Stop the Status: Improving Outcomes in Pediatric Epilepsy Syndromes Michelle Welborn, PharmD ICE Alliance
Overview Seizures and Epilepsy Syndromes Seizure Emergencies Febrile Seizures Critical Population for Treatment of Community Based Seizure Emergencies: Epilepsy syndromes in children
Seizure Epilepsy Syndrome Facts 2.5 million Americans have epilepsy (defined as 2 or more unprovoked seizures) Children with epilepsy syndromes represent about 15% of the childhood epilepsy population About ½ of the epilepsy syndromes in children are considered catastrophic, drug resistant, and prone to status epilepticus There are approximately 150,000 cases of status epilepticus (seizure > 30 minutes) each year in the US; most cases occur in children 2 and under and the elderly The children with catastrophic epilepsy syndromes often have status epilepticus multiple times per week Epilepsy Foundation of America.:http://www.epilepsyfoundation.org/ Pellock JM. Hosp Med. 1999;60:43-49. DeLorenzo RJ, et al. Epilepsia. 1999;40:164-169. Begley CE, et al. Epilepsia. 2000;41:342-35.
Seizure and Epilepsy Syndrome Facts While most seizures are brief and self-limiting, if a seizure lasts >5 minutes, it is likely to be prolonged and raises the risk of status epilepticus. Status epilepticus is a seizure emergency with a 20% mortality rate at 30 minutes and 40% mortality rate at 2 hours. The longer a seizure lasts, the greater the risk of morbidity and mortality, including permanent neuronal damage leading to developmental delays, behavioral abnormalities, and probability of the need for life-long care. There is an unmet need in the US for community-based treatment of prolonged seizures and status epilepticus. Fulfilling this unmet need will decrease morbidity and mortality of children with epilepsy syndromes. Epilepsy Foundation of America.:http://www.epilepsyfoundation.org/ Pellock JM. Hosp Med. 1999;60:43-49. DeLorenzo RJ, et al. Epilepsia. 1999;40:164-169. Begley CE, et al. Epilepsia. 2000;41:342-35
Seizure Emergency Definitions Status Epilepticus Operational Definition is seizure duration of 5 minutes or longer. Seizures that last 5 minutes should be treated. Convulsive Status Epilepticus occurs when seizure last 30 minutes or longer OR patient has 2 or more seizures without full recovery between seizures. Acute Repetitive Seizures are multiple seizures within 24 hours for adults (12 hours for children) despite optimal therapy and recognizable by the patient s caregiver as distinguishable from other seizures. Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol 2001;49(5):659-64. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970-976. Mitchell WG Status Epilepticus and Acute Serial Seizures in Children. J Ch Neur 2002;17:S36.
Types of Seizure Emergencies Seizure Duration Most Seizures: <1min Usual Prolonged: >5min Unusual Prolonged SE: >30 min SE RSE HRSE > ARS:. Cluster/12-24hrs Usual ARS ARS ARS ARS 1-2 min 2-4 min 5-29 min 30-120 min 2 hrs 12-24 hrs 24-48 hrs Lowenstein DH, Bleck T, Macdonald RL: It s time to revise the definition of status epilepticus. Epilepsia 1999, 40:120-122. Mitchell WG Status Epilepticus and Acute Serial Seizures in Children. J Ch Neur 2002;17:S36. 5
Who Is at Risk for Seizure Emergencies? Patient History Unstable AED Levels Situational Triggers Acute repetitive seizures Early-onset epilepsy Developmental disabilities Neurologic illnesses or injuries Frequent seizure emergencies Pediatric seizure syndromes and encephalopathies 42% have history of epilepsy 5% of patients with refractory epilepsy have repeat prolonged seizures or SE Treatment noncompliance Missed doses Irregular physician visits Changes to chronic AED therapy Drug-drug interaction/enzyme induction Variations in generic drug formulations may affect blood levels Illness Hormonal changes Travel Stress or anxiety Disruption of sleep patterns Fatigue AED=Antiepileptic drug. Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319. Devinsky O. N Engl J Med. 1999;340:1565-1570. Ramsay RE, et al. J Child Neurol. 2007;22(suppl):53S-60S. Mitchell WG. Epilepsia. 1996;37(suppl 1):S74-S80. Jones RM, et al. Seizure. 2006;15:504-508. Patsalos PN, et al. Epilepsia. 2002;43:365-385. Kramer G, et al. Epilepsy Behav. 2007;11:46-52. Epilepsy Foundation of America. http://www.epilepsyfoundation.org/about/statistics.cfm. Accessed March 17, 2008. Trevorrow T. Seizure 2006;15:320-327.
Morbidity and Mortality of Status Epilepticus: Every Minute Counts For each minute delay from start of convulsive status epilepticus (seizure lasting five minutes) to time patient arrives at emergency department (ED), there is a 5% added cumulative risk that the seizure will last > 60 minutes. In one prospective study, arrival at ED 40 minutes after onset of convulsive status epilepticus irrespective of pre-hospital treatment with rectal diazepam was associated with a 4.3x increased risk of seizure lasting > 60 minutes compared to arrival at ED within 10 minutes. Delaying treatment with a benzodiazepine causes resistance to benzodiazepine treatment through internalization of benzodiazepine receptors as seizure length increases, making it harder to stop a seizure as time goes on. Chin R et al. Treatment of community onset childhood convulsive status epilepticus: a prospective population based study. LanNeur 2008:7(8):696-703. Abend N et al. Medical treatment of pediatric status epilepticus; SemPedNeur2010;173:169-75.
Delayed Medical Treatment for Status Epilepticus in the US Leads to Increased Morbidity and Mortality Pellock J. J Child Neurol. 2007;22(suppl):9S-13S 8
Delayed Medical Treatment for Status Epilepticus in the US Leads to Increased Morbidity and Mortality Community based treatment of children with epilepsy syndromes is imperative, as morbidity and mortality from seizures increases proportionately to time lapse from seizure onset An 85 minute average time to medical treatment from seizure onset is unacceptable in lifethreatening situations such as status epilepticus These children are chronically at high risk of death and brain damage
Mortality Associated with Prolonged Seizures and Status Epilepticus DURATION STAGE % INTERVENTIONS SETTING MORTALITY 0-2 min Seizure 100% Supportive measures Community <1% >2 min Prolonged 10% Benzodiazepine Com/Amb/ER <5% >30 min SE 5-7% 1st line: Benzodiazepine ER 10-20% 2nd line: Fosphenytoin/Phenytoin 3rd line: Phenobarbital/Valproate/ Levetiracetam 2 hours RSE 1-2% Continuous Infusion therapy ICU 40% Midazolam/Propofol/Pentobarbital >48 hours HRSE <1% Alternative Continuous Infusion Therapy ICU >60% Novel Therapeutic Options Working Group on Status Epilepticus. JAMA. 1993;270:854-85 10 10
Potential for Neuronal Injuries Seizure Emergencies and Risk of Seizure Emergencies Recurrent, Unprovoked Seizures Isolated Seizures Prolonged Seizures Neuronal Injuries Acute Repetitive Seizures (ARS) * Seizure Duration Status Epilepticus Estimated to affect 90-180,000 patients in the US Seizures persisting 5-10 minute rarely resolve spontaneously Efficacy of treatment including benzodiazepines decreases as seizure duration increases Early termination of prolonged or repetitive seizures is key to minimizing morbidity History of seizure clusters increases likelihood of experiencing status epilepticus * Also known as cluster, crescendo, multiple recurrent, serial, or sequential seizures. Figure adapted from Pellock J. J Child Neurol. 2007;22(suppl):9S-13S. Mitchell WG. Epilepsia. 1996;37(suppl 1):S74-S80. Shinnar S, et al. Ann Neurol. 2001;49:659-664. Cereghino JJ. Curr Treat Options Neurol. 2007;9:249-255. Working Group on Status Epilepticus. JAMA. 1993;270:854-859.
Morbidity of Status Epilepticus in Children Association with development of temporal lobe epilepsy 20-40% risk of developing epilepsy with status epilepticus as first seizure vs. 10% risk in first seizure lasting < 30 minutes Chronic encephalopathy and brain atrophy found in 6-15% of cases Focal neurologic signs in 9-11% of cases of children with SE Fountain N et al. Status Epilepticus: Risk Factors and Complications. Epilepsia, 41(Suppl. 2):S23-S30, 2000. Akiyama et al. Long term outcomes in adults with Dravet syndrome. Epilepsia. 2010 Jun;51(6):1043-52.
Morbidity and Mortality of Status Epilepticus in Children Retrospective and hospital based study concluded the major determinant of intelligence quotient (IQ) in children with generalized idiopathic epilepsy was a history of convulsive status epilepticus Prevention of recurrent episodes of SE are critical to long term seizure prevention and cognitive outcome in certain epilepsy syndromes, such as Dravet syndrome. In a study of 31 adults with Dravet syndrome, seizure freedom in adulthood was correlated to < 3 episodes of convulsive status epilepticus as a child 3-10% Akiyama et al. Long term outcomes in adults with Dravet syndrome. Epilepsia. 2010 Jun;51(6):1043-52. Singhi PD, Bansal U, Singhi S, Pershad D.(1992) Determinants of IQ profile in children with idiopathic generalized epilepsy. Epilepsi
Febrile Seizures Occurs in 2-4% of children in the US Approximately 25% of initial FS lasts more than 10 minutes and are considered complex 30-50% of patients with an initial FS will have a second FS Occurrence of a prolonged FS increases the risk of Epilepsy (30 % risk with prolonged seizure vs. 10% risk with seizure< 5 minutes) If a child with an initial prolonged FS experiences a second FS it is likely to be prolonged Pellock J. J Child Neurol. 2007;22(suppl):9S-13S.
Percent Cases With Duration t (time) Duration of Recurrent Seizure as a Function of Duration of Initial Seizure 50 First seizure 30 min (n = 25) First seizure 6 to 29 min (n = 42) First seizure 5 min (n = 115) Total n = 182 20 10 5 2 1 0 10 20 30 40 50 60 Duration of Recurrent Seizure (min) Duration of second seizure highly correlated with duration of initial seizure (p<0.0001). Shinnar S, et al. Ann Neurol. 2001;49:659-664.
Morbidity in Febrile Status Epilepticus Relationship between prolonged febrile seizures and later temporal lobe epilepsy associated with mesial temporal sclerosis is important, because the incidence of epilepsy following a prolonged febrile seizure may potentially be reduced by stopping the seizure and/or using neuroprotective agents. Raspall-Chaure M, Chin RF, Neville BG, Scott RC. (2006) Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 5:769 779.
Have A Plan Have a written plan to treat your child with a benzodiazepine such as rectal diazepam (Diastat) or buccal midazolam (Epistatus available in UK) to prevent status epilepticus If there are intravenous drugs that worsen seizures in your child (such as phenytoin or fosphenytoin in Dravet syndrome), these should be listed as contraindicated on the written plan Don t wait. The seizure should be stopped in under an hour for best outcome.