205: Anti Epileptic Drugs: Out with the Old In with the New!

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1 39 th National Conference on Pediatric Health Care March 19-22, 2018 CHICAGO 205: Anti Epileptic Drugs: Out with the Old In with the New! Disclosures Cathy Haut has no conflicts of interest to report in relation to this presentation. Cathy Haut, DNP, CPNP AC/PC, CCRN, FAANP Interim Director of Nursing Research Nemours AI Dupont Hospital for Children Wilmington, DE ACPNP: Pediatrix/Mednax Baltimore, MD Learning Objectives At the end of this presentation, the participant will: Review the history of seizure treatment and discuss this evolution based on drug action and efficacy. Describe the mechanism of action of the newest anti epileptic medications and compare these drugs to those previously prescribed. Identify the most effective, evidence based anti epileptic drugs and list potential side effects of the older and the newest therapies. Case Study #1 A 4 month old infant arrives to the ED in status epilepticus. Treated with rectal valium by EMS. Ativan.05mg/kg given 3 times in the ED, followed by a Fosphenytoin load. Infant is shallow breathing with desaturations. Electively intubated and placed on a midazolam drip. Subclinical seizures are noted by EEG. Dilantin level post bolus is 11, another load of dilantin Keppra added to therapy. Case Study #2 An 18 month old is seen in the PC office for intermittent fever, today was up to 102. Picked up from daycare and brought directly to office where his initial temperature was rectally. Last tylenol dose was about 3.5 hours prior to office visit. Immediately after PNP exam, child began to stare, then had some tonic clonic movements briefly which continued to increase for generalized seizure over 3.5 minutes. Temp after seizure stopped was rectally. QUESTIONS?? What treatments are warranted and why? What diagnostic testing do you want to obtain that address the vital signs. Simple Febrile Seizure versus complex generalized seizures; what is the difference in patient risk? What are the best treatments for Status epilepticus? What side effects to expect in commonly used Anti epileptics? What monitoring is important in AED? 1

2 History of Seizures 1067 BC: Babylonians described seizures as evil forces, supernatural 400 BC: Hippocrates described seizure disorders as incurable brain disease. 1857: first seizure drug, Potassium Bromide 1873: seizures identified as the relationship of electrochemical discharge in brain 1920: German psychiatrist developed EEG to measure brain waves in epilepsy. SEIZURE Definition: occurrence of transient paroxysms of excessive or uncontrolled neuronal discharges caused by a variety of possible etiologies. SEIZURE Incidence/Etiology 1.2% of the US population has epilepsy 470,000 children with seizures in the US (2015) States with the highest incidence: CA, FL, NC, GA, PA, NY, IL (between 92, ,000) Teens between the ages of have highest death rate from seizures than other pediatric age groups. Incidence of status epilepticus is 10 25/100,000; higher in the first year of life. Pediatric status epilepticus is associated with short term mortality of 0 3%, long term mortality of 7%. Seizure Types in Children Febrile Seizures Chronic Seizures/Epilepsy Refractory seizures Status Epilepticus Absence Seizures *CDC: SEIZURE Causes Fever Medications Abnormalities in ion channels, electrolytes Genetic or abnormal cortical development Stroke Traumatic brain injury Toxic ingestion/exposure Acute illness; ie: meningitis Metabolic disturbance/disease Mitochondrial diseases SEIZURE Pathophysiology Gamma AminoButyric Acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. Seizures occur when this balance is disturbed; most often blocked GABA receptors result in rhythmic, hypersynchronous discharge of neurons. Acetylcholine, glutamate, aspartate are excitatory neurotransmitters. Focal seizures differ from generalized with cellular excitability increased, but with different mechanisms of excitability. 2

3 SEIZURE Pathophysiology Paroxysmal manifestations of the electrical properties of the cerebral cortex. Seizure occurs with a sudden imbalance between the excitatory and inhibitory forces within the neural cortical network. Anti Epileptics??? Postictal state following a seizure is a time when the seizure threshold is massively elevated. In SE, there is little time for homeostasis, and seizures occur in succession, with unknown rationale. GABA is inhibited and glutamate excitatory actions are enhanced. Anti Epileptic medications must either enhance GABA or decrease glutamate activities. GABA and glutamate receptors effect medication efficacy over the time of SE, benzodiazepines become less effective. Additional AED are needed at that time. Drugs that increase synaptic GABA are potent anticonvulsants. Alford, Wheless, Phelps, 2015: Journ of Ped Pharmacology and Therapeutics Review Seizures in Children Types of Seizures Generalized or tonic clonic seizure; absence seizures which involve both hemispheres of the brain. Can be myoclonic, clonic, tonic clonic, atonic Focal (partial) seizures: one area of the brain is involved, can remain awake or interrupt consciousness, symptoms based on location of involvement in brain. Continuous seizure types: Status Epilepticus, Refractory SE Febrile Seizures Simple Febrile Seizure: generalized seizure in an otherwise normal child, aged 6 mo to 5 yrs, associated with a spike in temperature, without CNS infection, lasting less than 15 min. Etiology: Viral illness responsible for 70% of Sz: rhinovirus, enterovirus, influenza, adenovirus Vaccine related (very few) Genetic predisposition Hypocalcemia, Hypoglycemia, other electrolyte disturbances AAP Clinical Practice Guidelines: management Despite a typically uncomplicated course and full recovery after a febrile seizure, some children go on to experience more frequent seizures, complex seizures, or epilepsy with neurobehavioral and developmental effects. Francis, Richmond, Robins, et al, 2016 Complex Febrile Seizures Complex Febrile Seizure: focal or localized to a specific body part, lasting from min, or recurrence of seizure in a 24 hr period. Majority of complex febrile seizures do not result in neurologic sequelae, but est % will have diagnosed neurologic/developmental problems later on. Prevention?? Multiple studies exist, but systematic review indicates that preventative anti epileptics are not warranted, nor is using acetaminophen or ibuprofen. Whelan, Harmelink, Chou, et al,

4 Evidence: Complex Febrile Seizures AAP Practice Guidelines for Neurodiagnostic evaluation of the child with a simple febrile illness. (AAP; Pediatrics. 2011;127(2)) No guidelines for neurodiagnostic evaluation of the child with complex febrile seizure. Rady Children s Hospital: 193 eligible records of children with complex febrile seizure, 6 mo 5 reviewed 70% of these patients had LP, remainder did not return to hospital 1 patient had diagnosis of acute bacterial meningitis Fletcher EM & Sharieff G, 2013; West Journal of Emer Med Evidence: Complex Febrile Seizure Systematic review of 1877 journal articles Medical College of Wisconsin and Western Michigan University Routine, preventative anti epileptics are not recommended, but intermittent use of phenobarbital and antipyretics, clobazam or rectal valium may be supported.* Recommends that all patients with complex febrile seizures, receive nonurgent MRI Case basis for LP based on presentation and other factors Head CT is not recommended; Routine EEG is recommended Whelan H, Harmelink M, Chou E, Sallowmn D, Kahn M, et al. 2017: Disease amonth Status Epilepticus A seizure that lasts longer than 30 minutes Most common life threatening childhood neurologic emergency Mortality is 3 5%, neurologic sequelae is up to 34% Benzodiazepines are first line therapy (Midazolam/Ativan) Refractory/Super refractory Status Epilepticus: Refractory: seizures that continue despite treatment with benzodiazepine and one AED Super Refractory: seizures that continue for 24 hours without response to benzodiazepines and one AED. Seizure Therapy Anti epileptic medications classified with affects of: sodium channels calcium current GABA activity Glutamate receptors Some have multiple mechanisms of action. Other mechanisms Treatment of Seizures Through the Years Medication: Genetics: 1857: potassium bromide 1903: relationship between seizures 1912: Phenobarbital and genetics Diet/Other therapy: Ketogenic diet Bleeding by cuffing Surgical: 1831: neurosurgery remove abscess 1886: hemispherectomy 1951: lobectomy 1980: hippocampectomy SEIZURE Medications through the years 1857: Potassium Bromide 1912: Phenobarbital 1928: Phenytoin 1953: Carbamazepine; Primidone 1958: Ethosuximide 1967: Valproate 1970 s: Clobazam, Clonazepam 1990: Lamotrigine; Oxcarbazepine 1993: Gabapentin; Felbamate 1995: Topiramate 2000: Zonisamide; *Levetiracetam 2008: Lacosamide 2009: Eslicarbazepine 2012: Perampanel *Between , the use of Class 3 anti epileptics increased ; Lamotrigine, Levetiracem, Topiramate, are a few. Magiorkinis, Diamante, Sidoropoulous, et al Research and Treatment. Liu, Carney, Bussing, Segal, et al Trends in Antiepileptic Drug Use in Children and adolescents with epilepsy. 4

5 Classes of Anti Epileptic Drugs Classes of AED Voltage Dependent Sodium Channels Carbamazepin e Eslicarbazepin e Lacosamide Lamotrigine Oxcarbazepine Phenytoin Zonisamide Affect Calcium Currents Ethosuximide Affect GABA Activity Benzodiazepines Clobazam Midazolam Lorazepam Phenobarbital Affect Glutamate Receptors Perampanel Multiple Mechanism of Action Felbamate Topiramate Valproate Other Mechanisms Gabapentin Levetiracetam First and Second Generation Anti epileptics Third Generation Anti Epileptics Phenobarbital Felbamate Primidone Gabapentin (Neurotin) 25.00/month Benzodiazepines (Valium, Lorazepam, Lamotrigine (Lamictal) Midazolam) Hydantoins (Dilantin, Phenytoin) Lacosamide (Zimpat) /month Succimides Levetiracetam (Keppra) 50.00/month Acetazolamide Oxcarbazepine (Tegretol) Valproic acid Topiramate (Topamax) Carbamazepine (Tegretol) Zonisamide (Zonegram) *Third generation drugs are more expensive, but have less side effects, more effective than first and second generation Anti Epileptic Drug Characteristics Treatment of Status Epilepticus Narrow Spectrum: used for specific seizure types (focal). Phenobarbital Carbamazepine (Tegretol) Oxcarbazepine (Trileptal) Gabapentin (Neurontin) Clobazam (Onfi) Gabapentin Broad Spectrum: used for multiple seizure types Valproic Acid Topiramate (Topamax) Levetiracetam (Keppra) Clonazepam Lamotrigine (Lamictal) Lorazepam (Ativan) Based on Guidelines Based on Evidence Clinical decision making Specific patient perspectives Evidence: Status Epilepticus American Epilepsy Society Practice Guidelines Evidence Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society Evidence; New medications Still benzodiazepine first AED if benzo is not effective 5

6 Highlights of American Epilepsy Assn Guidelines Evidence: Treatment for Status Epilepticus First Phase: (5 20 min) IM Midazolam IV Lorazepam 0.1 mg/kg IV Diazepam mg/kg Or IV Phenobarbital Rectal Diazepam Intranasal midazolam Secondary Phase: min Fosphenytoin 20mg/kg Valproic Acid 40mg/kg Levetiracetam 60mg/kg Phenobarbital if none of others available Third Phase: 40+ min Repeat Phase 2 Anesthetic Doses of: Thiopental, Midazolam Pentobarbital Propofol Descriptive information and literature review for treatment of refractory SE and super refractory SE. Medications: BZD: Midazolam or Ativan, AED: Phenytoin, Phenobarbital or Valproate, Lacosamide, Keppra. Some hesitancy to use hydantoin, based on side effects Super refractory: continuous infusion of Pentobarbital, Thiopental, Midazolam, Propofol Other modalities: ketogenic diet, Isoflurane, ECT, hypothermia, vagus nerve stimulation. Alford, Wheless & Phelps. 2017: Journal of Pediatric Pharmacology Therapeutics. Evidence: Refractory Status Epilepticus Perspective, descriptive study comparing children with status epilepticus, with and without epilepsy. Multiple centers: CHOP, CNMC, Boston Childrens, Phoenix Childrens, Duke and others. 189 participants, average age 4, about 50% with previous SE Compared time to first BZD, AED, continuous infusion, intubation, ICU care. Results: previous history of SE, abortive therapy was sooner; protocol improved steps to treatment 88:2017 Fernandez, Jackson, Abend, Arya, Benton, Carpenter. Neurology Prescribing History, medical exam, results of EEG and other neurodiagnostic testing determines need for treatment Seizure and EEG classifications will determine choice of anti epileptic. Start with monotherapy; Add another drug if one is not efficacious, or the adverse reactions are severe. Continue treatment until child is 2 years without seizures. Other considerations: Topamax, Zonegram can cause weight loss, valproic acid and gabapentin can contribute to weight gain. Can use genotyping to determine best medication for patient. Dang and Silverstein, 2017: Pediatric Clinics of North America, AED Therapeutic Drug Levels General Side Effects of AED Medication Therapeutic Level Carbamazepime Ethosuximide Phenytoin 4 mcg/ml to 12 mcg/ml 40 mcg/ml to 100 mcg/ml 10 mcg/ml to 20 mcg/ml Neurologic Drowsiness, dizziness, visual disturbances, lethargy, headache, ataxia, sedation, personality changes?? Valproic Acid Levetiracetam 50 mg/ml to 100 mcg/ 12 mg/ml to walking Gastrointestinal Nausea, vomiting, diarrhea, weight gain Lamotrigine Topiramate 3 15 mg/ml 5 20 mg/ml Skin/Cutaneous Rash, Pruritis, SJS, TEN, Serum sickness Free Phenytoin 1 2 mg/ml after 21 days Cardiovascular Prolonged QT sydnrome **Most important to check drug levels on children with epilepsy who present with seizures Immune Hypersensitivity reactions 6

7 Specific Drug Reactions Carbazepine Oxcarbazepine Hyponatremia, Aplastic anemia Eslicarbazepine Lamotrigine: Phenytoin Topiramate Valproate Ethosuximide Felbamate Stevens Johnson, Toxic Epidermylosis Hormone therapy and OCP s can decrease blood levels Altered bone and mineral metabolism *Lacosamide and Keppra have fewer side effect profiles Metabolic acidosis** UpToDate, 2018 OCP s decrease blood levels Aplastic anemia Liver failure Anti epileptic Med Responses/Issues Based on Age Neonates and Infants to age 2 Children to Adolescent Valproic Acid: hepatotoxicity, not recommended in this age group. Considerations based on availability of liquid medication Dilantin is poorly absorbed in infants and young children when given orally Age < 9 increases the clearance of Keppra Many medications are not approved for use in children less than age 2 Most neonatal seizures are resulting from injury, often HIE Age < 9 increases the clearance of Keppra Some medications can cause weight gain Many of the anti epileptics can cause drowsiness or sedation. Rectal Diastat can be embarrassing for this age group Phenytoin vs Fosphenytoin Phenytoin Effective 60% of the time for SE Potent inducer of hepatic enzymes, so reduces levels of other anti epileptic Adverse effects: Cardiac arrhythmias, hypotension Precipitates with dextrose Fosphenytoin Prodrug of phenytoin so can take longer for effects Can be given IM More rapid intravenous administration. Lower potential for cardiac or local tissue toxicity IM Midazolam vs IV Lorazepam 2012 RAMPART trial, a multi center, double blind randomized comparison of intramuscular (IM) midazolam to IV lorazepam in adults and children with status epilepticus Dosing was standardized to 10 mg (5 mg in children weighing kg) IM midazolam or 4 mg (2 mg in children weighing kg) IV lorazepam. SE convulsions persisting for longer than 5 minutes that were still occurring after paramedic arrival. Treatment success: absence of seizures without additional rescue therapy at time of arrival in the emergency department 893 subjects were randomized to either IM midazolam (n = 448) or IV lorazepam (n = 445). Primary efficacy endpoint was achieved in 73% of subjects in the IM midazolam group compared with 63% in the IV lorazepam group, resulting) Superiority of midazolam for both the per protocol and ITT analyses in patients without established IV access Levetiracetam (Keppra) Used as first and second line treatment for SE Easy to administer, can be given as a five minute infusion into a peripheral line; also comes in oral versions. Has limited side effects EcLIPSE study randomized controlled trial comparing the use of Keppra and Phenytoin as second line therapy for SE. Keppra levels vary between young children and teens, recommend sampling trough levels, especially in children < 9 and when used with other AED* *Naik, Kodagali, Mathew, et al. 2015) Dalzel, Furyk, Bonisch, Oakley, A multicentre randomised controlled trial in Levetiracetam vs Phenytoin for Status Epilepticus EcLipse Study: multi center, randomized controlled trial in 30 ED s in the UK, commenced in Participants are children between 6 months and 18 who present in status epilepticus, randomized to receive either Keppra or Dilantin. Blood levels for each medication obtained 1 2 hours after infusion. Keppra has very few and less severe side effects, as compared to Phenytoin and can be infused more rapidly than Dilantin. Results to be analyzed in spring Lyttle, et al The EcLipse study: Trial 7

8 Lacosamide (Zimpat) New generation anti epileptic which selectively enhances the slow inactivation component of the neuronal voltage gated sodium channels. Childrens Hospital of Minnesota published in the European Journal of Pediatric Neurology, a retrospective study of the safety and efficacy of oral and IV Zimpat. N = 47, with 18 children less than age 3 and 8 less than 1 year. Used as adjunct with >2 other AED with good results in refractory seizures. (Arkilo, Gustafson and Ritter at Systematic review: lacosamide efficacy of 57% in SE. Efficacy in nonconvulsive and generalized convulsive. (Strzelczyk, Zollner, Williams, Jost, et al. 2017) Intranasal Midazolam as Rescue Therapy Historically and currently rectal Valium is the standard for rescue treatment of seizures in children. Intranasal Midazolam has emerged as a safe, effective alternative. Utilized in schools, primary care practices, neurology practices Crawford, D. 2017: Journal of Neuroscience Nursing Intranasal Midazolam vs Rectal Valium Midazolam has a small molecular weight, easy permeation of nasal mucosa. Time to maximum concentration 12 minutes, half life of 2.2 hrs, dosing 0.2mg/kg. Studies indicate midazolam is at least as effective as rectal valium. Cost per dose is $12 Studies have indicated a shorter time to seizure cessation. Medications given rectally bypass hepatic first pass metabolism. Rectal diazepam has been used safely for 20 years. After several doses, rectal valium can accumulate and cause resp depression. Rectal bioavailability is highly variable, from 50% 100%. Cost per dose is $350 Cannabidiol Oil and Artisanal Marijuana Artisanal marijuana provided seizure reduction Marijuana without the psycho for 86% of patients. altering effects Problems with quality control and regulation. Early research in benefits, Inaccurate product labeling especially for: Availability, especially in states where illegal Lennox Gastault Dravet syndrome Children had better benefits with seizure Can have interactions with other medications: insulin, statins Humphries LK & Eiland LS, 2013: Journal of Pediatric Pharmacology and Therapeutics Talan, J. (2017) Cannabidiol research offers Hope for Seizure Disorders Newest AED Rufinamide (Banzel): adjunctive therapy, Lennox Gastault, ages 1+ Contraindicated with LQT, may cause drowsiness Perampanel (Fycompa): glutamate antagonist, for partial onset seizures Dizziness, fatigue, drowsiness, nausea Vigabatrin (Sabril): epileptic spasm monotherapy for age 1 24, adjunctive therapy for ages >10 with refractory focal Sz Vision loss Newest AED Clobazam (Onfi): adjunctive therapy for ages >/=2 for LGS Somnolence and sedation as side effects Brivaracetam (Briviact): adjunctive or monotherapy for >/=16 for focal epilepsy Drowsiness, dizziness, nausea, vomiting Dang & Silverstein (2017) Dang & Silverstein,

9 Future Anti Epileptic medications have been developed significantly over the past 20 years. 30% of the population of people with seizures are still not stabilized on therapies. One objective is to develop analogs of current drugs with less side effects and better efficacy. Focal epilepsy, refractory seizures require more consideration. Future Carbamazepime analogs Eslicarbazepine, electroshock and limbic seizures in rats, not yet approved for trial Levetiracetam Analogs Brivaracetam and Selectracetam: have similar properties as LEV, broad spectrum, minimum metabolism, excellent pharma profile Carbamates Derivatives Carisbamate: Broad spectrum anticonvulsant; generalized and local seizure activity Valproate Analogs Not yet developed as the mechanism of action is not really known *Striano P, Belcastro v, Coppola, Minetti and Striano (2016) Future Neuroactive steroids Randomized, double blind, placebo controlled study, evaluate ganaxolone, indicated a significant decrease in seizures Glutamate AMPA Antagonists Perampanel is select noncompetitive AMPA receptor agonist Potassium Channels Blockers Block voltage gated K+ resulting in powerful anticonvulsant Retigabine began clinical trials, but stopped due to side effects, urinary retention References Collins Yoder, Lowell Valproic acid: Special considerations and targeted monitoring. Journal Neuroscience Nursing. 2017:49(1); Dalziel SR, Furyk J, Bonisch M, Oakley E, Borland M, Neutz J, Donath S, et al. A multicentre randomised controlled trial of Levetiracetam versus phenytoin for convulsive status epilepticus in children. BMC Pediatrics. 2017:17(1):152. Dang LT & Silverstein FS. Drug treatment of seizures and epilepsy in children and neonates. Pediatric Clinics of North America. 2017:64; Francis JR, Richmond P, Robins C, Lindsay K, Levy A, Effler PV, et al. An observational study of febrile seizures: the importance of viral infection and immunization. BMC Pediatrics. 2016:16(202) Whelan H, Harmelink M, Chou E, Sallowm D, Khan N, Patil R, et al. Complex febrile seizures: A systematic review. Disease a Month. 2017:63;5 23 Striano P, Belcastro v, Coppola, Minetti and Striano (2016) Magiorkinis, Diamante, Sidoropoulous, et al. (2014) Highlights in the history of epilepsy. Research and Treatment. Volume 2014 (2014), Article ID , Striano P, Belcastro V, Coppola A, Minetti C & Striano S. Antiepileptic drugs under investigation for treatment of focal epilepsy. Clinical Neuropharmacology. 2016;39(6): Naik GS, Kodagali R, Mathew BS, Thomas M, Prabha R, Mathew V, Fleming DH. Therapeutic drug monitoring of Levetiracetam and Lamotrigine: Is there a need? The Drug Monitor. 2015;37(4): Fletcher EM & Sharieff G. Necessity of lumbar puncture in patients presenting with new onset complex febrile seizure. 2013;14(3): Whelan H, Harmelink M, Chou E, Sallowmn D, Kahn M, Patil R, Sannagawl K, et al. Complex febrile seizures: A systematic review. Disease a month: 2017;63: Strzelczyk A, Zollner JP, Williams LM, Jost J, Paule E, Schubert Bast, Rosenow F, et al. Lacosamide in status epilepticus: systematic review of current evidence. Epilepsia. 2017:58(6): Liu, Carney, Bussing, Segal, et al. Trends in Antiepileptic. Trends in Antiepileptic Drug Use in Children and adolescents with epilepsy. Pediatric Neurology Alford, Wheless & Phelps. Treatment of generalized convulsive status epilepticus in pediatric patients. Journal of Pediatric Pharmacology Therapeutics. 2015:20(4): Johannessen SI & Johannessen C. Antiepileptic drug interactions Principles and clinical implications. Clinical Neuropharmacology. 2010;8(10): Humphries Lk & Eiland LS. Treatment of acute seizures: Is intranasal midazolam a viable option? Journal of Pediatric Pharmacology and Therapeutics. 2013:18(2):79 87 Crawford D. Implementation of intranasal midazolam for prolonged seizures in a child neurology practice. Journal of Neuroscience Nursing. 2016:48(6); Arkilo D, Gustafson M, & Ritter FJ. Clinical experience of intravenous lacosamide in infants and young children. European Journal of Pediatric Neurology. 2016:20; Lyttle MD, Gamble C, Messahil S, Hickey H, Iyer A, Woolfall K, Humphreys A, et al. Emergency treatment with levetiracetem or phenytoin in status epilepticus in children The EcLipse study: study protocol for a randomised controlled trial. 2017:18;283. 9