifications may contribute to the development of SUDEP. The data suggest that the main tools helping to decrease mortality in epilepsy nowadays are as follows: optimal seizure control, effective treatment of concomitant psychiatric conditions and monitoring for potentially dangerous heart dysrhythmias as well as respiration disorders.

Pediatric experience with sudden unexplained death in epilepsy at a tertiary epilepsy center.

Sudden unexplained death in epilepsy is rare in children, and few studies report risk factors. We reviewed our experience with 17 cases of sudden unexplained death in epilepsy to determine risk factors in children. The charts of all patients with onset of epilepsy at less than age 18 years who suffered sudden unexplained death in epilepsy between August 1992 and April 2004 at our epilepsy center were retrospectively reviewed. Deaths were classified as possible, probable, or definite sudden unexplained death in epilepsy. There were seven cases of definite, nine cases of probable, and one case of possible sudden unexplained death in epilepsy. Generalized tonic-clonic seizures and prone position during sleep were found to be major risk factors. Sudden unexplained death in epilepsy in children and adolescents is associated with convulsive seizures, and aggressive treatment of nocturnal generalized tonic-clonic seizures might help lower the occurrence.

Case-control study of SUDEP.

OBJECTIVE: To examine the influence of various factors on the risk of sudden unexpected death in epilepsy (SUDEP). METHODS: The authors investigated 154 cases in which a postmortem examination was performed. Each case had four controls with epilepsy from the community, matched for age and geographic location. Backward stepwise conditional logistic regression analysis was performed and odds ratios for risk and protection were determined. RESULTS: The risk of SUDEP was increased with a history of generalized tonic-clonic seizures in the previous 3 months (odds ratio [OR]: 13.8, 95% CI: 6.6 to 29.1). The presence of supervision at night was found to be protective (OR: 0.4, 95% CI: 0.2 to 0.8) when a supervising individual shared the same bedroom or when special precautions such as a listening device were employed (OR: 0.1, 95% CI: 0.0 to 0.3). CONCLUSION: This work lends support to the view that SUDEP is a seizure-related phenomenon and that control of tonic-clonic seizures is important in its prevention. Nocturnal supervision seems to protect against SUDEP.

Generalized tonic-clonic status epilepticus in the elderly in China.

The proportion of elderly people in China is projected to increase rapidly but there is limited information on status epilepticus (SE) in this population. We evaluated retrospectively the etiology, response to treatment, outcome and predictors of mortality in a group of elderly patients with generalized tonic-clonic SE in Hong Kong, China. Factors for increased mortality were analyzed using a logistic regression model. Of the 80 acute admissions for SE from two large urban hospitals over a seven-year period, 1996-2002, the two leading causes were attributed to cerebral infarct (n=28, 35%) and cerebral haemorrhage (n=14, 17.5%). The mean age was 74.2 years (range 60-93 years). At six months from the onset of seizures, 26 patients (32.5%) had made a good recovery but another 28 (35%) had died. Results showed that mortality was associated with increasing age (OR 1.08, 95% CI 1.01-1.16) and SE due to an acute symptomatic disturbance (OR 4.90, 95% CI 1.17-13.67). SE is associated with significant morbidity and mortality in this age group.

Fulminant hepatitis after grand mal seizures: mechanisms and role of liver transplantation.

Fulminant liver failure is a rare complication of grand mal seizures with a high mortality, the prognosis being largely determined by the combination of the hepatic and neurologic insults. The mechanisms of acute liver failure secondary to grand mal epilepsy and the place of liver transplantation in this context are poorly defined and are the subject of this report. A series of 6 such patients is presented. All had a history of chronic primary or post-traumatic epilepsy and presented with acute liver failure shortly after a grand mal fit. Detailed accounts of background, presentation, and management are given and integrated with blood, radiologic, and histologic investigations. Two of the 6 patients survived, 1 making a full recovery and the other with neurologic sequelae. Two patients underwent liver transplantation but died with severe neurologic sequelae despite improving liver function. The remaining 2 patients were considered too ill to undergo liver transplantation and died in multiple organ failure. Liver histology from needle biopsy and/or native liver explants identified lesions compatible with a combination of steatosis and necrosis. Factor V and transaminase levels may allow early identification of patients in whom liver function is likely to improve spontaneously. In conclusion, the mechanisms of liver failure occurring after grand mal seizures appear multifactorial, including hypoxia, steatosis, and drug-induced components. The neurological prognosis and overall survival of these patients remains poor.

Excess mortality in remote symptomatic epilepsy.

BACKGROUND: Published estimates of excess mortality associated with epilepsy vary greatly. How much, if any, of the excess is attributable to the seizures themselves as opposed to an underlying condition causing the epilepsy is not clear from the literature. This article offers evidence that epilepsy per se is associated with excess mortality. The excess varies according to severity and frequency of seizures. MATERIALS AND METHODS: The authors studied mortality rates of developmentally disabled persons in California with and without epilepsy. In order to focus on the effect on mortality risk of epilepsy per se, they included only persons with good motor function (able to walk and climb stairs) and at worst moderate mental retardation (MR). The data were 506,204 person-years and 1523 deaths among 80,682 California subjects of age 5 to 65 years during the 1988-1999 study period. Mortality rates for persons with epilepsy were compared to rates for persons with no history of epilepsy. RESULTS: Mortality rates were higher for persons with epilepsy than for those without. Excess death rates (EDRs) varied according to type and frequency of seizures. Combined EDRs were 6 (deaths per 1000 person-years) for persons with recent (< 12 months) history of status epilepticus, 5 for recent history of generalized tonic-clonic (GTC) seizures, 3 for recent history of seizures but no recent GTC seizures, and less than 1 for a history of seizures but no recent events. CONCLUSIONS: The data presented here are evidence that epilepsy per se is associated with increased mortality. The EDRs reported here may be better measures of excess mortality due to epilepsy than previously published estimates.

Is sudden unexplained death in adult epileptic patients associated with geomagnetic disturbances at the day of death or the 4 days before?

Geomagnetic disturbances are controversially discussed as risk factor for sudden unexplained death in epilepsy (SUDEP). An autopsy-based cohort of 39 adult patients with definite SUDEP were compared to 102 epileptic patients with known cause of death (KCD), who died between 1981 and 1992. Most of them had suffered from therapy-resistant epilepsies, predominantly characterized by generalized tonic-clonic seizures (about 70%). We analyzed an international geomagnetic index, the mean planetary daily amplitude (Ap), and the appearance of storm sudden commencement (SSC) at the individual day of decease and the 4 days before (and after). The SUDEP and KCD patients did not substantially differ with respect to the Ap values (Mann-Whitney test; P>0.2) and frequency of SSC (Fisher test; P>0.2) at death or the 4 premortem days. In addition, Ap values above 50 nanoTesla, postulated as critical threshold by other authors, showed no significant difference between SUDEP and KCD group for the day of death (5.1 versus 3.9%) or the 4 days before (5.1 versus 11.8%) (Fisher test; P>0.2). Consequently, the current data did not support the hypothesis that geomagnetic activities may act as a relevant risk factor for SUDEP.

Role of cocaethylene in toxic symptoms due to repeated subcutaneous cocaine administration modified by oral doses of ethanol.

The present study investigated the toxicity of repeated subcutaneous cocaine administrations combined with oral doses of ethanol, and discussed the role of the toxic metabolite cocaethylene. Subcutaneous cocaine (70 mg/kg) was given to male ICR mice at 45 min after an oral administration of either ethanol (maximum 3 g/kg) (cocaine-ethanol group; n = 50) or saline control (cocaine group; n = 30), once per day, for up to 5 days. In the combined cocaine-ethanol group, the total frequency of death was significantly increased (86%) as compared to the cocaine group (40%). In both administration groups, regardless of the day of death, "late" deaths characterized by the late and unexpected onset of fatal symptoms could be differentiated from "early" deaths on the basis of the survival time after the last cocaine injection, the drug concentrations in the tissues at the time of death, and/or the observed physical disorders. In the combined cocaine-ethanol group, a late death group with survival times exceeding 12 hr and two early death groups could be differentiated, based on the presence or absence of cocaethylene and the different types of clinical symptoms. In the early death group in which cocaethylene could be detected, the volume of ethanol ingested was not significantly different from the late death group with large ethanol consumption and slow exacerbation of the respiratory and locomotive symptoms. Furthermore, the severity of the cocaine-induced seizures was also similarly decreased by ethanol. In the other early death group in which cocaethylene could not be detected, the volume of ethanol ingested was significantly lower than in the late death group, and seizures as severe as in the cocaine-only group were observed.

Deficiency in protein L-isoaspartyl methyltransferase results in a fatal progressive epilepsy.

Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of aged protein spontaneously incorporated with isoaspartyl residues. We generated PIMT-deficient mice by targeted disruption of the PIMT gene to elucidate the biological role of the gene in vivo. PIMT-deficient mice died from progressive epileptic seizures with grand mal and myoclonus between 4 and 12 weeks of age. An anticonvulsive drug, dipropylacetic acid (DPA), improved their survival but failed to cure the fatal outcome. L-Isoaspartatate, the putative substrate for PIMT, was increased ninefold in the brains of PIMT-deficient mice. The brains of PIMT-deficient mice started to enlarge after 4 weeks of age when the apical dendrites of pyramidal neurons in cerebral cortices showed aberrant arborizations with disorganized microtubules. We conclude that methylation of modified proteins with isoaspartyl residues is essential for the maintenance of a mature CNS and that a deficiency in PIMT results in fatal progressive epilepsy in mice.