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This document provides an overview of a presentation on care for seizure emergencies. It introduces the faculty members Gregory D. Cascino and Juliann M. Paolicchi and discusses topics that will be covered, including an overview of care for seizure emergencies, the pediatric perspective, advances in prehospital management of acute repetitive seizures, focusing on caregivers and healthcare providers, and optimal management of seizure emergencies. It also lists modules that will be presented on status epilepticus disease burden, guidelines for managing status epilepticus, and the pediatric perspective.

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Meet the faculty Gregory D. Cascino, MD Lucretia Long, C-ANP Juliann M. Paolicchi, MD
Audience response WHAT SHOULD BE THE GOAL OF THE TREATMENT THE PATIENT RECEIVES FROM CAREGIVERS AND FIRST RESPONDERS? a) Use smallest benzodiazepine dose b) Avoid unnecessary benzodiazepine c) Provide supportive treatment d) Reduce seizure activity e) Terminate seizure quickly f) Terminate seizure safely g) Prevent recurrent seizures h) Shorten seizure i) Reduce seizure severity j) Avoid seizures lasting >30’ PICK UP TO 3 RESPONSES
Audience response HOW COULD THE MEDICAL TREATMENT THE PATIENT RECEIVED HAVE BEEN IMPROVED? a) Sooner rescue medication b) IV treatment from EMS c) Faster transport d) Faster EMS response e) Rescue medication from EMS f) Rescue medication from caregivers g) Better emergency plan h) Better caregiver response i) Faster treatment in ED PICK UP TO 3 RESPONSES
Audience response HOW COULD THE HEALTHCARE SYSTEM BETTER PREPARE CAREGIVERS TO MANAGE SEIZURE EMERGENCIES? a) Training from a specialist b) Seizure action plan training c) More rescue medication training d) Referral for training e) Better rescue medications f) Easier rescue medications g) Status epilepticus education h) EMS training PICK UP TO 3 RESPONSES
Program overview • Overview of care for seizure emergencies • Pediatric perspective • Advances in prehospital management of ARS • Faculty discussion: unanswered questions and emerging trends • Focus on caregivers and healthcare providers • Optimal management of seizure emergencies for caregivers • Key points summary • Faculty Q&A panel
MODULE 2—STATUS EPILEPTICUS DISEASE BURDEN
Overview of care for seizure emergencies Gregory D. Cascino, MD, FAAN, FANA, FACNS, FAES Whitney MacMillan Jr, Professor of Neuroscience Mayo Clinic Alix School of Medicine Enterprise Director of Epilepsy Consultant Department of Neurology Mayo Clinic Rochester, Minnesota
Epilepsy introduction • Epilepsy is common • Twice the prevalence as autism spectrum disorders, multiple sclerosis, and Parkinson’s combined • Incidence: 200,000 per year • Overall goals of treating epilepsy • Seizure free • Avoid neurological morbidity • Eliminate lifestyle limitations England MJ, et al. Epilepsy Across the Spectrum: Promoting Health and Understanding. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)2012.
Morbidity and mortality ANNUAL 25,000 TO SEIZURE MORTALITY 50,000 COGNITIVE DISORDERS DEPRESSION ANXIETY AND SEIZURE MORBIDITY INJURY STATUS EPILEPTICUS SUDDEN UNEXPLAINED DEATH IN EPILEPSY AND PHYSICAL TRAUMA
When is epilepsy treatment not successful? • Most patients with new-onset epilepsy respond to treatment • 30%-40% of patients do not respond to medical treatment • Persistent seizures are more likely in patients with symptomatic epilepsy Brodie MJ, et al. Neurology. 2012;78:1548-53. Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-19. Seizure-free Patients (%) Respond to 1st AED Respond to 2nd or 3rd AED Refractory 47% 13% 4% 36%
Defining seizure emergencies Duration Criteria Brief seizures <5 minutes Status epilepticus (SE) >30 minutes • Continuous seizure activity • ≥2 sequential seizures without full recovery of consciousness • Cerebral autoregulation and neuronal damage after 30 minutes Prolonged seizures Last 5-30 minutes Acute repetitive seizures • Mental status preserved between seizures • ≥3 within 24 hours (in patients whose habitual seizure frequency is ≤3 per day) • Increased risk of prolonged seizures • Physically and socially disabling • Common concern for patients with intractable epilepsy Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
Rationale for the 5- and 30-minute definitions Glauser T, et al. Epilepsy Curr. 2016;16:48-61. • Most seizures are brief • After 5 minutes of seizure activity, risk of a prolonged seizure increases • 5-minute threshold minimizes • Risk of prolonged seizures • Adverse outcomes from needless intervention during brief, self-limited seizures • 30-minute definition • Duration of convulsive status epilepticus that may lead to permanent neuronal injury
Pathophysiology of prolonged seizures Perks A, et al. BJA Br J Anaesth. 2012;108:562–571. • Loss of cerebral autoregulation and neuronal damage in 30ʹ • Hippocampal and neocortical neuronal loss • Complications • Hyperthermia • Acidosis • Hypotension • Respiratory failure • Rhabdomyolysis
Status epilepticus presentations Convulsive • Repeated generalized tonic-clonic seizures • Persistent postictal depression of neurologic function between seizures • Myoclonic Nonconvulsive • Subtle status epilepticus • Continuous or fluctuating epileptic twilight state • Spike-wave-stupor Repeated partial • Focal motor signs, focal sensory symptoms, or focal impairment of function • Not associated with altered awareness (epilepsia partialis continua) Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
Who is at risk for SE? SE, status epilepticus DeLorenzo RJ, et al. Epilepsia. 1992;33(S4):S15-25. • Risk is related to age • Very young and elderly • Precipitating events for SE • Acute insults • Neurologic abnormality • Risk in patients with epilepsy • 10% with epilepsy present with SE • 25% of SE occurs in those with epilepsy • 15% of epilepsy patients experience SE Epilepsy Causes (adults)
Mortality risk following status epilepticus • 55,000 deaths per year • Overall incidence of SE between 102,000 and 150,000 • 25% of SE cases are nonconvulsive • Risk is related to • Seizure type and etiology • Patient age • Bimodal mortality distribution • Overall 26% risk in adults  38% over 60 years old  50% over 80 years old • Seizure duration AED, antiepileptic drug; SE, status epilepticus Behrouz R, et al. J Am Osteopath Assoc. 2009;109:237-245. Boggs JG. Epilepsy Curr. 2004;4:25-27. Neligan A, Shorvon SD. Arch Neurol. 2010;67:931-940.
Seizure duration is a risk factor for mortality 0% 5% 10% 15% 20% SE Duration 30-day mortality 10-29 minutes >30 minutes SE, status epilepticus Behrouz R, et al. J Am Osteopath Assoc. 2009;109:237-245. Boggs JG. Epilepsy Curr. 2004;4:25-27.
Mortality: Rochester population-based studies (1965-1984) • 30-day mortality • First-episode SE (N=184) • Deaths: 38 of 201 episodes • (19%, or 21% of patients) • Characteristics of fatal cases • Nonfebrile acute symptomatic SE • >65 years of age • 10-year mortality • 30-day survivors (N=145) • Deaths: 63 (43%) • Rate 3x general population • High-risk characteristics • Myoclonic SE • Duration >24 hours • Acute symptomatic SE SE, status epilepticus Logroscino G, et al. Epilepsia. 1997;38: 1344-1349. Logroscino G, et al. Neurology. 2002;58:537-41.
Refractory status epilepticus SE, status epilepticus Pandian JD, et al. Arch Neurol. 2004;61:1090-1094. Outcomes in patients with generalized convulsive SE (n=45)
Morbidity: Rochester population-based studies (1965-1984) SE, status epilepticus Cascino GD, et al. Epilepsia. 1998;39:829-832. Logroscino G, et al. Epilepsia. 1997;38: 1344-1349. Logroscino G, et al. Neurology. 2002;58:537-41. MORBIDITY Morbidity and mortality in Rochester studies
Status epilepticus imaging findings • Focally increased T2 signal • Focally reduced ADC • Transient cytotoxic and vasogenic edema • Secondary hippocampal sclerosis ADC, apparent diffusion coefficient
MODULE 3—GUIDELINES FOR MANAGING STATUS EPILEPTICUS
Audience response WHAT SHOULD BE THE GOAL OF THE TREATMENT THE PATIENT RECEIVES FROM CAREGIVERS AND FIRST RESPONDERS?
Glauser T, et al. Epilepsy Curr. 2016;16:48-61. The goal of therapy is the rapid termination of both clinical and electrical seizure activity, since appropriate and timely therapy of status epilepticus reduces the associated mortality and morbidity
Pitfalls in achieving optimal treatment • Basic critical care and emergency principles apply and are widely accepted, BUT • Pharmacologic management varies • Patients may not receive adequate treatment because • Therapy is aimed at reducing rather than terminating seizures • Inefficient therapies are used (eg, sedatives or paralytics) • Insufficient anticonvulsant doses are used • Prehospital care is neglected • Acute rescue medication is underutilized Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
SE treatment algorithm overview* *Summary of guidelines; see publication for complete recommendations; ABCD, Airway, Breathing, Circulation, Disability (Neurologic); B, buccal; ECG, electrocardiogram; ED, emergency department; EEG, electroencephalogram; IM, intramuscular; IN, intranasal; IV, intravenous; SE, status epilepticus. Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
Initial-therapy phase highlights ≳, indicates non-significant trend; IM, intramuscular; IV, intravenous Treiman DM, et al. N Engl J Med. 1998;339:792–798. Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Silbergleit R, et al. Epilepsia. 2013;54:74–77. 1998 VA SE Study (adults) Equivalent treatments IV lorazepam = IV diazepam = IV phenobarbital Superiority IV lorazepam > IV phenytoin 2001 Alldredge trial (adults, prehospital) Treatments IV lorazepam ≳ IV diazepam > IV placebo 2011 RAMPART study (adults and children, prehospital) Treatments IM midazolam > IV lorazepam when no IV access established
Adverse events (adults) • Respiratory and cardiac symptoms are most common TEAEs • Respiratory depression • Lower in patients treated with benzodiazepine than with placebo • May be a consequence of untreated SE • No substantial difference between benzodiazepines and phenobarbital in the incidence of cardiorespiratory AEs AE, adverse events; TEAEs, treatment-emergent adverse events; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
Initial phase treatment conclusions (adults) • Without IV access • IM midazolam > IV lorazepam • No significant difference between lorazepam and diazepam • Benzodiazepines preferred over phenobarbital because of slower administration rate • New approvals IM, intramuscular; IV, intravenous Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
Second-therapy phase highlights Treiman DM, et al. N Engl J Med. 1998;339:792–798. 1998 VA SE Study, second blinded treatment (adults) Equivalent treatments IV lorazepam followed by IV phenytoin IV phenobarbital followed by IV phenytoin IV phenytoin followed by IV lorazepam IV diazepam + phenytoin followed by IV lorazepam
Trials in second phase therapies: ESETT Established Status Epilepticus Treatment Trial (ESETT) Endpoint: Absence of clinically evident seizures and improved responsiveness at 60 minutes (N=384) Levetiracetam (60 mg/kg) Fosphenytoin (20 mg/kg) Valproate (40 mg/kg) 47% 45% 46% Adverse events • Similar incidences with all treatments • Nonsignificant difference in hypotension and endotracheal intubation (fosphenytoin) • Nonsignificant difference in deaths (levetiracetam) Kapur J, et al. N Engl J Med. 2019;381:2103-2113.
Trials in second phase therapies: TRENDS Trial Husain AM, et al. Ann Neurol. 2018;83:1174-1185. Treatment of Recurrent Electrographic Nonconvulsive Seizures Trial (TRENDS) Endpoint • Absence of electrographic seizures for 24 hours (N=74) • Noninferiority Lacosamide (400 mg) Fosphenytoin (20 mg/kg) 63% 50% Adverse events • Similar incidence
Third-phase therapy • Begin when seizure duration reaches 40 minutes • No clear evidence to guide selection • Considered substantially less effective than previous phases of therapy • Treatment options • Repeat second phase therapy or anesthetic doses of thiopental, midazolam, pentobarbital, propofol Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
MODULE 4—PEDIATRIC PERSPECTIVE ON CARE FOR SEIZURE EMERGENCIES
Pediatric perspective on care for seizure emergencies Juliann M. Paolicchi, MA, MD, FAES, FANA Co-Director, Clinical Research Pediatric Epileptologist Northeast Regional Epilepsy Group Professor, Pediatrics and Neurology Hackensack-Meridian Medical School Seton Hall University Hackensack, New Jersey
Seizure emergencies in children: developing brain at risk! • Epidemiology • Generalized seizures more common in children (60%) than adults (40%) • Pediatric seizure syndromes are uniquely defined by their intractability: • Congenital malformations such as hemimeganencephaly, Sturge-Weber syndrome, or Rasmussen’s encephalitis, where 40-100 seizures a day are not an unusual occurrence despite maximal medical therapy compared to 1 per month in adult syndromes • Etiology • Pediatric epilepsy more varied etiology • Febrile seizures, cortical dysplasias, infection-related, hypoxia, genetic and congenital malformations, intrauterine and postnatal insults, anoxic injuries, vascular malformations and compromise (eg, ischemia), trauma, and tumors • Concomitant respiratory disease common in children • Adult epilepsy: MTS most common MTS, mesial temporal sclerosis
Seizure emergencies in children: special considerations in treatment • Adjust dosing for body weight • Specific medication precautions (eg, propofol) • Little direct clinical research in pediatric patients • “Bioequivalent” is not equal • Rapid metabolism, especially in very young children
Outcome of SE in pediatric patients: a global issue Outcomes based on 6 prospective studies in pediatric SE (UK, USA, sub-Saharan Africa) One-year recurrence after the first-ever CSE (prolonged febrile or afebrile) 16% (95% CI: 10-24) Percentage with recurrence within 4 years 20% Case fatality during hospitalization UK, US 2.7-5.2% Sub-Saharan Africa 15% Subsequent epilepsy, 9 years post-CSE (cumulative incidence) 25% (95% CI: 16-36) • Neurological, cognitive, and behavioral impairments outside of epilepsy are detectable within 6 weeks of CSE, and by 9 years follow-up, at least 1/3 of patients have some consequence • Long-term mortality ranges from 5-17%, with the true estimate at 9 years follow-up to be 8% with standardized mortality ratio of 46 CSE, convulsive status epilepticus; SE, status epilepticus Chin RFM. Epilepsy Behav. 2019;101(Pt B):106286. doi: 10.1016/j.yebeh.2019.04.039.
Logroscino G, et al. Epilepsia. 1997;38: 1344-1349. 30- DAY M ORTALITY R ISK
2-5 years 6-12 years 13-17 years 18-25 years Taste Forget Swallow Embarrassed Refuse Activity Run Out Pharmacy Adherence Barrier Type Level of Adherence Barrier Endorsement (1-4) 1 2 3 P<0.001 P<0.05 P<0.001 Antiseizure medicine adherence differences based on age Gutierrez-Colina AM, et al. Epilepsy Behav. 2018;80:229-234.
Gutierrez-Colina AM, et al. Epilepsy Behav. 2018;80:229-234. 2-5 YEARS Caregivers 6-12 YEARS Caregivers 13-17 YEARS Caregivers 13-17 YEARS Adolescents 1. Run out of meds 2. Forget to give meds 3. Competing activities 1. Run out of meds 2. Forget to give meds 3. Difficult to obtain from pharmacy 1. Run out of meds 2. Competing activities 3. Difficult to swallow 1. Dislikes taste 2. Competing activities 3. Refuses to take med 1. Dislikes taste 2. Difficult to swallow 3. Ran out of meds 1. Difficultto swallow 2. Embarrassed to take 3. Forget to give meds 1. Refuses to take 2. Competing activities 3. Difficult to swallow 1. Difficult to obtain from pharmacy 2. Dislikes taste 3. Competing activities 1. Dislikes taste 2. Difficult to obtain from pharmacy 3. Forget to give med 1. Run out of meds 2. Forget to give meds 3. Competing activities 1. Dislikes tastes 2. Difficult to swallow 3. Difficult to obtain from pharmacy 1. Forget to take meds 2. Dislikes taste 3. Competing activities A DHERENCE S EIZURES HRQOL
Treatment escalation may be more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
Treatment escalation may be more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
Treatment escalation may be more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
Treatment escalation may be more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
AES summary for pediatric patients: initial-therapy phase highlights B, buccal; IM, intramuscular; IN, intranasal; IV, intravenous; PR, rectal; SL, sublingual *Small number of children enrolled limited statistical power; **Based on small and/or lower quality studies Chamberlain JM, et al. J Am Med Assoc. 2014;311:1652-1660. Silbergleit R, et al. Epilepsia. 2013;54:74–77. Glauser T, et al. Epilepsy Curr. 2016;16:48-61. 2014 Chamberlain study (children) Equivalent treatments IV diazepam = IV lorazepam Other studies Probably effective treatments** PR diazepam, IM midazolam, IN midazolam, and B midazolam Insufficient data IN lorazepam, SL lorazepam, PR lorazepam, valproic acid, levetiracetam, phenobarbital, and phenytoin 2011 RAMPART study (children, prehospital) Equivalent treatments* IM midazolam = IV lorazepam when no IV access established
Pooled meta-analysis: midazolam vs diazepam in children and young adults B, buccal; IM, intramuscular; IN, intranasal; IV, intravenous; R, rectal; SL, sublingual McMullan J, et al. Acad Emerg Med. 2010;17:575-582. Glauser T, et al. Epilepsy Curr. 2016;16:48-61. • Erratic absorption of PR diazepam  low/delayed peak plasma drug concentration • AES conclusion: non-IV midazolam is probably more effective than IV or PR diazepam
AES summary for pediatric patients: second- therapy phase highlights IV, intravenous Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Lyttle MD, et al. Lancet. 2019;393:2125. Dalziel SR, et al. Lancet. 2019;393:2135. 2014 Chamberlain study (children) Equivalent treatments Efficacy: IV valproic acid = IV phenobarbital Tolerability: IV valproic acid > IV phenobarbital EcLiPSE trial (2019); ConSEPT (2019) Non-inferior/Equivalent Phenytoin or levetiracetam Established Status Epilepticus Treatment Trial (ESETT) Included pediatric patients (<18 years of age, n=225)
AES summary for pediatric patients: adverse events AE, adverse event; IV, intravenous Chamberlain JM, et al. J Am Med Assoc. 2014;311:1652-1660. 2014 Chamberlain study (children) Equivalent AE risks Assisted ventilation: IV lorazepam (17.6%) ≈ IV diazepam (16.0%) Aspiration pneumonia: IV lorazepam (n=2) = IV diazepam (n=2) Sedation: IV lorazepam (66.9%) > IV diazepam (50%)
Importance of prehospital care SE, status epilepticus Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Chin RF, et al. Lancet Neurol. 2008;7:696–703. McKee HR, et al. CNS Drugs. 2015;1:55–70. Sanchez Fernandez I, et al. Neurology. 2015;23:2304– 2311.
Importance of prehospital care SE, status epilepticus Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Chin RF, et al. Lancet Neurol. 2008;7:696–703. McKee HR, et al. CNS Drugs. 2015;1:55–70. Sanchez Fernandez I, et al. Neurology. 2015;23:2304– 2311. WHEN PREHOSPITAL CARE IS NEGLECTED…
Prehospital treatment may reduce seizure duration Factors associated with SE lasting >60 min Adjusted Odds Ratio (95% CI) P value No prehospital treatment vs prehospital treatment 2.4 (1.2-4.5) 0.008 Time from onset to arrival at ED 1.05 (1.03-1.06) <0.0001 >2 benzodiazepine doses vs ≤2 3.6 (1.9-6.7) <0.0001 Intermittent vs continuous SE 2.5 (1.4-4.8) 0.003 CI, confidence interval; ED, emergency department; SE, status epilepticus Chin RFM, et al. Lancet Neurol. 2008;7:696-703.
Prehospital management affects outcomes SE, status epilepticus Alldredge BK, et al. Pediatr Neurol. 1995;12:213–216. DURATION OF SE RATE OF SE RECURRENCE PREHOSPITAL TREATMENT WITH 32 MIN 58% WITHOUT 60 MIN 85%
AOR, adjusted odds ratio; CI, confidence interval; RCSE, recurrent convulsive status epilepticus Gaínza-Lein M, et al. JAMA Neurol. 2018;75(4):410–418. doi:10.1001/jamaneurol.2017.4382. PSERG Trial: multicenter observational study of pediatric patients (N=218) with RCSE First-line benzodiazepine treatment timing Within 10 min Delayed treatment 74 (33.9%) 144 (66.1%) Multivariate analysis of delayed group Risk of death Need for continuous infusion Increased convulsive seizure duration Risk of hypotension Adjusted Odds Ratio (95% CI) 11.0 (1.43 to ∞) 1.8 (1.01-3.36) 2.6 (1.38-4.88) 2.3 (1.16-4.63) P-value 0.02 0.047 0.003 0.02
Gaínza-Lein M, et al. JAMA Neurol. 2018;75(4):410–418. doi:10.1001/jamaneurol.2017.4382. CONCLUSIONS AND RELEVANCE Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.
Stredny CM, et al. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
Stredny CM, et al. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
Stredny CM, et al. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
Stredny CM, et al. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
Stredny CM, et al. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
MODULE 5—RESCUE MEDICATION OPTIONS
Current standard of care for prehospital management Gainza-Lein M, et al. Seizure. 2017;52:188-194. de Haan GJ, et al. Epilepsia. 2010;51:478–482. Holsti M, et al. Arch Pediatr Adoles Med. 2010;164:747–753. PREFER NON-RECTAL ROUTE SATISFIED WITH RECTAL DIAZEPAM
Off-label options sometimes used for SE • Nonrectal benzodiazepine formulations • Buccal midazolam • Compounded midazolam • Acidity can cause irritation • Limitations of device (eg, not preloaded/premeasured) • Shelf-life and storage limitations • Clonazepam orally-disintegrating tablets • VNS magnets VNS, vagal nerve stimulating
Characteristics of an ideal prehospital treatment for SE • Immediate duration of action • Rapid cessation of seizures • Easy to use • Safe, without causing discomfort • Low inter- and intra-patient variability • Long shelf life Maglalang PD, et al. Epilepsia. 2018;59:207-215.
Intranasal vs other administration routes CNS, central nervous system Maglalang PD, et al. Epilepsia. 2018;59:207-215. HIGH PERFUSION = RAPID ABSORPTION RAPID DISTRIBUTION INTO CNS SMALL VOLUME VS RECTAL EASY, MINIMAL TRAINING, LOW RISK
New approvals for seizure rescue medications Midazolam nasal spray • Patients ≥12 years of age with epilepsy • 5 mg dose Diazepam nasal spray • Patients ≥ 6 years of age with epilepsy • 5 mg, 10 mg, 15 mg, 20 mg doses Midazolam nasal spray package insert, 2019. Diazepam nasal spray package insert, 2020.
ARTEMIS 1 phase 3 trial MDZ-NS, midazolam nasal spray Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. Part 1: test dose phase Part 2: Comparative phase (N=201) Safety outcomes • Open-label, in-clinic • 2 doses 5 mg MDZ-NS Efficacy outcomes • Outpatient, administered by caregivers • Caregiver training = Patient Management Plans • Drug administration training • When to administer, requirements for second dose, and emergency rescue protocol • Double-blind first dose: MDZ-NS or placebo • Optional, open-label second dose: MDZ-NS Composite endpoint: treatment success • Seizure termination within 10 mins • No seizure recurrence 10 min to 6 hrs after treatment Primary outcome
ARTEMIS 1 efficacy outcomes MDZ-NS Placebo P-value Treatment success • Seizure termination within 10 mins • No seizure recurrence 10 min-60 hrs 53.7% 34.4% 0.01 Seizure recurrence 38.1% 59.7% 0.004 MDZ-NS, midazolam nasal spray Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.
ARTEMIS 1 efficacy outcomes Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 21% difference
ARTEMIS 1 safety outcomes • TEAEs • Consistent with known benzodiazepine AEs (eg, sedation) • Expected from IN administration (eg, nasal discomfort) • Low rate of respiratory depression type events (0.7%) • No discontinuations due to TEAE TEAEs, treatment associated adverse events; AE, adverse event; IN, intranasal Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.
ARTEMIS 1 extension trial • Open-label extension of ARTEMIS 1 • N=175 patients enrolled • 1998 seizure cluster episodes • Up to 2 doses MDZ-NS 5 mg during seizure clusters MDZ-NS, midazolam nasal spray Wheless JW, et al. Epilepsia. 2019;60:1809-1819. Outcome Treatment success, first dose 55.5% Patients requiring a 2nd dose 40% Treatment success, 2nd dose 80% Median time to return to full baseline functionality 1.2 hours
Diazepam nasal spray FDA approval NDA 211635 (Diazepam nasal spray). Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211635Orig1s000MedR.pdf …demonstration of comparable bioavailability between rectal and IN diazepam in the healthy adults … reasonably congruent results between ictal/peri-ictal and interictal PK in adults (adults in Study 01.04), and no notable differences between the PK in healthy adults and adult patients with epilepsy in a cross-study comparison would be necessary, as well as chronic safety data... Summary of Presubmission/Submission Regulatory Activity
DZP-NS phase 1 PK and safety study • Diazepam nasal spray formulation • Vitamin E (increases solubility) • Proprietary nonionic surfactant (increases transmucosal bioavailability) • Open-label phase 1 study (N=57) • Administration of DZP-NS during ictal/peri-ictal and inter-ictal periods • Dosing based on patient age and weight (5, 10, 15, or 20 mg doses) • PK conclusions • Profile comparable to PR diazepam • Lower interpatient variability DZP-NS, diazepam nasal spray; PR, rectal Hogan R, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May1, 2020.
DZP-NS phase 1 PK and safety study • No TEAEs resulted in discontinuation • Most TEAEs were consistent with events expected with nasal administration • No clinically significant abnormalities in vital signs • No changes in respiratory rate after DZP-NS administration • No clinically significant changes in clinical laboratory tests or ECGs DZP-NS, diazepam nasal spray; TEAEs, treatment emergent adverse events; ECG, electrocardiogram Hogan R, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May 1, 2020.
DZP-NS phase 3 study interim analysis • Safety and tolerability stratified by frequency of use • Moderate (1-2 doses/mo) vs frequent (>2 doses/mo) • No trends noted after 2274 episodes (N=132) • No trend observed with higher use frequency • Nasal irritation was mild and transient • Smell tests showed olfactory changes were minimal and transient and were not related to usage frequency DZP-NS, diazepam nasal spray; TEAEs, treatment emergent adverse events; ECG, electrocardiogram Miller I, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May 1, 2020.
MODULE 6—FACULTY DISCUSSION: ADDRESSING TREATMENT GAPS
MODULE 7—FOCUS ON CAREGIVERS AND HEALTHCARE PROVIDERS: IMPROVING PREHOSPITAL CARE
Focus on caregivers and healthcare providers: improving prehospital care Lucretia Long C-ANP, FAES Clinical Assistant Professor of Neurology Epilepsy Nurse Practitioner Department of Neurology Division of Epilepsy The Ohio State University Medical Center Columbus, Ohio
Audience response HOW COULD THE MEDICAL TREATMENT THE PATIENT RECEIVED HAVE BEEN IMPROVED?
Audience response HOW COULD THE HEALTHCARE SYSTEM BETTER PREPARE CAREGIVERS TO MANAGE SEIZURE EMERGENCIES?
Institute of Medicine Crossing the Quality Chasm Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C: National Academy Press; 2001.
Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Basic critical care and emergency principles of therapy…have achieved widespread acceptance and are routinely implemented…
Glauser T, et al. Epilepsy Curr. 2016;16:48-61. …approaches to the pharmacologic treatment of status epilepticus continue to vary dramatically [and] patients still receive inadequate treatment for a variety of reasons including…use of inefficient therapies such as sedatives and paralytics, and administration of insufficient anticonvulsant doses.
Delays in antiseizure medication are frequent Sanchez Fernandez I, et al. Neurology. 2015;84:2304–11. 1st AED treatment 2nd AED treatment 3rd AED treatment 3rd therapy 2nd therapy 1st therapy Stabilization AES Recommendations Pediatric patients (N=81)
Delays in antiseizure medication are frequent BZD, benzodiazepine; IV, intravenous; SE, status epilepticus Sanchez Fernandez I, et al. Neurology. 2015;84:2304–11. Capovilla G, et al. Epilepsia. 2013;54:23–34. Chin RF, et al. Presented at the annual meeting of the American Epilepsy Society; 2004: 89. Gainza-Lein M, et al. Seizure. 2017;52:188-194. 1st BZD dose 2nd BZD dose Treatment delays also happen in patients with a prior epilepsy diagnosis or prior SE episodes • Out-of-hospital seizure onset in patients with epilepsy diagnosis (N=27) • Only 12 received 1st BZD before arriving to hospital • Family administered in 7 cases • EMS administered in 5 cases • Consistent with other studies • Families are reluctant to administer rescue medication • EMS may not administer rescue medication • EMS may not consider non-IV administration
Caregiver education is a barrier to early administration of rescue medications Gainza-Lein M, et al. Seizure. 2017;52:188-194. HAVE A RESCUE MEDICATION Chart review and survey of families of pediatric patients (N=100)
0% 25% 50% 75% 100% A Seizure Action Plan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. KNEW THE CORRECT RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
0% 25% 50% 75% 100% A Seizure Action Plan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. KNEW WHEN TO GIVE RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
0% 25% 50% 75% 100% A Seizure Action Plan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. INFORMED SCHOOL OF PATIENT’S DIAGNOSIS HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
0% 25% 50% 75% 100% A Seizure Action Plan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. SCHOOL HAD ACCESS TO RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
A Seizure Action Plan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. 0% 25% 50% 75% 100% KNEW WHAT TO DO IF RESCUE MEDICATION FAILED HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
SAPs work, but they aren’t widely being used SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. PARENTS WHO RECALLED HAVING AN SAP (PARENTS NOT USING AN SAP) Chart review and survey of families of pediatric patients (N=100)
Seizure Action Plans • Detailed information about patient’s epilepsy symptoms • Instructions for how to respond during a seizure • Rescue medication administration • Other treatments (eg, vagus nerve stimulator) • A clear definition of what constitutes a seizure emergency • Reduces unnecessary treatment • Reduces treatment delays American Academy of Pediatrics. Available at https://www.healthychildren.org/English/health- issues/conditions/seizures/Pages/Children-with-Epilepsy-at-School.aspx. Accessed November 17, 2020.
Resources for Seizure Action Plans • Epilepsy Foundation • https://bit.ly/3nHjqJr • Child Neurology Foundation • https://bit.ly/2IE7Qjn • Expert Opinion Consensus Recommendations for Development of Acute Seizure Action Plans (ASAPs) • Penovich P, Glauser T, Becker D, et al. Neurol Clin Pract (submitted).
Caregiver training can be improved Gainza-Lein M, et al. Seizure. 2017;52:188-194. Patient Age (years) Parents Trained on Rescue Medication Administration • Quality of training • Preference for training by neurologist • Training by other medical staff also good • (Small but significant difference) • Parents asked for • More hands-on training • Refresher training after a few years • Seizure Action Plans • Educational materials for other caregivers Chart review and survey of families of pediatric patients (N=100)
Caregiver training is still needed Terry D, et al. J Child Neurol. 2016;31:1602-1606. HAD ENOUGH INFORMATION ABOUT INDIVIDUAL STUDENT’S SEIZURES AND MANAGEMENT School nurses (N=83)
Caregiver training is still needed IN, intranasal; PR, rectal *Off-label IN midazolam Terry D, et al. J Child Neurol. 2016;31:1602-1606. TRAINED TO ADMINISTER PR DIAZEPAM TRAINED TO ADMINISTER IN MIDAZOLAM*
Keeping SAPs up to date Gainza-Lein M, et al. Seizure. 2017;52:188-194. PATIENTS WHOSE RESCUE MEDICATION DOSE WAS WITHIN ACCEPTED GUIDELINE RANGE CORREC T 41% HIGH 8% LOW 51% • WEIGHT CHANGES IN CHILDREN • AVAILABILITY OF DOSE • CONCERNS ABOUT OVERDOSING • CONCERNS ABOUT RESPIRATORY COMPLICATION RISK Chart review and survey of families of pediatric patients (N=100)
Critical junctures are training opportunities At diagnosis During first year after diagnosis Change in developmental status • Beginning school • Transition from pediatric to adult care • Transition from adult care to geriatric care Change in seizure pattern • Change in seizure frequency • Change in seizure type • Breakthrough seizures New treatment-related concerns • Change in medication • Side effects • Nonadherence Change in health status • Pregnancy • Injury • Mental, neurological, somatic comorbid conditions Employment or social change • Life stressor • Travel England MJ, et al. Epilepsy Across the Spectrum: Promoting Health and Understanding. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)2012.

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58750-79_Slides.pptx

  • 2.
    Meet the faculty GregoryD. Cascino, MD Lucretia Long, C-ANP Juliann M. Paolicchi, MD
  • 3.
    Audience response WHAT SHOULDBE THE GOAL OF THE TREATMENT THE PATIENT RECEIVES FROM CAREGIVERS AND FIRST RESPONDERS? a) Use smallest benzodiazepine dose b) Avoid unnecessary benzodiazepine c) Provide supportive treatment d) Reduce seizure activity e) Terminate seizure quickly f) Terminate seizure safely g) Prevent recurrent seizures h) Shorten seizure i) Reduce seizure severity j) Avoid seizures lasting >30’ PICK UP TO 3 RESPONSES
  • 4.
    Audience response HOW COULDTHE MEDICAL TREATMENT THE PATIENT RECEIVED HAVE BEEN IMPROVED? a) Sooner rescue medication b) IV treatment from EMS c) Faster transport d) Faster EMS response e) Rescue medication from EMS f) Rescue medication from caregivers g) Better emergency plan h) Better caregiver response i) Faster treatment in ED PICK UP TO 3 RESPONSES
  • 5.
    Audience response HOW COULDTHE HEALTHCARE SYSTEM BETTER PREPARE CAREGIVERS TO MANAGE SEIZURE EMERGENCIES? a) Training from a specialist b) Seizure action plan training c) More rescue medication training d) Referral for training e) Better rescue medications f) Easier rescue medications g) Status epilepticus education h) EMS training PICK UP TO 3 RESPONSES
  • 6.
    Program overview • Overviewof care for seizure emergencies • Pediatric perspective • Advances in prehospital management of ARS • Faculty discussion: unanswered questions and emerging trends • Focus on caregivers and healthcare providers • Optimal management of seizure emergencies for caregivers • Key points summary • Faculty Q&A panel
  • 7.
  • 8.
    Overview of carefor seizure emergencies Gregory D. Cascino, MD, FAAN, FANA, FACNS, FAES Whitney MacMillan Jr, Professor of Neuroscience Mayo Clinic Alix School of Medicine Enterprise Director of Epilepsy Consultant Department of Neurology Mayo Clinic Rochester, Minnesota
  • 9.
    Epilepsy introduction • Epilepsyis common • Twice the prevalence as autism spectrum disorders, multiple sclerosis, and Parkinson’s combined • Incidence: 200,000 per year • Overall goals of treating epilepsy • Seizure free • Avoid neurological morbidity • Eliminate lifestyle limitations England MJ, et al. Epilepsy Across the Spectrum: Promoting Health and Understanding. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)2012.
  • 10.
    Morbidity and mortality ANNUAL 25,000 TO SEIZURE MORTALITY 50,000COGNITIVE DISORDERS DEPRESSION ANXIETY AND SEIZURE MORBIDITY INJURY STATUS EPILEPTICUS SUDDEN UNEXPLAINED DEATH IN EPILEPSY AND PHYSICAL TRAUMA
  • 11.
    When is epilepsytreatment not successful? • Most patients with new-onset epilepsy respond to treatment • 30%-40% of patients do not respond to medical treatment • Persistent seizures are more likely in patients with symptomatic epilepsy Brodie MJ, et al. Neurology. 2012;78:1548-53. Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-19. Seizure-free Patients (%) Respond to 1st AED Respond to 2nd or 3rd AED Refractory 47% 13% 4% 36%
  • 12.
    Defining seizure emergencies DurationCriteria Brief seizures <5 minutes Status epilepticus (SE) >30 minutes • Continuous seizure activity • ≥2 sequential seizures without full recovery of consciousness • Cerebral autoregulation and neuronal damage after 30 minutes Prolonged seizures Last 5-30 minutes Acute repetitive seizures • Mental status preserved between seizures • ≥3 within 24 hours (in patients whose habitual seizure frequency is ≤3 per day) • Increased risk of prolonged seizures • Physically and socially disabling • Common concern for patients with intractable epilepsy Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 13.
    Rationale for the5- and 30-minute definitions Glauser T, et al. Epilepsy Curr. 2016;16:48-61. • Most seizures are brief • After 5 minutes of seizure activity, risk of a prolonged seizure increases • 5-minute threshold minimizes • Risk of prolonged seizures • Adverse outcomes from needless intervention during brief, self-limited seizures • 30-minute definition • Duration of convulsive status epilepticus that may lead to permanent neuronal injury
  • 14.
    Pathophysiology of prolonged seizures PerksA, et al. BJA Br J Anaesth. 2012;108:562–571. • Loss of cerebral autoregulation and neuronal damage in 30ʹ • Hippocampal and neocortical neuronal loss • Complications • Hyperthermia • Acidosis • Hypotension • Respiratory failure • Rhabdomyolysis
  • 15.
    Status epilepticus presentations Convulsive •Repeated generalized tonic-clonic seizures • Persistent postictal depression of neurologic function between seizures • Myoclonic Nonconvulsive • Subtle status epilepticus • Continuous or fluctuating epileptic twilight state • Spike-wave-stupor Repeated partial • Focal motor signs, focal sensory symptoms, or focal impairment of function • Not associated with altered awareness (epilepsia partialis continua) Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 16.
    Who is atrisk for SE? SE, status epilepticus DeLorenzo RJ, et al. Epilepsia. 1992;33(S4):S15-25. • Risk is related to age • Very young and elderly • Precipitating events for SE • Acute insults • Neurologic abnormality • Risk in patients with epilepsy • 10% with epilepsy present with SE • 25% of SE occurs in those with epilepsy • 15% of epilepsy patients experience SE Epilepsy Causes (adults)
  • 17.
    Mortality risk followingstatus epilepticus • 55,000 deaths per year • Overall incidence of SE between 102,000 and 150,000 • 25% of SE cases are nonconvulsive • Risk is related to • Seizure type and etiology • Patient age • Bimodal mortality distribution • Overall 26% risk in adults  38% over 60 years old  50% over 80 years old • Seizure duration AED, antiepileptic drug; SE, status epilepticus Behrouz R, et al. J Am Osteopath Assoc. 2009;109:237-245. Boggs JG. Epilepsy Curr. 2004;4:25-27. Neligan A, Shorvon SD. Arch Neurol. 2010;67:931-940.
  • 18.
    Seizure duration isa risk factor for mortality 0% 5% 10% 15% 20% SE Duration 30-day mortality 10-29 minutes >30 minutes SE, status epilepticus Behrouz R, et al. J Am Osteopath Assoc. 2009;109:237-245. Boggs JG. Epilepsy Curr. 2004;4:25-27.
  • 19.
    Mortality: Rochester population-basedstudies (1965-1984) • 30-day mortality • First-episode SE (N=184) • Deaths: 38 of 201 episodes • (19%, or 21% of patients) • Characteristics of fatal cases • Nonfebrile acute symptomatic SE • >65 years of age • 10-year mortality • 30-day survivors (N=145) • Deaths: 63 (43%) • Rate 3x general population • High-risk characteristics • Myoclonic SE • Duration >24 hours • Acute symptomatic SE SE, status epilepticus Logroscino G, et al. Epilepsia. 1997;38: 1344-1349. Logroscino G, et al. Neurology. 2002;58:537-41.
  • 20.
    Refractory status epilepticus SE,status epilepticus Pandian JD, et al. Arch Neurol. 2004;61:1090-1094. Outcomes in patients with generalized convulsive SE (n=45)
  • 21.
    Morbidity: Rochester population-basedstudies (1965-1984) SE, status epilepticus Cascino GD, et al. Epilepsia. 1998;39:829-832. Logroscino G, et al. Epilepsia. 1997;38: 1344-1349. Logroscino G, et al. Neurology. 2002;58:537-41. MORBIDITY Morbidity and mortality in Rochester studies
  • 22.
    Status epilepticus imagingfindings • Focally increased T2 signal • Focally reduced ADC • Transient cytotoxic and vasogenic edema • Secondary hippocampal sclerosis ADC, apparent diffusion coefficient
  • 26.
    MODULE 3—GUIDELINES FORMANAGING STATUS EPILEPTICUS
  • 27.
    Audience response WHAT SHOULDBE THE GOAL OF THE TREATMENT THE PATIENT RECEIVES FROM CAREGIVERS AND FIRST RESPONDERS?
  • 28.
    Glauser T, etal. Epilepsy Curr. 2016;16:48-61. The goal of therapy is the rapid termination of both clinical and electrical seizure activity, since appropriate and timely therapy of status epilepticus reduces the associated mortality and morbidity
  • 29.
    Pitfalls in achievingoptimal treatment • Basic critical care and emergency principles apply and are widely accepted, BUT • Pharmacologic management varies • Patients may not receive adequate treatment because • Therapy is aimed at reducing rather than terminating seizures • Inefficient therapies are used (eg, sedatives or paralytics) • Insufficient anticonvulsant doses are used • Prehospital care is neglected • Acute rescue medication is underutilized Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 30.
    SE treatment algorithmoverview* *Summary of guidelines; see publication for complete recommendations; ABCD, Airway, Breathing, Circulation, Disability (Neurologic); B, buccal; ECG, electrocardiogram; ED, emergency department; EEG, electroencephalogram; IM, intramuscular; IN, intranasal; IV, intravenous; SE, status epilepticus. Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 31.
    Initial-therapy phase highlights ≳,indicates non-significant trend; IM, intramuscular; IV, intravenous Treiman DM, et al. N Engl J Med. 1998;339:792–798. Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Silbergleit R, et al. Epilepsia. 2013;54:74–77. 1998 VA SE Study (adults) Equivalent treatments IV lorazepam = IV diazepam = IV phenobarbital Superiority IV lorazepam > IV phenytoin 2001 Alldredge trial (adults, prehospital) Treatments IV lorazepam ≳ IV diazepam > IV placebo 2011 RAMPART study (adults and children, prehospital) Treatments IM midazolam > IV lorazepam when no IV access established
  • 32.
    Adverse events (adults) •Respiratory and cardiac symptoms are most common TEAEs • Respiratory depression • Lower in patients treated with benzodiazepine than with placebo • May be a consequence of untreated SE • No substantial difference between benzodiazepines and phenobarbital in the incidence of cardiorespiratory AEs AE, adverse events; TEAEs, treatment-emergent adverse events; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 33.
    Initial phase treatmentconclusions (adults) • Without IV access • IM midazolam > IV lorazepam • No significant difference between lorazepam and diazepam • Benzodiazepines preferred over phenobarbital because of slower administration rate • New approvals IM, intramuscular; IV, intravenous Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 34.
    Second-therapy phase highlights TreimanDM, et al. N Engl J Med. 1998;339:792–798. 1998 VA SE Study, second blinded treatment (adults) Equivalent treatments IV lorazepam followed by IV phenytoin IV phenobarbital followed by IV phenytoin IV phenytoin followed by IV lorazepam IV diazepam + phenytoin followed by IV lorazepam
  • 35.
    Trials in secondphase therapies: ESETT Established Status Epilepticus Treatment Trial (ESETT) Endpoint: Absence of clinically evident seizures and improved responsiveness at 60 minutes (N=384) Levetiracetam (60 mg/kg) Fosphenytoin (20 mg/kg) Valproate (40 mg/kg) 47% 45% 46% Adverse events • Similar incidences with all treatments • Nonsignificant difference in hypotension and endotracheal intubation (fosphenytoin) • Nonsignificant difference in deaths (levetiracetam) Kapur J, et al. N Engl J Med. 2019;381:2103-2113.
  • 36.
    Trials in secondphase therapies: TRENDS Trial Husain AM, et al. Ann Neurol. 2018;83:1174-1185. Treatment of Recurrent Electrographic Nonconvulsive Seizures Trial (TRENDS) Endpoint • Absence of electrographic seizures for 24 hours (N=74) • Noninferiority Lacosamide (400 mg) Fosphenytoin (20 mg/kg) 63% 50% Adverse events • Similar incidence
  • 37.
    Third-phase therapy • Beginwhen seizure duration reaches 40 minutes • No clear evidence to guide selection • Considered substantially less effective than previous phases of therapy • Treatment options • Repeat second phase therapy or anesthetic doses of thiopental, midazolam, pentobarbital, propofol Glauser T, et al. Epilepsy Curr. 2016;16:48-61.
  • 38.
    MODULE 4—PEDIATRIC PERSPECTIVEON CARE FOR SEIZURE EMERGENCIES
  • 39.
    Pediatric perspective oncare for seizure emergencies Juliann M. Paolicchi, MA, MD, FAES, FANA Co-Director, Clinical Research Pediatric Epileptologist Northeast Regional Epilepsy Group Professor, Pediatrics and Neurology Hackensack-Meridian Medical School Seton Hall University Hackensack, New Jersey
  • 40.
    Seizure emergencies inchildren: developing brain at risk! • Epidemiology • Generalized seizures more common in children (60%) than adults (40%) • Pediatric seizure syndromes are uniquely defined by their intractability: • Congenital malformations such as hemimeganencephaly, Sturge-Weber syndrome, or Rasmussen’s encephalitis, where 40-100 seizures a day are not an unusual occurrence despite maximal medical therapy compared to 1 per month in adult syndromes • Etiology • Pediatric epilepsy more varied etiology • Febrile seizures, cortical dysplasias, infection-related, hypoxia, genetic and congenital malformations, intrauterine and postnatal insults, anoxic injuries, vascular malformations and compromise (eg, ischemia), trauma, and tumors • Concomitant respiratory disease common in children • Adult epilepsy: MTS most common MTS, mesial temporal sclerosis
  • 41.
    Seizure emergencies inchildren: special considerations in treatment • Adjust dosing for body weight • Specific medication precautions (eg, propofol) • Little direct clinical research in pediatric patients • “Bioequivalent” is not equal • Rapid metabolism, especially in very young children
  • 42.
    Outcome of SEin pediatric patients: a global issue Outcomes based on 6 prospective studies in pediatric SE (UK, USA, sub-Saharan Africa) One-year recurrence after the first-ever CSE (prolonged febrile or afebrile) 16% (95% CI: 10-24) Percentage with recurrence within 4 years 20% Case fatality during hospitalization UK, US 2.7-5.2% Sub-Saharan Africa 15% Subsequent epilepsy, 9 years post-CSE (cumulative incidence) 25% (95% CI: 16-36) • Neurological, cognitive, and behavioral impairments outside of epilepsy are detectable within 6 weeks of CSE, and by 9 years follow-up, at least 1/3 of patients have some consequence • Long-term mortality ranges from 5-17%, with the true estimate at 9 years follow-up to be 8% with standardized mortality ratio of 46 CSE, convulsive status epilepticus; SE, status epilepticus Chin RFM. Epilepsy Behav. 2019;101(Pt B):106286. doi: 10.1016/j.yebeh.2019.04.039.
  • 43.
    Logroscino G, etal. Epilepsia. 1997;38: 1344-1349. 30- DAY M ORTALITY R ISK
  • 44.
    2-5 years 6-12 years 13-17years 18-25 years Taste Forget Swallow Embarrassed Refuse Activity Run Out Pharmacy Adherence Barrier Type Level of Adherence Barrier Endorsement (1-4) 1 2 3 P<0.001 P<0.05 P<0.001 Antiseizure medicine adherence differences based on age Gutierrez-Colina AM, et al. Epilepsy Behav. 2018;80:229-234.
  • 45.
    Gutierrez-Colina AM, etal. Epilepsy Behav. 2018;80:229-234. 2-5 YEARS Caregivers 6-12 YEARS Caregivers 13-17 YEARS Caregivers 13-17 YEARS Adolescents 1. Run out of meds 2. Forget to give meds 3. Competing activities 1. Run out of meds 2. Forget to give meds 3. Difficult to obtain from pharmacy 1. Run out of meds 2. Competing activities 3. Difficult to swallow 1. Dislikes taste 2. Competing activities 3. Refuses to take med 1. Dislikes taste 2. Difficult to swallow 3. Ran out of meds 1. Difficultto swallow 2. Embarrassed to take 3. Forget to give meds 1. Refuses to take 2. Competing activities 3. Difficult to swallow 1. Difficult to obtain from pharmacy 2. Dislikes taste 3. Competing activities 1. Dislikes taste 2. Difficult to obtain from pharmacy 3. Forget to give med 1. Run out of meds 2. Forget to give meds 3. Competing activities 1. Dislikes tastes 2. Difficult to swallow 3. Difficult to obtain from pharmacy 1. Forget to take meds 2. Dislikes taste 3. Competing activities A DHERENCE S EIZURES HRQOL
  • 46.
    Treatment escalation maybe more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
  • 47.
    Treatment escalation maybe more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
  • 48.
    Treatment escalation maybe more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
  • 49.
    Treatment escalation maybe more aggressive than recommended by the AES AES, American Epilepsy Society 2016 Evidence Based Guidelines protocol for managing SE; ILAE, International League Against Epilepsy timepoints that define brief seizures and seizures that have increased risk for neurological damage; SE, status epilepticus Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Vasquez A, et al. Pediatr Neurol. 2018;86:33-41.
  • 50.
    AES summary forpediatric patients: initial-therapy phase highlights B, buccal; IM, intramuscular; IN, intranasal; IV, intravenous; PR, rectal; SL, sublingual *Small number of children enrolled limited statistical power; **Based on small and/or lower quality studies Chamberlain JM, et al. J Am Med Assoc. 2014;311:1652-1660. Silbergleit R, et al. Epilepsia. 2013;54:74–77. Glauser T, et al. Epilepsy Curr. 2016;16:48-61. 2014 Chamberlain study (children) Equivalent treatments IV diazepam = IV lorazepam Other studies Probably effective treatments** PR diazepam, IM midazolam, IN midazolam, and B midazolam Insufficient data IN lorazepam, SL lorazepam, PR lorazepam, valproic acid, levetiracetam, phenobarbital, and phenytoin 2011 RAMPART study (children, prehospital) Equivalent treatments* IM midazolam = IV lorazepam when no IV access established
  • 51.
    Pooled meta-analysis: midazolamvs diazepam in children and young adults B, buccal; IM, intramuscular; IN, intranasal; IV, intravenous; R, rectal; SL, sublingual McMullan J, et al. Acad Emerg Med. 2010;17:575-582. Glauser T, et al. Epilepsy Curr. 2016;16:48-61. • Erratic absorption of PR diazepam  low/delayed peak plasma drug concentration • AES conclusion: non-IV midazolam is probably more effective than IV or PR diazepam
  • 52.
    AES summary forpediatric patients: second- therapy phase highlights IV, intravenous Glauser T, et al. Epilepsy Curr. 2016;16:48-61. Lyttle MD, et al. Lancet. 2019;393:2125. Dalziel SR, et al. Lancet. 2019;393:2135. 2014 Chamberlain study (children) Equivalent treatments Efficacy: IV valproic acid = IV phenobarbital Tolerability: IV valproic acid > IV phenobarbital EcLiPSE trial (2019); ConSEPT (2019) Non-inferior/Equivalent Phenytoin or levetiracetam Established Status Epilepticus Treatment Trial (ESETT) Included pediatric patients (<18 years of age, n=225)
  • 53.
    AES summary forpediatric patients: adverse events AE, adverse event; IV, intravenous Chamberlain JM, et al. J Am Med Assoc. 2014;311:1652-1660. 2014 Chamberlain study (children) Equivalent AE risks Assisted ventilation: IV lorazepam (17.6%) ≈ IV diazepam (16.0%) Aspiration pneumonia: IV lorazepam (n=2) = IV diazepam (n=2) Sedation: IV lorazepam (66.9%) > IV diazepam (50%)
  • 54.
    Importance of prehospitalcare SE, status epilepticus Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Chin RF, et al. Lancet Neurol. 2008;7:696–703. McKee HR, et al. CNS Drugs. 2015;1:55–70. Sanchez Fernandez I, et al. Neurology. 2015;23:2304– 2311.
  • 55.
    Importance of prehospitalcare SE, status epilepticus Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Chin RF, et al. Lancet Neurol. 2008;7:696–703. McKee HR, et al. CNS Drugs. 2015;1:55–70. Sanchez Fernandez I, et al. Neurology. 2015;23:2304– 2311. WHEN PREHOSPITAL CARE IS NEGLECTED…
  • 56.
    Prehospital treatment mayreduce seizure duration Factors associated with SE lasting >60 min Adjusted Odds Ratio (95% CI) P value No prehospital treatment vs prehospital treatment 2.4 (1.2-4.5) 0.008 Time from onset to arrival at ED 1.05 (1.03-1.06) <0.0001 >2 benzodiazepine doses vs ≤2 3.6 (1.9-6.7) <0.0001 Intermittent vs continuous SE 2.5 (1.4-4.8) 0.003 CI, confidence interval; ED, emergency department; SE, status epilepticus Chin RFM, et al. Lancet Neurol. 2008;7:696-703.
  • 57.
    Prehospital management affectsoutcomes SE, status epilepticus Alldredge BK, et al. Pediatr Neurol. 1995;12:213–216. DURATION OF SE RATE OF SE RECURRENCE PREHOSPITAL TREATMENT WITH 32 MIN 58% WITHOUT 60 MIN 85%
  • 58.
    AOR, adjusted oddsratio; CI, confidence interval; RCSE, recurrent convulsive status epilepticus Gaínza-Lein M, et al. JAMA Neurol. 2018;75(4):410–418. doi:10.1001/jamaneurol.2017.4382. PSERG Trial: multicenter observational study of pediatric patients (N=218) with RCSE First-line benzodiazepine treatment timing Within 10 min Delayed treatment 74 (33.9%) 144 (66.1%) Multivariate analysis of delayed group Risk of death Need for continuous infusion Increased convulsive seizure duration Risk of hypotension Adjusted Odds Ratio (95% CI) 11.0 (1.43 to ∞) 1.8 (1.01-3.36) 2.6 (1.38-4.88) 2.3 (1.16-4.63) P-value 0.02 0.047 0.003 0.02
  • 59.
    Gaínza-Lein M, etal. JAMA Neurol. 2018;75(4):410–418. doi:10.1001/jamaneurol.2017.4382. CONCLUSIONS AND RELEVANCE Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.
  • 60.
    Stredny CM, etal. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
  • 61.
    Stredny CM, etal. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
  • 62.
    Stredny CM, etal. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
  • 63.
    Stredny CM, etal. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
  • 64.
    Stredny CM, etal. Seizure. 2018;58:133-140. doi: 10.1016/j.seizure.2018.04.011. Rapid initiation and escalation of SR treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. [PSERG and other studies have shown that] time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications…. Conclusion: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management….
  • 65.
  • 66.
    Current standard ofcare for prehospital management Gainza-Lein M, et al. Seizure. 2017;52:188-194. de Haan GJ, et al. Epilepsia. 2010;51:478–482. Holsti M, et al. Arch Pediatr Adoles Med. 2010;164:747–753. PREFER NON-RECTAL ROUTE SATISFIED WITH RECTAL DIAZEPAM
  • 67.
    Off-label options sometimesused for SE • Nonrectal benzodiazepine formulations • Buccal midazolam • Compounded midazolam • Acidity can cause irritation • Limitations of device (eg, not preloaded/premeasured) • Shelf-life and storage limitations • Clonazepam orally-disintegrating tablets • VNS magnets VNS, vagal nerve stimulating
  • 68.
    Characteristics of anideal prehospital treatment for SE • Immediate duration of action • Rapid cessation of seizures • Easy to use • Safe, without causing discomfort • Low inter- and intra-patient variability • Long shelf life Maglalang PD, et al. Epilepsia. 2018;59:207-215.
  • 69.
    Intranasal vs otheradministration routes CNS, central nervous system Maglalang PD, et al. Epilepsia. 2018;59:207-215. HIGH PERFUSION = RAPID ABSORPTION RAPID DISTRIBUTION INTO CNS SMALL VOLUME VS RECTAL EASY, MINIMAL TRAINING, LOW RISK
  • 70.
    New approvals forseizure rescue medications Midazolam nasal spray • Patients ≥12 years of age with epilepsy • 5 mg dose Diazepam nasal spray • Patients ≥ 6 years of age with epilepsy • 5 mg, 10 mg, 15 mg, 20 mg doses Midazolam nasal spray package insert, 2019. Diazepam nasal spray package insert, 2020.
  • 71.
    ARTEMIS 1 phase3 trial MDZ-NS, midazolam nasal spray Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. Part 1: test dose phase Part 2: Comparative phase (N=201) Safety outcomes • Open-label, in-clinic • 2 doses 5 mg MDZ-NS Efficacy outcomes • Outpatient, administered by caregivers • Caregiver training = Patient Management Plans • Drug administration training • When to administer, requirements for second dose, and emergency rescue protocol • Double-blind first dose: MDZ-NS or placebo • Optional, open-label second dose: MDZ-NS Composite endpoint: treatment success • Seizure termination within 10 mins • No seizure recurrence 10 min to 6 hrs after treatment Primary outcome
  • 72.
    ARTEMIS 1 efficacyoutcomes MDZ-NS Placebo P-value Treatment success • Seizure termination within 10 mins • No seizure recurrence 10 min-60 hrs 53.7% 34.4% 0.01 Seizure recurrence 38.1% 59.7% 0.004 MDZ-NS, midazolam nasal spray Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.
  • 73.
    ARTEMIS 1 efficacyoutcomes Detyniecki K, et al. Epilepsia. 2019;60:1797-1808. 21% difference
  • 74.
    ARTEMIS 1 safetyoutcomes • TEAEs • Consistent with known benzodiazepine AEs (eg, sedation) • Expected from IN administration (eg, nasal discomfort) • Low rate of respiratory depression type events (0.7%) • No discontinuations due to TEAE TEAEs, treatment associated adverse events; AE, adverse event; IN, intranasal Detyniecki K, et al. Epilepsia. 2019;60:1797-1808.
  • 75.
    ARTEMIS 1 extensiontrial • Open-label extension of ARTEMIS 1 • N=175 patients enrolled • 1998 seizure cluster episodes • Up to 2 doses MDZ-NS 5 mg during seizure clusters MDZ-NS, midazolam nasal spray Wheless JW, et al. Epilepsia. 2019;60:1809-1819. Outcome Treatment success, first dose 55.5% Patients requiring a 2nd dose 40% Treatment success, 2nd dose 80% Median time to return to full baseline functionality 1.2 hours
  • 76.
    Diazepam nasal sprayFDA approval NDA 211635 (Diazepam nasal spray). Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211635Orig1s000MedR.pdf …demonstration of comparable bioavailability between rectal and IN diazepam in the healthy adults … reasonably congruent results between ictal/peri-ictal and interictal PK in adults (adults in Study 01.04), and no notable differences between the PK in healthy adults and adult patients with epilepsy in a cross-study comparison would be necessary, as well as chronic safety data... Summary of Presubmission/Submission Regulatory Activity
  • 77.
    DZP-NS phase 1PK and safety study • Diazepam nasal spray formulation • Vitamin E (increases solubility) • Proprietary nonionic surfactant (increases transmucosal bioavailability) • Open-label phase 1 study (N=57) • Administration of DZP-NS during ictal/peri-ictal and inter-ictal periods • Dosing based on patient age and weight (5, 10, 15, or 20 mg doses) • PK conclusions • Profile comparable to PR diazepam • Lower interpatient variability DZP-NS, diazepam nasal spray; PR, rectal Hogan R, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May1, 2020.
  • 78.
    DZP-NS phase 1PK and safety study • No TEAEs resulted in discontinuation • Most TEAEs were consistent with events expected with nasal administration • No clinically significant abnormalities in vital signs • No changes in respiratory rate after DZP-NS administration • No clinically significant changes in clinical laboratory tests or ECGs DZP-NS, diazepam nasal spray; TEAEs, treatment emergent adverse events; ECG, electrocardiogram Hogan R, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May 1, 2020.
  • 79.
    DZP-NS phase 3study interim analysis • Safety and tolerability stratified by frequency of use • Moderate (1-2 doses/mo) vs frequent (>2 doses/mo) • No trends noted after 2274 episodes (N=132) • No trend observed with higher use frequency • Nasal irritation was mild and transient • Smell tests showed olfactory changes were minimal and transient and were not related to usage frequency DZP-NS, diazepam nasal spray; TEAEs, treatment emergent adverse events; ECG, electrocardiogram Miller I, et al. Presented at the American Academy of Neurology Annual Meeting. Toronto. April 25- May 1, 2020.
  • 80.
    MODULE 6—FACULTY DISCUSSION:ADDRESSING TREATMENT GAPS
  • 81.
    MODULE 7—FOCUS ONCAREGIVERS AND HEALTHCARE PROVIDERS: IMPROVING PREHOSPITAL CARE
  • 82.
    Focus on caregiversand healthcare providers: improving prehospital care Lucretia Long C-ANP, FAES Clinical Assistant Professor of Neurology Epilepsy Nurse Practitioner Department of Neurology Division of Epilepsy The Ohio State University Medical Center Columbus, Ohio
  • 83.
    Audience response HOW COULDTHE MEDICAL TREATMENT THE PATIENT RECEIVED HAVE BEEN IMPROVED?
  • 84.
    Audience response HOW COULDTHE HEALTHCARE SYSTEM BETTER PREPARE CAREGIVERS TO MANAGE SEIZURE EMERGENCIES?
  • 85.
    Institute of MedicineCrossing the Quality Chasm Institute of Medicine (IOM). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, D.C: National Academy Press; 2001.
  • 86.
    Glauser T, etal. Epilepsy Curr. 2016;16:48-61. Basic critical care and emergency principles of therapy…have achieved widespread acceptance and are routinely implemented…
  • 87.
    Glauser T, etal. Epilepsy Curr. 2016;16:48-61. …approaches to the pharmacologic treatment of status epilepticus continue to vary dramatically [and] patients still receive inadequate treatment for a variety of reasons including…use of inefficient therapies such as sedatives and paralytics, and administration of insufficient anticonvulsant doses.
  • 88.
    Delays in antiseizuremedication are frequent Sanchez Fernandez I, et al. Neurology. 2015;84:2304–11. 1st AED treatment 2nd AED treatment 3rd AED treatment 3rd therapy 2nd therapy 1st therapy Stabilization AES Recommendations Pediatric patients (N=81)
  • 89.
    Delays in antiseizuremedication are frequent BZD, benzodiazepine; IV, intravenous; SE, status epilepticus Sanchez Fernandez I, et al. Neurology. 2015;84:2304–11. Capovilla G, et al. Epilepsia. 2013;54:23–34. Chin RF, et al. Presented at the annual meeting of the American Epilepsy Society; 2004: 89. Gainza-Lein M, et al. Seizure. 2017;52:188-194. 1st BZD dose 2nd BZD dose Treatment delays also happen in patients with a prior epilepsy diagnosis or prior SE episodes • Out-of-hospital seizure onset in patients with epilepsy diagnosis (N=27) • Only 12 received 1st BZD before arriving to hospital • Family administered in 7 cases • EMS administered in 5 cases • Consistent with other studies • Families are reluctant to administer rescue medication • EMS may not administer rescue medication • EMS may not consider non-IV administration
  • 90.
    Caregiver education isa barrier to early administration of rescue medications Gainza-Lein M, et al. Seizure. 2017;52:188-194. HAVE A RESCUE MEDICATION Chart review and survey of families of pediatric patients (N=100)
  • 91.
    0% 25% 50% 75% 100% A Seizure ActionPlan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. KNEW THE CORRECT RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
  • 92.
    0% 25% 50% 75% 100% A Seizure ActionPlan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. KNEW WHEN TO GIVE RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
  • 93.
    0% 25% 50% 75% 100% A Seizure ActionPlan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. INFORMED SCHOOL OF PATIENT’S DIAGNOSIS HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
  • 94.
    0% 25% 50% 75% 100% A Seizure ActionPlan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. SCHOOL HAD ACCESS TO RESCUE MEDICATION HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
  • 95.
    A Seizure ActionPlan lowers the barriers to caregivers administering rescue medication SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. 0% 25% 50% 75% 100% KNEW WHAT TO DO IF RESCUE MEDICATION FAILED HAD AN SAP DIDN’T HAVE AN SAP P<0.01 Patients with a Seizure Action Plan Patients without a Seizure Action Plan Chart review and survey of families of pediatric patients (N=100)
  • 96.
    SAPs work, butthey aren’t widely being used SAP, Seizure Action Plan Gainza-Lein M, et al. Seizure. 2017;52:188-194. PARENTS WHO RECALLED HAVING AN SAP (PARENTS NOT USING AN SAP) Chart review and survey of families of pediatric patients (N=100)
  • 97.
    Seizure Action Plans •Detailed information about patient’s epilepsy symptoms • Instructions for how to respond during a seizure • Rescue medication administration • Other treatments (eg, vagus nerve stimulator) • A clear definition of what constitutes a seizure emergency • Reduces unnecessary treatment • Reduces treatment delays American Academy of Pediatrics. Available at https://www.healthychildren.org/English/health- issues/conditions/seizures/Pages/Children-with-Epilepsy-at-School.aspx. Accessed November 17, 2020.
  • 98.
    Resources for SeizureAction Plans • Epilepsy Foundation • https://bit.ly/3nHjqJr • Child Neurology Foundation • https://bit.ly/2IE7Qjn • Expert Opinion Consensus Recommendations for Development of Acute Seizure Action Plans (ASAPs) • Penovich P, Glauser T, Becker D, et al. Neurol Clin Pract (submitted).
  • 99.
    Caregiver training canbe improved Gainza-Lein M, et al. Seizure. 2017;52:188-194. Patient Age (years) Parents Trained on Rescue Medication Administration • Quality of training • Preference for training by neurologist • Training by other medical staff also good • (Small but significant difference) • Parents asked for • More hands-on training • Refresher training after a few years • Seizure Action Plans • Educational materials for other caregivers Chart review and survey of families of pediatric patients (N=100)
  • 100.
    Caregiver training isstill needed Terry D, et al. J Child Neurol. 2016;31:1602-1606. HAD ENOUGH INFORMATION ABOUT INDIVIDUAL STUDENT’S SEIZURES AND MANAGEMENT School nurses (N=83)
  • 101.
    Caregiver training isstill needed IN, intranasal; PR, rectal *Off-label IN midazolam Terry D, et al. J Child Neurol. 2016;31:1602-1606. TRAINED TO ADMINISTER PR DIAZEPAM TRAINED TO ADMINISTER IN MIDAZOLAM*
  • 102.
    Keeping SAPs upto date Gainza-Lein M, et al. Seizure. 2017;52:188-194. PATIENTS WHOSE RESCUE MEDICATION DOSE WAS WITHIN ACCEPTED GUIDELINE RANGE CORREC T 41% HIGH 8% LOW 51% • WEIGHT CHANGES IN CHILDREN • AVAILABILITY OF DOSE • CONCERNS ABOUT OVERDOSING • CONCERNS ABOUT RESPIRATORY COMPLICATION RISK Chart review and survey of families of pediatric patients (N=100)
  • 103.
    Critical junctures aretraining opportunities At diagnosis During first year after diagnosis Change in developmental status • Beginning school • Transition from pediatric to adult care • Transition from adult care to geriatric care Change in seizure pattern • Change in seizure frequency • Change in seizure type • Breakthrough seizures New treatment-related concerns • Change in medication • Side effects • Nonadherence Change in health status • Pregnancy • Injury • Mental, neurological, somatic comorbid conditions Employment or social change • Life stressor • Travel England MJ, et al. Epilepsy Across the Spectrum: Promoting Health and Understanding. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)2012.