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.

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.

Update on causes of premature death in people with convulsive epilepsy in rural West China.

This longitudinal prospective study updated a previous report on premature mortality and focused on the risk factors among patients with convulsive epilepsy in resource-poor settings. The present cohort size (7,231) and follow-up (mean 33.4 months) were expanded. The basic epidemiologic aspects of this cohort were similar to the original report (case fatality: 3.26% vs. 2.97%, respectively; injury contributed more than half of the deaths). Cox regression analysis suggested that male patients, late ages of onset (>45 years old), short duration of epilepsy (<10 years), and high convulsive seizure frequency (>2 per month) were independent risk factors for overall premature death. Male patients with late ages of onset and high seizure frequency had a higher risk of injury-specific death. This study emphasizes the preventable nature of injuries that are leading putative causes of death among people with convulsive epilepsy in rural West China. Education on specific populations and efficient seizure control are of paramount importance in reducing the risk of premature mortality.

[Current possibilities of treatment of generalized convulsive seizures].

Current possibilities of treatment of generalized convulsive seizures are presented. Progress in the field of pharmacotherapy of epilepsy allowed to introduce new antiepileptic drugs (AED). Some of them are modified AED with higher efficacy or better tolerability and others represent a generation of new drugs with different mechanisms of action. Perampanel, an agonist of AMPA-receptors, is a new drug approved in more than 40 countries, including Russia. At present, the use of some AED is limited by the high risk of sudden death (sudden unexpected death in epilepsy (SUDEP)). SUDEP is a common cause of death directly associated with epilepsy, with the highest frequency in patients with active epilepsy. Subtherapeutic concentrations of SED in the serum of SUDEP patients may be the consequence of inadequate treatment and low compliance to treatment that causes the development of pseudoresistant seizures and, hence, the higher risk of SUDEP. At the same time, AED per se play an important role in the modification of functions of the autonomic nervous system and may induce disturbances of heart rate and conductivity.

Idiopathic epilepsy in the Italian Spinone in the United Kingdom: prevalence, clinical characteristics, and predictors of survival and seizure remission.

BACKGROUND: There is lack of data on idiopathic epilepsy (IE) in the Italian Spinone (IS). OBJECTIVES: To estimate the prevalence of IE in the IS in the United Kingdom (UK) and to investigate predictors of survival and seizure remission. ANIMALS: The target population consisted of 3331 IS born between 2000 and 2011 and registered with the UK Kennel Club (KC). The owners of 1192 dogs returned phase I questionnaire. Sixty-three IS had IE. METHODS: Population survey. The owners of all UK KC-registered IS were invited to complete the phase I questionnaire. Information from the phase I questionnaire and veterinary medical records was used to identify IS with IE and obtain data on treatment and survival. Additional information was obtained from owners of epileptic IS who completed the phase II questionnaire. RESULTS: The prevalence of IE in the IS in the UK was estimated as 5.3% (95% CI, 4.03-6.57%). Survival time was significantly shorter in IS euthanized because of poorly controlled IE compared with epileptic IS that died of unrelated disorders (P = 0.001). Survival was significantly longer in IS with no cluster seizures (CS) (P = 0.040) and in IS in which antiepileptic medication was initiated after the second seizure rather than after ≥3 seizures (P = 0.044). Seizure remission occurred only in 3 IS. CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of IE in IS (5.3%) is higher than in dogs (0.6%) in the UK. Idiopathic epilepsy in IS has a severe phenotype. Antiepileptic medication initiation after the second seizure and aggressive treatment of CS may improve survival.

Risk factors for survival in a university hospital population of dogs with epilepsy.

BACKGROUND: Although a common neurological disorder in dogs, long-term outcome of epilepsy is sparsely documented. OBJECTIVES: To investigate risk factors for survival and duration of survival in a population of dogs with idiopathic epilepsy or epilepsy associated with a known intracranial cause. ANIMALS: One hundred and two client owned dogs; 78 dogs with idiopathic epilepsy and 24 dogs with epilepsy associated with a known intracranial cause. METHODS: A retrospective hospital based study with follow-up. Dogs diagnosed with epilepsy between 2002 and 2008 were enrolled in the study. Owners were interviewed by telephone using a structured questionnaire addressing epilepsy status, treatment, death/alive, and cause of death. RESULTS: Median life span was 7.6 years, 9.2 years, and 5.8 years for all dogs, and dogs with idiopathic epilepsy or dogs with epilepsy associated with a known intracranial cause (P < .001), respectively. Survival time for dogs with idiopathic epilepsy was significantly (P = .0030) decreased for dogs euthanized because of epilepsy (median: 35 months) compared to dogs euthanized for other reasons (median: 67.5 months). Neutered male dogs with idiopathic epilepsy had a significant (P = .031) shorter survival (median: 38.5 months) after index seizure compared to intact male dogs (median: 71 months). Treatment with two antiepileptic drugs (AED's) did not negatively influence survival (P = .056). CONCLUSION AND CLINICAL IMPORTANCE: Dogs with idiopathic epilepsy can in many cases expect a life span close to what is reported for dogs in general. In dogs where mono-therapy is not sufficient, the need for treatment with two AED's is not linked to a poor prognosis.

Generalized periodic epileptiform discharges in critically ill children: clinical features, and outcome.

PURPOSE: Generalized periodic epileptiform discharges (GPDs) are a specific periodic EEG pattern, reported as having a poor clinical outcome. The incidence and clinical implications of this EEG pattern in children are not known. In this study, we examined the clinical features of children with GPDs. METHODS: EEG-video monitoring reports of children with critical illness in the intensive care unit were retrospectively reviewed to detect GPDs. The clinical history, hospital course and seizure characteristics were reviewed and outcome was based on the clinical findings at hospital discharge. RESULTS: Twenty one children (age 2-18 years) were identified with GPDs. The most common underlying etiology was encephalitis (N=11). At the time of EEG, a continuous intravenous infusion (cIV) of an anticonvulsant drug was used to treat refractory status epilepticus (RSE). Non-convulsive seizures (NCS) were identified in 15, and clinical seizures in 13 children after GPDs were detected. GPDs occurred after a dose reduction in the cIV in 43%. Neuroimaging done in 16 children showed an acute change in 13/16 (81%) and chronic changes in 2/16 (13%). Five children (23%) died. Seven (33%) children had a favorable outcome, whereas the remaining children had a moderate to severe disability at the time of hospital discharge. CONCLUSION: GPDs are seen during the course of RSE in critically ill children and are associated with seizure recurrence. A lower mortality rate occurs in children with GPDs compared to adult counterparts, likely related to different etiologies. Although the significance of GPDs must be determined within the context of the clinical situation, GPDs suggest a still active epileptic process.

Premature mortality risk in people with convulsive epilepsy: long follow-up of a cohort in rural China.

PURPOSE: Detailed data on the mortality of epilepsy are still lacking from resource-poor settings. We conducted a long-term follow-up survey in a cohort of people with convulsive epilepsy in rural areas of China. In this longitudinal prospective study we investigated the causes of death and premature mortality risk among people with epilepsy. METHODS: We attempted to trace all 2,455 people who had previously participated in a pragmatic assessment of epilepsy management at the primary health level. Putative causes of death were recorded for those who died, according to the International Classification of Diseases. We estimated proportional mortality ratios (PMRs) for each cause, and standardized mortality ratios (SMRs) for each age-group and cause. Survival analysis was used to detect risk factors associated with increased mortality. KEY FINDINGS: During 6.1 years of follow-up there were 206 reported deaths among the 1,986 people with epilepsy who were located. The highest PMRs were for cerebrovascular disease (15%), drowning (14%), self-inflicted injury (13%), and status epilepticus (6%), with probable sudden unexpected death in epilepsy (SUDEP) in 1%. The risk of premature death was 2.9 times greater in people with epilepsy than in the general population. A much higher risk (SMRs 28-37) was found in young people. Duration of epilepsy and living in a waterside area were independent predictors for drowning. SIGNIFICANCE: Drowning and status epilepticus were important, possibly preventable, causes of death. Predictors of increasing mortality suggest interventions with efficient treatment and education to prevent premature mortality among people with epilepsy in resource-poor settings.

A population-based study of long-term outcomes of cryptogenic focal epilepsy in childhood: cryptogenic epilepsy is probably not symptomatic epilepsy.

PURPOSE: To compare long-term outcome in a population-based group of children with cryptogenic versus symptomatic focal epilepsy diagnosed from 1980 to 2004 and to define the course of epilepsy in the cryptogenic group. METHODS: We identified all children residing in Olmsted County, MN, 1 month through 17 years, with newly diagnosed, nonidiopathic focal epilepsy from 1980 to 2004. Children with idiopathic partial epilepsy syndromes were excluded. Medical records were reviewed to determine etiology, results of imaging and EEG studies, treatments used, and long-term outcome. Children were defined as having symptomatic epilepsy if they had a known genetic or structural/metabolic etiology, and as cryptogenic if they did not. KEY FINDINGS: Of 359 children with newly diagnosed epilepsy, 215 (60%) had nonidiopathic focal epilepsy. Of these, 206 (96%) were followed for > 12 months. Ninety-five children (46%) were classified as symptomatic. Median follow-up from diagnosis was similar in both groups, being 157 months (25%, 75%: 89, 233) in the cryptogenic group versus 134 months (25%, 75%: 78, 220) in the symptomatic group (p = 0.26). Of 111 cryptogenic cases, 66% had normal cognition. Long-term outcome was significantly better in those with cryptogenic versus symptomatic etiology (intractable epilepsy at last follow-up, 7% vs. 40%, p < 0.001; seizure freedom at last follow-up, 81% vs. 55%, p < 0.001). Of those who achieved seizure freedom at final follow-up, 68% of the cryptogenic group versus only 46% of the symptomatic group were off antiepileptic medications (p = 0.01). One-third of the cryptogenic group had a remarkably benign disorder, with no seizures seen after initiation of medication, or in those who were untreated, after the second afebrile seizure. A further 5% had seizures within the first year but remained seizure-free thereafter. With the exception of perinatal complications, which predicted against seizure remission, no other factors were found to significantly predict outcome in the cryptogenic group. SIGNIFICANCE: More than half of childhood nonidiopathic localization-related epilepsy is cryptogenic. This group has a significantly better long-term outcome than those with a symptomatic etiology, and should be distinguished from it.

Resective pediatric epilepsy surgery in Lennox-Gastaut syndrome.

OBJECTIVE: The objective of this study was to evaluate the role of resective pediatric epilepsy surgery for Lennox-Gastaut syndrome (LGS). METHODS: We analyzed clinical data of 27 children and adolescents who had LGS and underwent resective epilepsy surgery despite abundant (>30% of preoperative interictal and/or ictal epileptiform discharges) generalized or generalized contralateral maximal and multiregional electroencephalogram abnormalities. RESULTS: On high-resolution MRI, cerebral lesions were noted in 23 (85.2%) patients but not in 4 (14.8%) patients. The age of patients at the time of surgery was between 1.7 and 17.3 years (mean: 7.8 years). Surgeries were lobar or multilobar resection in 21 (77.8%) patients and hemispherotomy in 6 (22.2%). At a mean of 33.1 months' postoperative follow-up, 16 (59.3%) patients had no seizures and 4 (14.8%) had infrequent seizures. Of 4 patients without brain abnormalities found on MRI, 2 patients became seizure-free after resective surgery was performed on the basis of electrophysiologic studies and concordant results in other multimodal neuroimages. Malformation of cortical development was the most common pathology and was seen in 20 (74.1%) patients, but 2 (7.4% patients) did not show any abnormal pathology. Sixteen (72.7%) patients, including 14 who had no seizures and 2 who had infrequent seizures after surgery, showed an increase in developmental quotient. No clinical profile was significantly associated with postoperative seizure-free rate. CONCLUSIONS: Resective epilepsy surgery should be considered for children with LGS, despite abundant generalized and multiregional electroencephalogram abnormalities.

Prognostic implications of periodic epileptiform discharges.

BACKGROUND: Periodic epileptiform discharges (PEDs) are an abnormal finding on electroencephalograms (EEGs), the significance of which is uncertain. OBJECTIVE: To investigate long-term outcome in patients with PEDs. DESIGN: We retrospectively analyzed the outcomes of patients who had PEDs diagnosed during a 7-year period. We abstracted and tabulated clinical parameters from the time of EEG, imaging findings, EEG measurements, and subsequent clinical outcome from medical records. We used descriptive, inferential, and logistic regression analysis to determine the factors associated with clinical outcomes in patients with PEDs. We divided PEDs into the following subgroups: periodic lateralized epileptiform discharges (PLEDs), generalized PEDs, and bilateral PEDs and analyzed these subgroups individually. SETTING: University-affiliated teaching hospital. Subjects One hundred sixty-two patients with PEDs. RESULTS: We obtained complete clinical, neuroimaging, neurophysiologic, and long-term outcome data in 118 patients. In the subgroup of patients with PLEDs, absence of seizures at onset (odds ratio, 0.21 per point; 95% confidence interval, 0.04-0.97) and an acute etiology for the PLEDs (odds ratio, 0.14 per point; 95% confidence interval, 0.03-0.72) were associated with death. A nonneoplastic cause for PLEDs was associated with independent functionality (odds ratio, 0.45 per point; 95% confidence interval, 0.3-0.67). CONCLUSION: In patients with PLEDs, the absence of clinical seizures at the time of detection and presumed acute etiology are associated with death, whereas a nonneoplastic etiology was associated with a good clinical outcome.

[Epileptic seizures in critically ill patients]. / Epilepsiniai priepuoliai, istinkantys kritiniu bukliu ligonius.

THE AIM OF THIS ARTICLE: To review the causes, clinical signs, pathophysiology, consequences, and treatment of seizures and status epilepticus in critically ill patients. Only 25% of people, who have seizures and status epilepticus, have epilepsy as well. In the intensive care settings, seizures and status epilepticus are a common neurologic complication, which is attributable to primary neurologic pathology (stroke, hemorrhage, tumor, central nervous system infection, head trauma) or secondary to critical illness (anoxic brain damage, intoxications, metabolic abnormalities) and clinical management. There are three main subtypes of status epilepticus in intensive care units: generalized convulsive status epilepticus, focal motor status epilepticus, and nonconvulsive status epilepticus. A seizure is a consequence of electrical neurological derangement because of sudden imbalance between the inhibitory and excitatory forces within the network of cortical neurons. The main inhibiting neurotransmitter in the brain is gamma-aminobutyric acid (GABA), which binds to GABA-A and GABA-B receptors. The main excitatory neurotransmitter is glutamate, which binds to N-methyl-D-aspartate receptors. Different ions (Cl(-), K(+), Na(+), Ca(2+)) also play a role in the pathophysiology of seizures. Prolonged status epilepticus may lead to different systemic and neurologic consequences. Generalized convulsive status epilepticus is one of the most common emergencies encountered in clinical practice, which requires immediate treatment. The first-line drugs are benzodiazepines (lorazepam, diazepam), the second-line ones - phenytoin and fosphenytoin. For the treatment of refractory status epilepticus, barbiturates (phenobarbital, pentobarbital, thiopental), valproate, midazolam, propofol, and isoflurane are used. The dosage of drugs and parameters to monitor are referred in the article. The mortality from generalized convulsive status epilepticus is 15-50%; the main factors, influencing prognosis, are the cause and the duration of status epilepticus and age of a patient.

Twenty years after childhood-onset symptomatic generalized epilepsy the social outcome is usually dependency or death: a population-based study.

AIMS: To document the adult social outcome for childhood onset symptomatic generalized epilepsies (SGE). METHODS: Using the Nova Scotia population-based epilepsy cohort we identified children who developed SGE between 1977 and 1985. Social outcome for those >18 years old was assessed in 2003-5 by semi-structured interview with patients and/or caretakers. RESULTS: Eighty children developed SGE, 12% of childhood epilepsy. Syndromes at onset were: SGE undefined 32 (37%), West 32 (42%), Lennox-Gastaut 4, myoclonic astatic 9, other 3. Nineteen (24%) died. Fifty-two survivors (22 women, 30 men) were 23.7 SD 3.6 years old: 46 (88%) had mental retardation; 34 (65%) continued AEDs; and 27 (51%) were unable to walk. Social outcome was good (live independently) in 7 (13%), moderate (unable to live independently but independent for most daily activities) in 15 (29%) and poor (dependent for nearly all activities) in 30 (58%). Twenty-nine (56%) remained at home, 40% in group homes or institutions. Financial dependency was marked - complete dependence on parents/state in 90%. Eleven (20%) were socially isolated, and only 7 (13%) had significant social interaction in community activities. Health was satisfactory in 49 (94%). There were no pregnancies. Only 2 were seizure-free, off AEDs, living independently and financially independent. CONCLUSION: The social outcome of children with SGE 20 years after diagnosis is usually disappointing. One quarter die and nearly all survivors have mental retardation and are highly dependent.

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.