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Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? John M. Pellock, MD Professor and Chairman Division.

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Presentation on theme: "Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? John M. Pellock, MD Professor and Chairman Division."— Presentation transcript:

1 Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? John M. Pellock, MD Professor and Chairman Division of Child Neurology Interim Senior Associate Dean for Professional Education and CEO of UHS-PEP Children’s Hospital of Richmond Virginia Commonwealth University/Medical College of Virginia Richmond, VA USA

2 Division of Child Neurology Children’s Pavilion 1001 East Marshall Street, First Floor Richmond, Virginia 23298-0211

3 CompanyAdvisory BoardConsultantResearch NIH/NINDS YES CDC/HRSA YES Acorda YES Catalyst YES Eisai YES GlaxoSmithKline YES King Pharmaceuticals YES Marinus Pharmaceuticals YES Medscape YES Neuropace YES Lundbeck YES Pfizer YES Questcor YES Sepracor YES Sunovion YES UCB Pharmaceuticals YES Upshur Smith YES Valeant YES John M. Pellock, MD Professor and Chairman, Division of Child Neurology Virginia Commonwealth University/ Medical College of Virginia Children’s Hospital of Richmond Richmond, Virginia Dr. Pellock has received grants/research support in excess of $10,000 and is a paid consultant as listed below. All grants, research support, consultant fees and honoraria are paid to Virginia Commonwealth University or the physician practice plan (MCV Physicians). Dr. Pellock has NO equity, stock or any other ownership interest in any of these companies. 10/2013

4 Status Epilepticus: Epidemiology A prolonged seizure or recurrent seizures without recovery of consciousness Annual Incidence of status epilepticus is 41-61 / 100,000 Annual mortality of Status Epilepticus is 19 / 100,000 From Delorenzo et al. Neurology 1996 46: 1029-1035 Other studies report lower incidence, see: A systematic review of Epidemiology of SE, European Journal of Neurology 2004, 11: 800-810.

5 Mortality After Initial Pediatric Status Epilepticus Age (Years) % % 1 1 1 Logroscino G et al, Epilepsia, 1997; 38: 1344-1349. Barry E, Hauser WA, Neurol., 1993; 43: 1473-1478. 1 Logroscino G et al, Epilepsia, 1997; 38: 1344-1349. Barry E, Hauser WA, Neurol., 1993; 43: 1473-1478.

6 Treatment of Status Epilepticus 1. Lorazepam 0.1 mg/Kg at 2 < mg/min; if seizures stop, no other therapy may be required if cause is corrected. 2. Fosphenytoin 20 mg PE/Kg at 3 mg PE/Kg/min (150 mg PE/min max) 3. Fosphenytoin 5-10 mg PE/Kg Lowenstein DH, Alldredge BK. N Engl J Med, 1998: 970-976. Cochrane Database Syst Rev. 2008;16 (3): CD001905

7 Treatment of Status Epilepticus (cont’d) 4. Phenobarbital 20 mg/Kg at 50-75 mg/min 5. Phenobarbital 10 mg/Kg 6. Anesthesia: Phenobarbital Midazolam Propofol Midazolam 0.2 mg/Kg, then 1-10 µm/Kg/min Lowenstein DH, Allredge BK. N Engl J Med, 1998: 970-976.

8 SE: Treatment Overview Rossetti & Lowenstein Lancet Neurol 2011


10 Treatment of Convulsive Status Epilepticus in Adults and Children: A Systematic Review and Treatment Algorithm Tracy Glauser, MD, Shlomo Shinnar, MD, PhD, Lisa Garrity, PharmD, Jacquelyn Bainbridge, PharmD, Mary Bare, MD, Thomas Bleck, MD, W. Edwin Dodson, MD, Andy Jagoda, MD, Daniel Lowenstein, MD, John Pellock, MD, James Riviello, MD, Edward Sloan, MD, David Treiman, MD

11 Proposed treatment algorithm for status epilepticus Glauser, et. al., in press, 2014 Interventions IV Access Available Seizure continues

12 Need for ESETT There is no well-controlled prospective clinical trial to guide the treatment of SE in patients who fail benzodiazepines. Episodes of SE in US in 2010: 41- 61/100,000 X 309 million = 120,000-188459. 25-45 % of patients with convulsive SE do not respond to benzodiazepines i.e.42-72,000 refractory patients. Increasing seizure durations associated with higher mortality, and increasing neuronal damage, and refractoriness to drugs. These patients often require intensive care, which is expensive. Bleck et al, 2013

13 Methods Randomized, double blind comparison of fosphenytoin (FOS) levetiracetam (LVT), and valproic acid (VPA). Primary Outcome: Clinical determination of cessation of seizures, as defined by the termination of clinical seizures within 20 minutes of beginning of drug infusion and improving mental status, and without further intervention, sustained hypotension or cardiac arrhythmias, maintained until 1 hour after starting treatment. Secondary Outcomes: 1) efficacy in children; 2) duration of SE; 3) intubation within 24 hours; 4) admission to ICU within 24 hours; 4) mortality.

14 Bleck et al, 2013

15 Newly emerging therapies for neonatal seizures. Pressler RMPressler RM, Mangum B.Mangum B Source Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK. Abstract The treatment of neonatal seizures has not changed significantly over the last 50 years despite advances in antiepileptic drug (AED) development for older children and adults. Recently new drugs have emerged some of which address age-specific challenges or mechanisms and will be discussed in this review. The loop diuretic bumetanide blocks the neuronal NKCC1 co-transporter and is thought specifically to supress seizures in the immature brain. Levetiracetam has been used in children and infants with good efficacy, an excellent safety profile, and near-ideal pharmacokinetic characteristics. Randomised controlled trials are now underway to test the efficacy of some newer AEDs for neonatal seizures. Topiramate has been shown to have neuroprotective properties in addition to its antiepileptic action and trials in babies with hypoxic-ischaemic encephalopathy are now planned. There is an urgent need to develop age-specific AEDs for preterm and term babies. These drugs must be evaluated with multicentre, collaborative trials using innovative methods and high ethical standards to overcome age-specific challenges with the ultimate aim of improving the outcome for neonates with seizures. Semin Fetal Neonatal Med.Semin Fetal Neonatal Med. 2013 Aug;18(4):216-23. doi: 10.1016/j.siny.2013.04.005. Epub 2013 May 18.

16 Clinical management of seizures in newborns : diagnosis and treatment van Rooij LGvan Rooij LG, van den Broek MP, Rademaker CM, de Vries LS.van den Broek MPRademaker CMde Vries LS Source Department of Neonatology, KE 04.123.1, Wilhelmina Children's Hospital, University Medical Centre Utrecht, PO Box 85090, 3508 AB, Utrecht, The Netherlands. Abstract Neonatal seizures can be classified as tonic, clonic, myoclonic, and subtle. A clinical diagnosis is not easy as seizures are usually subtle in neonates. In the majority of newborn infants seizures are subclinical. On the other hand, not all abnormal movements identified by clinicians as clinical seizures are accompanied by electroencephalographic seizure discharges in the EEG. Precise incidence is difficult to delineate and depends on study population and criteria used for diagnosis of seizures. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, or if the damage is primarily due to the underlying cause of the seizures. As a result of this controversy there is ongoing discussion whether all seizures (both clinical and subclinical) should be treated. In addition, when (sub)clinical seizures are treated, there is no consensus about the most appropriate treatment for neonatal seizures and how to assess the efficacy of treatment. Current therapeutic options to treat neonatal seizures (i.e. primarily first-generation antiepileptic drugs [AEDs]) are relatively ineffective. In practice, phenobarbital still remains the drug of first choice for EEG confirmed or suspected seizures. Benzodiazepines are also used in (phenobarbital) refractory cases. Several (small) studies indicate that lidocaine is an effective drug for refractory seizures as second- or third-line treatment. Although data are scarce, some AEDs with a wide acceptance in adult and pediatric neurology practice are being used to treat neonatal seizures (i.e. second-generation AEDs). These drugs are chemically different from all first-generation AEDs and they have an effect on other pathways so they provide new pharmacological targets for controlling seizures in newborns. Levetiracetam, topiramate, felbamate, bumetanide, lamotrigine and vigabatrin are examples of these second-generation AEDs. There is an urgent need for prospective, randomized, controlled trials to assess the efficacy and safety of these second- generation AEDs in neonates. The aim of this review is to provide an overview of the current knowledge of diagnosis, the effect on brain injury, and the treatment of neonatal seizures. Paediatr Drugs.Paediatr Drugs. 2013 Feb;15(1):9-18. doi: 10.1007/s40272-012-0005-1.

17 Initial treatment of generalized convulsive SE: Benzodiazepines 1) PECARN study: Use of lorazepam for the treatment of pediatric status epilepticus: a randomized, double-blinded trial of lorazepam and diazepam PHTSE Number of patients Convusions stoppedOngoing 0 20 40 60 Lorazepam Diazepam Placebo RAMPART Number of patients Seizure stopped Ongoing 0 100 200 300 400 Lorazepam Midazolam

18 Selbergleit, et al. NEJM, 366;7, Feb 2012 RAMPART

19 Intramuscular Midazolam Is The Best Option For The Prehospital Treatment Of Status Epilepticus R. Sibergleit et al. Epilepsia. 54 (Suppl. 6):74-77, 2013

20 Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools? Cross JHCross JH, Wait S, Arzimanoglou A, Beghi E, Bennett C, Lagae L, Mifsud J, Schmidt D, Harvey G.Wait SArzimanoglou ABeghi EBennett CLagae LMifsud JSchmidt DHarvey G Source UCL Institute of Child Health, Great Ormond Street Hospital NHS Foundation Trust,, London, UK. Abstract OBJECTIVE: This paper explores the issues that arise from the discussion of administering rescue medication to children who experience prolonged convulsive seizures in mainstream schools in the UK. SITUATION ANALYSIS: Current guidelines recommend immediate treatment of children with such seizures (defined as seizures lasting more than 5 min) to prevent progression to status epilepticus and neurological morbidity. As children are unconscious during prolonged convulsive seizures, whether or not they receive their treatment in time depends on the presence of a teacher or other member of staff trained and able to administer rescue medication. However, it is thought that the situation varies between schools and depends mainly on the goodwill and resources available locally. RECOMMENDATIONS: A more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. Possible ways forward include: greater use of training resources for schools available from epilepsy voluntary sector organisations; consistent, practical information to schools; transparent guidance outlining a clear care pathway from the hospital to the school; and implementation and adherence to each child's individual healthcare plan. IMPLICATIONS: Children requiring emergency treatment for prolonged convulsive seizures during school hours test the goals of integrated, person-centred care as well as joined-up working to which the National Health Service (NHS) aspires. As changes to the NHS come into play and local services become reconfigured, every effort should be made to take account of the particular needs of this vulnerable group of children within broader efforts to improve the quality of paediatric epilepsy services overall. Arch Dis Child.Arch Dis Child. 2013 Oct;98(10):777-80. doi: 10.1136/archdischild-2013-304089. Epub 2013 Jul 30.

21 Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. Chin RFChin RF, Verhulst L, Neville BG, Peters MJ, Scott RC.Verhulst LNeville BGPeters MJScott RC Source Neurosciences Unit, Institute of Child Health, University College London, WC1N 1EH, UK. Abstract OBJECTIVES: To characterise the clinical features, emergency pre-paediatric intensive care (PIC) treatment, and course of status epilepticus (SE) in children admitted to PIC. This may provide insight into reasons for admission to PIC and provide a framework for the development of strategies that decrease the requirement for intensive care. DESIGN: Cross sectional, retrospective study.SETTING: A tertiary paediatric institution's intensive care unit. PARTICIPANTS: The admission database and all discharge summaries of each admission to a tertiary paediatric institution's PIC over a three year period were searched for children aged between 29 days and 15 years with a diagnosis of SE or related diagnoses. The case notes of potential cases of SE were systematically reviewed, and clinical and demographic data extracted using a standard data collection form. RESULTS: Most children with SE admitted to PIC are aged less than 5 years, male to female ratio 1:1, and most (77%) will have had no previous episodes of SE. Prolonged febrile convulsions, SE related to central nervous system infection, and SE associated with epilepsy occur in similar proportions. Contrary to the Advanced Paediatric Life Support guidelines many children admitted to PIC for SE receive over two doses, or inadequate doses, of benzodiazepine. There is a risk of respiratory depression following administration of over two doses of benzodiazepine (chi2 = 3.4, p = 0.066). Children with SE admitted to PIC who had prehospital emergency treatment are more likely to receive over two doses of benzodiazepines (chi2 = 11.5, p = 0.001), and to subsequently develop respiratory insufficiency (chi2 = 6.2, p = 0.01). Mortality is low. Further study is required to determine the morbidity associated with SE in childhood requiring intensive care. CONCLUSIONS: As the risk of respiratory depression is greater with more than two doses of benzodiazepines, clinicians should not disregard prehospital treatment of SE. As pre-PIC treatment of SE is inadequate in many cases, appropriate audit and modifications of standard guidelines are required. J Neurol Neurosurg Psychiatry.J Neurol Neurosurg Psychiatry. 2004 Nov;75(11):1584-8.

22 FEBSTAT Treatment Recognition –EMS on arrival did not recognize 12% of seizure (18 children) –EMS during transport did not recognize 20 % of seizure (31 children) Only 40% (73 children) were given AED by EMS Median seizure duration 68 minutes for subjects given medication prior to ED and median seizure duration 72 minutes for subjects given treatment ONLY by ED Median time from the seizure onset to the first dose of medication by EMS or ED was 30 minutes 2.72 minute delay in administration of 1st AED is associated with a 1.32 minute increase in seizure duration Seinfeld et al. in press

23 FEBSTAT Treatment (continued) 83 children given lorazepam as 1 st AED –Optimal dose: > 0.05 mg/kg IV/IO/IM –24 suboptimal doses 83 children given diazepam as 1 st AED –Optimal dose: > 0.3 mg/kg pr OR > 0.1 mg/kg IV/IO/IM –32 suboptimal dose Children given respiratory support had more AEDs (p = <0.0001) Median seizure duration for respiratory support group 83 minutes; non-respiratory support group 58 minutes (p= 0.0003) Seinfeld et al. in press

24 Benzodiazapine for Acute Seizures Which Preparation Route of administration Time to seizure cessation or to next event

25 Studies of Prolonged/Recurrent Seizures Carefully define inclusion –Age –Etiology –Time to treatment –Dosing –Ethical considerations (Equipoise?) Exclusion –Medication failure (adequate Rx?) –Single or multiple events/recurrence

26 Spectrum of Seizures Recurrent, Unprovoked Seizures Acute Repetitive Seizures (ARS)* Prolonged Seizures Status Epilepticus (SE) Isolated Seizures * Also known as cluster, crescendo, multiple- recurrent, serial, or sequential seizures

27 Studies of Prolonged/Recurrent Seizures Outcome measures –Clinical cessation –EEG (how) –Stop event versus seizure freedom for X hours –Tolerability –Ease of use –Statistical reliability (controlled, non-inferiority, etc.)

28 Treatment of Acute Seizures: Practical Considerations: Medication availability Licensure (adults/pediatrics/age) Pharmacometric characteristics Ease of administration Social acceptance Cost Public acceptance


30 Status Epilepticus : Think Time Time to treatment needs to be shorter. Response to treatment is time dependent. Morbidity and mortality are related to etiology and duration (time) of status epilepticus. Subsequent epilepsy may depend on the duration (length of time) of the status epilepticus. Prolonged seizures predict future prolonged seizures.

31 Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? Do we need further studies? YES!!!! Neonates 1 st line, 2 nd line, refractory SE? Public health practices –Education, recognition –Following emergency protocols

32 Acute, Prolonged Seizures: Identification and Treatment Strategies Is there a need for further trials? Challenges – Controlled but probably not DBPC Large consortia; well defined study criteria and endpoints; observational Stratify by age, time to treatment, etiology

33 Status Epilepticus This is a medical emergency. Have a treatment plan. You can do it. Stay calm. Persons with epilepsy should have an individualized emergency plan in place.


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