John M. Pellock, MD Professor and Chairman Division of Child Neurology

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Acute, Prolonged Seizures: Identification and Treatment StrategiesIs there a need for further trials?

John M. Pellock, MDProfessor and Chairman

Division of Child NeurologyInterim Senior Associate Dean for Professional Education and CEO of UHS-PEP

Children’s Hospital of RichmondVirginia Commonwealth University/Medical College of Virginia

Richmond, VA USA

Division of Child NeurologyChildren’s Pavilion

1001 East Marshall Street, First FloorRichmond, Virginia 23298-0211

Company Advisory Board Consultant ResearchNIH/NINDS

YES YESCDC/HRSA

YESAcorda

YES YESCatalyst

YES YES Eisai YES YES YESGlaxoSmithKline YES King Pharmaceuticals

YES Marinus Pharmaceuticals YES YESMedscape

YES YESNeuropace YES Lundbeck YES YES YESPfizer YES YES YESQuestcor YES YES YESSepracor YES YES Sunovion YES UCB Pharmaceuticals YES YES YESUpshur Smith YES YES YESValeant YES

John M. Pellock, MDProfessor and Chairman, Division of Child Neurology

Virginia Commonwealth University/ Medical College of VirginiaChildren’s Hospital of Richmond

Richmond, VirginiaDr. 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

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.

020406080

100120140160

1 5 10 15 40 60 80 >80Age

Mortality After Initial Pediatric Status Epilepticus

< 1 1 to 19

30 Days180 Days

Age (Years)

1 Logroscino G et al, Epilepsia, 1997; 38: 1344-1349. Barry E, Hauser WA, Neurol., 1993; 43: 1473-1478.

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

Treatment of Status Epilepticus (cont’d)

4. Phenobarbital 20 mg/Kg at 50-75 mg/min

5. Phenobarbital 10 mg/Kg

6. Anesthesia: PhenobarbitalMidazolamPropofol

Midazolam 0.2 mg/Kg, then 1-10 µm/Kg/min

Lowenstein DH, Allredge BK. N Engl J Med, 1998: 970-976.

SE: Treatment Overview

Rossetti & Lowenstein Lancet Neurol 2011

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

Proposed treatment algorithm for status epilepticus Glauser, et. al., in press, 2014

Interventions

IV Access

Available

Seizure

continues

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.

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

Convusions stopped Ongoing0

60LorazepamDiazepamPlacebo

RAMPART

Seizure

stopped

Ongoing

400Lorazepam

Midazolam

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

RAMPART

Intramuscular Midazolam Is The Best Option For The Prehospital Treatment Of Status Epilepticus

R. Sibergleit et al. Epilepsia. 54 (Suppl. 6):74-77, 2013

Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools?Cross JH, Wait S, Arzimanoglou A, Beghi E, Bennett C, Lagae L, Mifsud J, Schmidt D, Harvey G.SourceUCL Institute of Child Health, Great Ormond Street Hospital NHS Foundation Trust, , London, UK.AbstractOBJECTIVE: 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. 2013 Oct;98(10):777-80. doi: 10.1136/archdischild-2013-304089. Epub 2013 Jul 30.

Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.Chin RF, Verhulst L, Neville BG, Peters MJ, Scott RC.SourceNeurosciences Unit, Institute of Child Health, University College London, WC1N 1EH, UK. r.chin@ich.ucl.ac.ukAbstractOBJECTIVES: 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. 2004 Nov;75(11):1584-8.

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

FEBSTAT Treatment (continued)

• 83 children given lorazepam as 1st AED– Optimal dose: > 0.05 mg/kg IV/IO/IM– 24 suboptimal doses

• 83 children given diazepam as 1st 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

Benzodiazapine for Acute Seizures

• Which• Preparation• Route of administration• Time to seizure cessation or to

next event

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

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,

Treatment of Acute Seizures:Practical Considerations:

• Medication availability• Licensure (adults/pediatrics/age)• Pharmacometric characteristics• Ease of administration• Social acceptance• Cost• Public acceptance

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.

Acute, Prolonged Seizures: Identification and Treatment Strategies

Is there a need for further trials?

Do we need further studies?

YES!!!!• Neonates• 1st line, 2nd line, refractory SE?• Public health practices

– Education, recognition– Following emergency protocols

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

Status EpilepticusThis 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.

John M. Pellock, MD Professor and Chairman Division of Child Neurology

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