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
Division of Child Neurology
Children’s Pavilion
1001 East Marshall Street, First Floor
Richmond, Virginia 23298-0211
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.
Company
NIH/NINDS
Advisory Board
Consultant
Research
YES
YES
CDC/HRSA
YES
Acorda
Catalyst
Eisai
YES
YES
YES
YES
YES
YES
GlaxoSmithKline
YES
King Pharmaceuticals
YES
Marinus Pharmaceuticals
Medscape
YES
YES
YES
Neuropace
YES
YES
YES
Lundbeck
YES
YES
YES
Pfizer
YES
YES
YES
Questcor
YES
YES
YES
Sepracor
YES
YES
Sunovion
YES
UCB Pharmaceuticals
YES
YES
YES
Upshur Smith
YES
YES
YES
Valeant
YES
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
160
140
Incidence
per 100,000
120
100
80
60
40
20
0
1
5
10
15
40
60
80
>80
Age
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
Mortality After Initial
Pediatric Status Epilepticus
40
30
%
30 Days 1
180 Days
20
10
0
<1
1 to 19
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
Midazolam 0.2
mg/Kg, then 1-10
µm/Kg/min
6. Anesthesia:
Phenobarbital
Midazolam
Propofol
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
Interventions
IV Access
Available
Seizure
continues
Glauser, et. al.,
in press, 2014
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
PHTSE
60
Number of patients
Lorazepam
Diazepam
Placebo
40
20
0
Convusions stopped
Ongoing
RAMPART
1) PECARN study: Use of lorazepam for the
treatment of pediatric status epilepticus: a
randomized, double-blinded trial of
lorazepam and diazepam
Number of patients
400
Lorazepam
300
200
100
0
Midazolam
RAMPART
Selbergleit, et al. NEJM, 366;7, Feb 2012
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.
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. 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.
Source
Neurosciences Unit, Institute of Child Health, University College London, WC1N 1EH, UK. r.chin@ich.ucl.ac.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. 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,
etc.)
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 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.